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Obesity & adipokines
 

Obesity & adipokines

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Adipose tissue as an endocrine organ: ...

Adipose tissue as an endocrine organ:
Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.

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  • Obesity and adipokines have been downloaded by Amirnader Emami Razavi, PhD student of Clinical Biochemistry at Isfahan University of Medical Sciences in Iran.
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  • Adipose tissue or fat is loose connective tissue composed of adipocytes . Adipose tissue is derived from lipoblasts . Its main role is to store energy in the form of fat, although it also cushions and insulates the body. Obesity or being overweight in humans and most animals does not depend on body weight but on the amount of body fat—specifically, adipose tissue. Physiology Free fatty acid is "liberated" from lipoproteins by lipoprotein lipase (LPL) and enters the adipocyte, where it is reassembled into triglycerides by esterifying it onto glycerol. Human fat tissue contains about 87% lipids. In humans, lipolysis is controlled though the balanced control of lipolytic B-adrenergic receptors and a2A-andronergic receptor mediated antilipolysis. Fat is not laid down when there is a surplus available and stored passively until it is needed; rather it is constantly being stored in and released from each cell. Fat cells have an important physiological role in maintaining triglyceride and free fatty acid levels, as well as determining insulin resistance. Abdominal fat has a different metabolic profile—being more prone to induce insulin resistance. This explains to a large degree why central obesity is a marker of impaired glucose tolerance and is an independent risk factor for cardiovascular disease (even in the absence of diabetes mellitus and hypertension).[ citation needed ] Recent advances in biotechnology have allowed for the harvesting of adult stem cells from adipose tissue, allowing stimulation of tissue regrowth using a patient's own cells. The use of a patient's own cells reduces the chance of tissue rejection and avoids the ethical issues associated with the use of human embryonic stem cells. Adipose tissue is the greatest peripheral source of aromatase in both males and females contributing to the production of estradiol.
  • Brown adipose tissue: A specialised form of adipose tissue in human infants, and some hibernating animals, is brown fat or brown adipose tissue. It is located mainly around the neck and large blood vessels of the thorax. This specialised tissue can generate heat by "uncoupling" the respiratory chain of oxidative phosphorylation within mitochondria, leading to the breakdown of fatty acids. This thermogenic process may be vital in neonates exposed to the cold, who then require this thermogenesis to keep warm as they are unable to shiver, or take other actions to keep themselves warm.[5] Attempts to stimulate this process pharmacologically have so far been unsuccessful, but might in the future be a target of weight loss therapy.
  • In humans, adipose tissue is located beneath the skin (subcutaneous fat), and is also found around internal organs (visceral fat). Adipose tissue is found in specific locations which are referred to as 'adipose depots.' Adipose tissue contains several cell types, with the highest percentage of cells being adipocytes, which contain fat droplets. Other cell types include fibroblasts, macrophages and endothelial cells. Adipose tissue contains many small blood vessels. In the integumentary system, which includes the skin, it accumulates in the deepest level, the subcutaneous layer, providing insulation from heat and cold. Around organs, it provides protective padding. However, its main function is to be a reserve of lipids, which can be burned to meet the energy needs of the body. Adipose depots in different parts of the body have different biochemical profiles. Integumentary system :The Integumentary System is an organ system that protects the body from damage, comprising the skin and its appendages[1](including hair, scales, and nails). This is usually anything that grows out of the skin like hair or nails (also includes skin). The integumentary system has a variety of functions; in animals, it may serve to waterproof, cushion and protect the deeper tissues, excrete wastes, regulate temperature and is the location of receptors for pain, sensation, pressure and temperature. In humans, the functions of the integumentary system are all the same, plus vitamin D synthesis. The integumentary system is the largest organ system. It distinguishes, separates, protects and informs the animal with regard to its surroundings. Small-bodied invertebrates of aquatic or continually moist habitats respire using the outer layer (integument). This gas exchange system, where gases simply diffuse into and out of the interstitial fluid, is called integumentary exchange .
  • Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.
  • واقعي‌، بتحقيق‌، بحقيقت‌، قابل‌ اثبات‌ حقيقت‌ = Veritable
  • Sedentary بدون جنبش =
  • Communication between adipose and other tissues has been hypothesized since at least the 1940s to be bidirectional. Despite this expectation, early progress was largely limited to adipose tissue’s role in metabolism and storage of fatty acids, its development, and its response to endocrine and neural cues. However, efforts of the last decade have identified several molecules that are secreted from adipocytes, apparently for the purpose of signaling to other tissues. Cloning of the mouse obesity gene in 1994 is perhaps the most famous impetus for recognition that adipocytes are active in the regulation of multiple body functions. The product of this gene, leptin, has since been found to inhibit feeding, enhance energy expenditure, and stimulate gonadotropes. Leptin is a strong appetite suppressant that, when deleted, causes an obese phenotype in mice. The discovery of leptin, and its effects on appetite, led to hopes of a treatment for type 2 diabetes and obesity, a major disease in the developed world. It has since been discovered that the brain can become resistant to leptin, even at supra-physiological levels, making treatment with leptin impossible. Nonetheless, intense interest in the existence of adipose derived hormones has since led to the discovery of numerous important protein hormones, and the full appreciation of adipose tissue as an important endocrine organ.
  • Leptin has a conserved homology among species and has a structural similarity to other proinflammatory cytokines such as IL-6 and IL-12 [129]. Leptin contains an intra-chain disulfide bond that appears to be necessary for its biological activity [130]. Leptin is mostly produced in adipose tissue although it has been detected in the gastric wall, vascular cells, placenta, ovary, skeletal muscle and liver [131]. Leptin expression is influenced by energy stores in fat [131]. Leptin levels increase within hours after a meal in rodents and after several days of overfeeding in humans [132]. Insulin stimulates leptin expression and secretion in primary adipocytes [133]. Other factors, such as dexamethasone [134], thyrotrophin (TSH) [135], TNF-[136] and IL-6 [137] also regulate leptin release. Divergent= متباعد ، متفاوت
  • Consistent= مطابق
  • The Signal Transducers and Activator of Transcription (STAT, also, called signal transduction and transcription) protein s regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
  • Congenital= مادرزادی ،ارثی
  • Coronary Artery Disease =CAD
  • Although resistin was first identified as an “insulin resistant hormone”, more and more evidence indicates it also plays a role in the immune system. Proinflammatory cytokines such as TNF-IL-6 and LPS regulated resistin gene transcription in both 3T3L1 adipocytes and human peripheral blood mononuclear cells (PBMC) [159]. Resistin also regulated the expression of proinflammatory cytokines [154]. For example, resistin increased the expression of IL-6 and TNF-by inducing translocation of NF-B [160]. Higher levels of resistin positively correlated with many inflammatory factors in persons with severe inflammation. Moreover, resistin was found to play a role in inflammation-related disease such as atherosclerosis, arthritis and Type 1 diabetes [154].
  • Resistin expression was also shown to be regulated by glitazones, a class of insulin-sensitizing drugs approved for the treatment of type 2 diabetes (5). Rosiglitazone and other glitazones lower glucose and lipid levels in patients with type 2 diabetes by activating the nuclear receptor peroxisome proliferator- activated receptor g (PPARg)1 (7). Rosiglitazone treatment was shown to reduce resistin expression in 3T3-L1 adipocytes in vitro and in the white adipose tissue (WAT) of mice fed a high fat diet (5). These data raised the interesting possibility that decreases in resistin levels might be integral to the antidiabetic actions of PPARg agonists. In this report, we have examined resistin expression in several different rodent models of obesity and its regulation in response to different classes of PPARg agonists. Surprisingly, we find that resistin expression is decreased in obese mice and increased in ob/ob mice and Zucker diabetic fatty (ZDF) rats in response to PPARg agonists.
  • Simplified model of insulin signaling. Insulin binding to the extracellular domain of the insulin receptor elicits a conformational change, which in turn leads to receptor autophosphorylation (P) and tyrosine phosphorylation of intracellular protein substrates. Two main branching pathways are activated by insulin: (a) One is the MAPK signaling cascade, in which the Grb2/Sos pathway leads to activation of Ras signaling, affecting cell proliferation and apoptosis. In view of their mitogenic nature, these can be characterized as "growth signal" effects. (b) The other is the IRS pathway, which leads to activation of kinases dependent upon the heterodimeric (p85/p110) PI3K, such as Akt, also referred to as protein kinase B (PKB); Akt modulates enzyme activities that, besides affecting NO generation and apoptosis, control glucose, lipid, and protein metabolism. This PI3K-branching pathway is termed the "metabolic signal." PI(4, 5)P2, phosphoinositide 4,5 di-phosphate; PI(3, 4, 5)P3, phosphoinositide 3,4,5 tri-phosphate; PDK1 phosphoinositide–dependent kinase–1; MEK, MAPK kinase. Greet Van den Berghe J. Clin. Invest. 114:1187-1195 (2004)
  • The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulating blood volume and systemic vascular resistance , which together influence cardiac output and arterial pressure . As the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3) aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex. Renin is a proteolytic enzyme that is released into the circulation primarily by the kidneys. Its release is stimulated by 1)  sympathetic nerve activation (acting via b1-adrenoceptors) 2)  renal artery hypotension (caused by systemic hypotension or renal artery stenosis) 3)  decreased sodium delivery to the distal tubules of the kidney. Juxtaglomerular (JG) cells associated with the afferent arteriole entering the renal glomerulus are the primary site of renin storage and release in the body. A reduction in afferent arteriole pressure causes the release of renin from the JG cells, whereas increased pressure inhibits renin release. Beta1-adrenoceptors located on the JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells ( macula densa ) of distal tubules lie adjacent to the JG cells of the afferent arteriole.  The macula densa senses the amount of sodium and chloride ion in the tubular fluid. When NaCl is elevated in the tubular fluid, renin release is inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. There is evidence that prostaglandins (PGE2 and PGI2) stimulate renin release in response to reduced NaCl transport across the macula densa. When afferent arteriole pressure is reduced, glomerular filtration decreases, and this reduces NaCl in the distal tubule. This serves as an important mechanism contributing to the release of renin when there is afferent arteriole hypotension. When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen , that undergoes proteolytic cleavage to form the decapeptide angiotensin I . Vascular endothelium, particularly in the lungs, has an enzyme, angiotensin converting enzyme (ACE) , that cleaves off two amino acids to form the octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can form AII.
  • TNF-A AND CLINICAL APPLICATIONS   TNF-A seems to serve as a mediator in various pathologies.  A few such examples include:  Septic shock, Cancer, AIDS, Transplantation rejection, Multiple Sclerosis, Diabetes, Rheumatoid arthritis, Trauma, Malaria, Meningitis, Ischemia-Reperfusion Injury, and Adult respiratory distress syndrome. Since TNF-A plays a role in several diseases, a substantial amount of research has been conducted concerning TNF-A therapies and anti-TNF-A therapies.  Because TNF-A exhibits anti tumor activity, research has been conducted to determine the protein's effectiveness against certain forms of cancers.  Utilizing TNF-A tumoricidal activities has proved problematic, especially due to the cytotoxin's systematic toxicity.  While higher doses of TNF-A may exhibit higher cytotoxicity, high doses also lead to systematic toxicity (National Cancer Institute, 1995).  Some studies involving TNFR-75 and TNFR-55 mutants have suggested that the TNFR-75 receptor plays a role in systematic toxicity, while TNFR-75 mutants will exhibit cytotoxicity but not systematic toxicity (Van Ostade et al., 1993).  Additionally, a mutant form of TNF-A which exists only in the transmembrane form acts only by cell-to-cell contact and may result only in cytotoxicity (Perez et al.,1990), suggesting that mutant forms of TNF-A might effectively be used therapeutically as against specific types of cancers. Other research has focused upon inhibiting the effects of TNF-A in such diseases as Rheumatoid Arthritis, Crohn's Disease, AIDS, bacterial septic shock (caused by certain gram negative bacteria), and bacterial toxic shock (caused by superantigens) as well as in prevention of alloreactivity and graft rejection.  Mutant mice that lack TNF-A are resistant to gram-negative bacteria induced sepsis (Janeway et al. 1999), and anti-TNF monoclonal antibodies have been used to effectively reduce or inhibit TNF-A activity (Beutler et al., 1985b).  One hypothetical advantage of treatment with anti-TNF-A antibodies results from its role in multiple types of inflammation.  It is often difficult to determine that inflammation in burn and trauma victims are of infectious etiology and warrant treatment with antibiotics; therefore another treatment strategy might involve anti-TNF-A therapy (Strieter, et al., 1993).   Strategies for preventing TNF-A activity include neutralization of the cytokine via either anti-TNF antibodies, soluble receptors, or receptor fusion proteins; supression of TNF-A synthesis via drugs such as cyclosporine A, glucocorticoides, or  cytokine IL-10; reduction of responsiveness to TNF-A via repeated low dose stimulation; and lastly, by inhibition of secondary mediators such as IL-1, IL-6, or nitric oxide (Tracey et al., 1993).   Pharmaceutical companies such as  Peptech Limited have developed different antibodies to TNF-A , some of which inhibit various TNF-A functions and others which do not affect protein activity.  For instance, Remicade (TM)   is a chimeric Igk monoclonal anti-TNF antibody manufactured by  Centocor which has been used to treat Crohn's disease--a chronic inflammatory disease of the intestines (Centocor 2000).   Soluble TNF-R will also neutralize TNF-A before it can bind to its target cell receptor.  Another drug, Enbrel (TM) , developed by Immunex Corporation, is a fusion of two soluble TNF receptors and a human immunoglobulin (Immunex Corporation, Nov. 1999).  It has been approved for treatment of rheumatoid arthritis. Additionally, Chloroquine inhibits transcription of the protein in macrophage (Zhu et al. 1993). However, the efficacy of preventing septic shock has been questioned as a result of recent research which suggests that, in the absence of TNF-A, other cytokines will eventually initiate the inflammatory response.  The authors of this study speculate that TNF-A production may instead play a key kinetic role by amplifying release of cytokines IL-A, IL-B, and IL-6 and thereby affecting the severity of a response to LPS (Amiot et al., 1997).  Additionally, eliminating the stimulatory affects of TNF-A in diseases such as AIDS presents problems because inactivation of TNF-A leaves the host at even greater risk for bacterial infections normally countered by TNF-A activity.
  •        STRUCTURE/BINDING SITES TNF-A is a trimeric protein encoded within the major histocompatibility complex.  It was first identified in its 17 kd secreted form, but further research then showed that a noncleaved 27kd precursor form also existed in transmembrane form (Perez, et al., 1990).  Stimulated macrophage produce 27kd TNF-A, which can either bind directly to TNFR-55 and TNFR-75 receptors through cell-to-cell contact or undergo cleavage and bind in its soluble form.  Due to its jelly roll like structure, which it shares in common with viral coat proteins, it has been hypothesized that TNF-A and viral originated from a common ancestor cell (Jones et al., 1989).  TNF-A shares only 36%  amino acid sequence homology  with TNF-B, also called lymphotoxin (LT) (Meager, 1991).  Yet, the tertiary structures of the two proteins are remarkably similar and both bind to TNF receptors TNFR-55 and TNFR-75.  These receptors are expressed on all somatic cells.                                Figure 2                       Signal transduction pathway initiated by trimeric TNF-alpha                         binding to its receptor, TNFR to initiate receptor clustering                         and signal transduction.  (Higashi, 1998).  Reproduced with permission from author.                         From Kyushu University Molecular  Gene Technics Signaling Pathway Database
  • Suppressor of cytokine signaling 3 , also known as SOCS3 , is a human gene . This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. For signaling of IL-6, Epo, GCSF and Leptin, binding of SOCS3 to the respective cytokine receptor has been found to be cruicial for the inhibitory function of SOCS3. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development. [1]
  • JAKs, which have tyrosine kinase activity, bind to some cell surface cytokine receptors . The binding of the ligand to the receptor triggers activation of JAKs. With increased kinase activity, they form phosphorylate tyrosine residues on the receptor and create sites for interaction with proteins that contain phosphotyrosine -binding SH2 domain . STATs possessing SH2 domains capable of binding these phosphotyrosine residues are recruited to the receptors, and are themselves tyrosine-phosphorylated by JAKs. These phosphotyrosines then act as docking sites for SH2 domains of other STATs, mediating their dimerisation. Different STATs form hetero- as well as homodimers . Activated STAT dimers accumulate in the cell nucleus and activate transcription of their target genes. [1] STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases , such as the epidermal growth factor receptor as well as by non-receptor tyrosine kinases , such as c-src . The pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases remove phosphates from cytokine receptors as well as activated STATs. [1] More recently identified Suppressors of Cytokine Signaling (SOCS) inhibit STAT phosphorylation by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors. [2] STATs are also negatively regulated by Protein Inhibitors of Activated STATs (PIAS) , which act in the nucleus through several mechanisms. [3] For example, PIAS1 and PIAS3 inhibit transcriptional activation by STAT1 and STAT3 respectively by binding and blocking access to the DNA sequences they recognise.
  • Suppressor of cytokine signaling 3 , also known as SOCS3 , is a human gene. This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma. The protein encoded by this gene can bind to JAK2 kinase, and inhibit the activity of JAK2 kinase. For signaling of IL-6, Epo, GCSF and Leptin, binding of SOCS3 to the respective cytokine receptor has been found to be cruicial for the inhibitory function of SOCS3. Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development.[1]
  • (ET-1, a potent endogenous vasoconstrictor)
  • Serum amyloid A (SAA) proteins are a family of apolipoproteins found predominantly associated with high-density lipoprotein (HDL) in plasma, with different isoforms being unequally expressed constitutively and in response to inflammatory stimuli. Although synthesized primarily in the liver, extrahepatic tissue_cellular expression of SAA has been widely documented. SAA has been linked to functions related to inflammation, pathogen defense, HDL metabolism, and cholesterol transport and thereby has been implicated in several pathological conditions including atherosclerosis, rheumatoid arthritis, Alzheimer's disease, and cancer. SAA is known best for its role during the acute phase response to an inflammatory stimulus such as infection, tissue injury, and trauma. During active inflammation the concentration of SAA in plasma can increase up to 1,000-fold within 24 h. It is believed that persistently high levels of SAA during chronic inflammation may contribute to the occasional development of the potentially fatal disease reactive amyloidosis (amyloid A (AA) amyloidosis). In AA amyloidosis, AA, an N-terminal (1-76) fragment of SAA, frequently is found to form amyloid deposits in the liver, kidney, and spleen. However, the presence, in vivo, of full-length SAA in amyloid deposits and the ability of various SAA isoforms to form fibrils in vitro suggest that proteolytic cleavage may not be a prerequisite for AA deposition but rather a postdeposition event. Of the three loci that express SAA in humans, SAA1 is the major, although not the only, precursor of AA deposits. Similarly, type A (i.e., BALB_c) mice contain two SAA isoforms, SAA2.1 and SAA1.1 [formerly known as SAA1 and SAA2, respectively], of which only the latter deposits into amyloid after chronic inflammation induced with casein or azocasein. In contrast, the CE_J mouse strain produces a single SAA isoform, SAA2.2 (formerly known as SAA CE_J), which is amyloid-resistant. Although the exact in vivo functions of SAA are still obscure, its high conservation from fish to humans, wide expression profile in tissues_cells, and dramatic increase in expression levels during the acute phase response suggest a fundamental protective role for SAA. Yet, despite its small size (12 kDa) and highly significant functions, there is very limited structural information about SAA because of its inherent poor solubility in the apolipoprotein form. It is intriguing to understand how such a small protein is able to mediate or directly carry out such a wide range of functions related to inflammatory reaction and other hostdefense mechanisms. The various functions of SAA may be modulated by factors such as conformational changes induced by ligand binding or by the ability to adopt more than one oligomeric state. Deciphering the molecular basis of the functional and potentially pathological properties of SAA will require understanding its structure under various conditions. In collaboration with Wilfredo Colón (Rensselaer Polytechnic Institute) and Thomas Walz (Harvard Medical School), we showed by various methods that murine SAA2.2 can exist in aqueous solution as a hexamer containing a putative central channel.
  • Figure 2 Enzymatic and protein changes within high-density lipoprotein (HDL) during an acute phase reaction. Serum amyloid A (SAA), apolipoprotein J (J), and secretory nonpancreatic phospholipase A2 (sPLA2) are present at higher serum concentrations and incorporate into HDL, while the HDL components apolipoprotein A-I (A-I), paraoxonase 1 (PON1), platelet activating factor acyl hydrolase (PAF-AH), cholesteryl ester transfer protein (CETP), lecithin:cholesterol acyltransferase (LCAT), and phospholipid transfer protein (PLTP) all decrease in concentration within HDL. High-density lipoprotein phospholipid content also falls, along with a reduction in cholesterol esters and an increase in triglycerides, free fatty acids, and free cholesterol. A-II = apolipoprotein A-II. From Rohrer et al. (31).
  • Role of Free Fatty Acids in Hyperglycemia Elevated rates of lipid oxidation in obesity contribute to the defect in glucose oxidation and glucose storage in insulin resistance. In healthy humans, high FFA concentrations have been shown to stimulate FFA oxidation and inhibit both glucose oxidation and glycogen synthesis. (DeFronzo, 1992; DeFronzo, 1997; Reaven, 1995) An increase in body fat mass in obese individuals—nondiabetics as well as diabetics—has been associated with increased lipolysis and elevated plasma FFA concentration. (Boden, 1999) The elevated FFA concentration can reproduce such major intracellular abnormalities observed in type 2 diabetes as decreased glucose transport and decreased glycogen synthase, and it can account for defects in glucose oxidation and storage. (Boden, 1999) Further, even after glucose ingestion, which, in nonobese individuals, would suppress plasma levels and lipid oxidation, FFA levels remain elevated despite the presence of hyperinsulinemia. (DeFronzo, 1992)
  • Visceral fat in particular contributes to endothelial dysfunction through the direct effect of adipokines, mainly adiponectin and TNF- , which are secreted by fat tissue after macrophage recruitment (through monocyte chemoattractant protein-1, MCP-1). Indirect effects of TNF- and IL-6 might influence inflammation (CRP) and endothelial dysfunction. Insulin resistance induced by cytokines (IL-6, TNF- and adiponectin), NEFA and retinol-binding protein 4 (RBP-4) may induce oxidative stress and subsequent endothelial dysfunction (PAI-1 and ICAM-1). Fat accumulation, insulin resistance, liver-induced inflammation and dyslipidaemic features may all lead to the premature atherosclerotic process.
  • Regulatory role of AMPK in fatty acid oxidation in skeletal muscle Leptin, adiponectin and a-adrenergic agonist activate a2AMPK in skeletal muscle via AMPKK. Activated a2AMPK containing the b2 subunit rapidly translocates the nucleus, where it induces PPAR a gene transcription. In contrast, a2AMPK containing the b1 subunit is retained in the cytoplasm, where it phosphorylates acetyl-CoA carboxylase (ACC) and thereby stimulates fatty acid oxidation.
  • Leptin inhibits food intake by suppression of AMPK activity in ARH-PVH axis Arcuate hypothalamus (ARH) expresses NPY/AGRP and a-MSH neruons. Leptin inhibits NPY/AGRP neurons by decreasing AMPK activity and thereby activates melanocortin 4 receptor (MC4R) in the PVH. Activated MC4R further decreases AMPK activity in the PVH, leading to leptin-induced anorexia. Recently, AMPK in the PVH was found to regulate food preference as well as calorie intake.
  • Leptin controls body energy metabolism by reciprocally regulating AMP kinase in the hypothalamus and skeletal muscle Leptin activates AMP kinase (AMPK) in skeletal muscle directly at the muscle level and indirectly through the hypothalamic-sympathetic nervous system. Leptin also inhibits food intake by suppressing AMPK activity in the hypothalamus. Reciprocal regualtion of AMPK activity in the hypothalamus and skeletal muscle is necessary for the leptin’s effect on energy metabolism.
  • Only limited data are available to describe the potential effects of adiponectin (and resistin) on adaptive immunity. In terms of T-cell proliferation, adiponectin suppresses the ability to evoke allogeneic T-cell responses. Adiponectin affects T helper 1 (TH1)-cell immunity by suppressing the production of interferon- (IFN ) and tumour-necrosis factor (TNF), and by inducing production of the anti-inflammatory cytokine interleukin-10 (IL-10). In terms of lymphopoiesis, adiponectin suppresses B-cell development through the induction of prostaglandin synthesis. Leptin is the best studied adipocytokine and has many influences on adaptive immunity, such as inducing a switch towards TH1-cell immune responses by increasing IFN and TNF secretion, the suppression of TH2-cell responses, and inducing the production of IgG2a by B cells. Leptin promotes the generation, maturation and survival of thymic T cells, and it increases the proliferation of and IL-2 secretion by naive T cells. COX, cyclooxygenase; PGE2, prostaglandin E2.
  • Figure 2. (click image to zoom) Effects of obesity on growth-factor production. In obesity, increased release from adipose tissue of free fatty acids (FFA), tumour-necrosis factor-α (TNFα) and resistin, and reduced release of adiponectin lead to the development of insulin resistance and compensatory, chronic hyperinsulinaemia (see "The Insulin-Resistance Syndrome or Metabolic Syndrome"). Increased insulin levels, in turn, lead to reduced liver synthesis and blood levels of insulin-like growth factor binding protein 1 (IGFBP1), and probably also reduce IGFBP1 synthesis locally in other tissues. Increased fasting levels of insulin in the plasma are generally also associated with reduced levels of IGFBP2 in the blood. This results in increased levels of bioavailable IGF1. Insulin and IGF1 signal through the insulin receptors (IRs) and IGF1 receptor (IGF1R), respectively, to promote cellular proliferation and inhibit apoptosis in many tissue types. These effects might contribute to tumorigenesis.
  • Figure 3. (click image to zoom) Effects of obesity on hormone production. Adipose tissue produces the enzymes aromotase and 17ß-hydroxysteroid dehydrogenase (17ß-HSD). So in obese individuals, there is typically an increased conversion of the androgens δ4-androstenedione (δ4A) and testosterone (T) into the oestrogens oestrone (E1) and oestradiol (E2), respectively, by aromatase. 17ß-HSD converts the less biologically active hormones δ4A and E1 into the more active hormones T and E2, respectively. In parallel, obesity leads to hyperinsulinaemia, which in turn causes a reduction in the hepatic synthesis and circulating levels of sex-hormone-binding globulin (SHBG). The combined effect of increased formation of oestrone and testosterone, along with reduced levels of SHBG, leads to an increase in the bioavailable fractions of E2 and T that can diffuse to target cells, where they bind to oestrogen and androgen receptors. The effects of sex steroids binding their receptors can vary, depending on the tissue types, but in some tissues (for example, breast epithelium and endometrium) they promote cellular proliferation and inhibit apoptosis.
  • Figure 4. (click image to zoom) Obesity, hormones and endometrial cancer. Obesity can increase risk of endometrial cancer through several parallel endocrine pathways. Obesity is associated with increased insulin levels, which lead to increases in insulin-like growth factor 1 (IGF1) activity and, in some individuals, an increased androgen production by the ovaries. An excessive increase in ovarian androgen production inhibits ovulation (chronic anovulation), which leads to progesterone deficiency. Increased adiposity also increases aromatase activity, leading to increased levels of bioavailable oestrogen levels in postmenopausal women. Oestrogens increase endometrial cell proliferation and inhibit apoptosis, partially by stimulating the local synthesis of IGF1 in endometrial tissue. Progesterone normally counteracts these effects through various mechanisms, in part by promoting synthesis of IGF-binding protein 1 (IGFBP1) -- the most abundant IGFBP in endometrial tissue. Among premenopausal women, the lack of progesterone, because of ovarian androgen production and continuous anovulation, leads to reduced production of IGFBP1 by the endometrium. Loss of progesterone production therefore seems to be the most important physiological risk factor for cancer in premenopausal women. After menopause (and in the absence of exogenous oestrogen production), when ovarian progesterone synthesis has ceased altogether, the more central risk factor seems to be obesity-related increases in bioavailable oestrogen levels. In addition to oestrogens and progesterone, insulin itself could also promote endometrial cancer development by reducing concentrations of sex-hormone-binding globulin (SHBG) in the blood, which would increase the levels of bioavailable oestrogens that can diffuse into endometrial tissue. Figure modified from Ref. 35.
  • Model depicting the control of energy homeostasis and hepatic glucose metabolism by adiposity- and nutrient-related signals. Neuronal systems sense and respond to input from hormones such as insulin and leptin that are secreted in proportion to body energy stores and from the metabolism of circulating nutrients (such as glucose and FFAs). In response to this input, adaptive changes occur in energy intake, energy expenditure, and hepatic glucose production. Michael W. Schwartz and Daniel Porte, Jr., Science, Vol 307, Issue 5708, 375-379 , 21 January 2005
  • Metabolism and immunity are closely linked. Both overnutrition and undernutrition have implications for immune function. Starvation and malnutrition can suppress immune function and increase susceptibility to infections. Obesity is associated with a state of aberrant immune activity and increasing risk for associated inflammatory diseases, including atherosclerosis, diabetes, airway inflammation, and fatty liver disease. Thus, optimal nutritional and metabolic homeostasis is an important part of appropriate immune function and good health. Kathryn E. Wellen and Gökhan S. Hotamisligil. J. Clin. Invest. 115:1111-1119 (2005)
  • Nutrient and pathogen sensing or response systems have important overlapping features, and their modulation by obesity or infection can lead to overlapping physiological outcomes. For example, the chronic inflammation of obesity leads to elevated plasma lipid levels and the development of insulin resistance, eventually resulting in fatty liver disease, atherosclerosis, and diabetes. Infection typically leads to a more transient and robust inflammatory response and short-term hyperlipidemia that aids in the resolution of the infection. In some circumstances of chronic infection, however, insulin resistance, diabetes, and atherosclerosis can result. Wellen and Gökhan S. Hotamisligil. J. Clin. Invest. 115:1111-1119 (2005)
  • Venn diagram modeling the effect of the interaction between glucose toxicity and lack of insulin on the vulnerable state of critical illness. Complications of type 1 and type 2 diabetes are explained by hyperglycemia and/or lack of insulin effect. Critical illness is also characterized by hyperglycemia and lack of insulin effect, but additional risk factors render both of these effects more acutely toxic, as indicated by the blue shading. These risk factors include the post-hypoxia reperfused state, iNOS-activated NO generation, increased expression of GLUT-1 and GLUT-3 transporters, and cytokine-, neurological-, and hormone-induced alterations in cellular processes. Hence, improved outcome of critical illness with insulin-titrated maintenance of normoglycemia is likely to be explained by the prevention of both direct glucose toxicity and insulin-induced effects that are independent of glucose control. Greet Van den Berghe J. Clin. Invest. 114:1187-1195 (2004)
  • Figure 1: Anti- and proinflammatory adipokines Adipose tissue serves as a rich source of proinflammatory mediators such as TNFα, IL-6, leptin, PAI-1, angiotensinogen, resistin and CRP, which promote endothelial dysfunction, insulin resistance and ultimately, atherosclerosis. Other adipocyte products such as NO and adiponectin confer protection, but these appear to decrease in amount with increasing levels of obesity. These proinflammatory mediators, released by adipocytes, exert effects on the vasculature promoting the various stages of atherogenesis, namely endothelial dysfunction, plaque initiation, plaque progression and plaque rupture. (monocyte chemoattractant protein-1 (MCP-1), (vascular cell adhesion molecule-1 (VCAM-1) (intercellular adhesion molecule-1 (ICAM-1)
  • Figure 2: Effects of the metabolic syndrome of insulin resistance on endothelial dysfunction. Insulin resistance and adaptive hyperinsulinemia are thought to cause endothelial dysfunction by promoting endothelial activation and a proatherogenic environment. The adipokines re-enforce these detrimental effects.
  • Figure 3: Adipokines serve as the cellular mediators of the metabolic syndrome and endothelial dysfunction.
  • (monocyte chemoattractant protein-1 (MCP-1), (vascular cell adhesion molecule-1 (VCAM-1) (intercellular adhesion molecule-1 (ICAM-1
  • (monocyte chemoattractant protein-1 (MCP-1), (vascular cell adhesion molecule-1 (VCAM-1) (intercellular adhesion molecule-1 (ICAM-1
  • (monocyte chemoattractant protein-1 (MCP-1), (vascular cell adhesion molecule-1 (VCAM-1) (intercellular adhesion molecule-1 (ICAM-1) (angiotensin II (AT-II) )
  • PPARs were originally cloned as nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. Three PPAR isotypes have been described: α, β, and γ. Binding of the ligands to these receptors results in activation of target gene transcription. Endocr Rev. 1999 Oct;20(5):649-88 .   The target genes of PPARs are involved in lipid transport and metabolism, including trans-membrane fatty acid uptake , fatty acid binding in cells, fatty acid oxidation in microsomes peroxisomes and mitochondria, as well as lipoprotein synthesis and transport.   PUFA binds to all three receptors, while long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and  eicosanoids bind mainly to PPAR α. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ. PPAR-α is predominantly expressed in brown adipose tissue and liver as well as kidney heart and skeletal muscle.  Biochemistry. 1999 Jan 5;38(1):185-90   PPAR-α modulates fatty acid catabolism in the liver. Long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and  eicosanoids form the main endogenous ligands for PPAR α. Fibrates (Bezafibrate, Gemfibrozil, fenofibrate) constitute the synthetic agonists for PPAR-α. Fibrates exert their actions (hepatic fatty acid oxidation and reduction of apo CIII expression to lower triglycerides; induction of Apolipoprotein AI and Apolipoprotein AII expression to increase HDL) through PPAR-α. PPAR γ   is mainly expressed in adipose tissue, and at lower levels in the colon, and immune system. No significant expression of PPAR-γ  has been demonstrated in the skeletal muscle the main site of glucose disposal. PPAR-γ induces the differentiation of pre-adipocytes into mature fat cells. Mol Cell. 1999 Oct;4(4):611-7 .   PPAR-γ regulates multiple genes in the adipose tissue regulating lipogenesis, including those encoding the adipocyte fatty acid binding protein (A-FABP), lipoprotein lipase, fatty acid transport protein (FATP) and acyl-CoA synthase. Thus PPAR γ influences the storage of fatty acids in adipose tissue. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ while Thiazolidinediones are the synthetic agonists at  PPAR-γ receptors.  Actions on PPAR-γ receptors by thiazolidinediones have been shown to down regulate PAI-1 levels   Biochem Biophys Res Commun. 1999 May 10;258(2):431-5.     suggesting one mechanism of the actions of this group of drugs on insulin resistance. Thiazolidinediones may increase the number of new fat cells which are smaller and hence more insulin sensitive with greater capability to store fat than the larger dysfunctional fat cells. This offers increased "buffering" capability for adipose tissue, thus preventing fat deposition in extra-adipose tissue as muscle and liver thus preventing or delaying onset of insulin resistance. This adipogenetic effect of thiazolidinediones is marked in the subcutaneous adipose tissue (SCAT) than the visceral adipose tissue (VAT),  J Clin Endocrinol Metab. 2002 Jun;87(6):2784-91     thus producing a more favourable fat distribution profile. PPAR-γ expression is stimulated by insulin J Clin Invest. 1997 May 15;99(10):2416-22 .   and by SREB-1 Mol Cell Biol. 1999 Aug;19(8):5495-503 . PPAR-γ has both an adipogenic effect as well as lipogenic effect. PPAR-γ expression is minimal in hepatocytes, but a rise in hepatic triglycerides produces a dramatic increase in PPAR-γ expression. This suggests the involvement of PPAR-γ in stimulating lipogenesis. J Clin Invest. 2000 Nov;106(10):1221-8. Thiazolidinediones are the synthetic agonists at  PPAR-γ receptors. Since PPAR-γ receptors are almost negligible in skeletal muscle, glucose disposal at this site mediated by PPAR-γ may not be the mode of hypoglycaemic action of thiazolidinediones. It is more likely that thiazolidinediones divert fatty acids away from skeletal muscle by increasing their uptake by adipose tissue thus improving insulin resistance at the muscular level. A beneficial effect on cholesterol metabolism independent of PPAR-γ may be an alternative mechanism for the beneficial effect of thiazolidinediones on glucose homeostasis. Diabetes. 1999 Feb;48(2):254-60. PPAR β has greatest expression in gut, kidney and heart.   PPAR-β is linked to colon cancer . PPAR-β regulates the expression of acyl-CoA synthetase2 in the brain, J Biol Chem. 1999 Dec 10;274(50):35881-8.  thus playing a role in basic lipid metabolism. PPAR-β is less widely hyped due to the paucity of clinical manifestations related to this receptor. PPAR-α and PPAR-γ can modulate the inflammatory response and foam cell formation, thus influencing development of atherosclerosis and plaque stability. PPAR-α may have anti-atherosclerotic effects mediated through reduction of plasma levels of pro-atherosclerotic proteins (CRP and fibrinogen). Blood. 1999 May 1;93(9):2991-8. In the fed state in humans (up to 4 hours after a meal), carbohydrates and fat enter the circulation as glucose and chylomicrons. The glucose enters the liver where it is stored as glycogen, and once glycogen stores are replete, the glucose is glycolytically converted to acetyl CoA (promoted by the rising SREBP-1 levels in the fed state) and diverted to synthesis of fatty acids and further into triglycerides and packaged as VLDL. Insulin increases SREBP and PPAR-γ in the adipose tissue. The fatty acid produced from the above process functions as an endogenous ligand for PPAR-γ in the adipose tissue, facilitating triglyceride storage in the adipose tissue. Triglyceride storage increases leptin production in the adipose tissue. Leptin facilitates lipolysis and fatty acid oxidation, processes which are prevented by PPAR-γ mediated negative regulation of Leptin. When PPAR-γ levels fall, Leptin increases with resultant lower fat storage (and  food intake) Mol Cell. 1999 Oct;4(4):597-609 . PPAR α expression which rises in the fasting state J Clin Invest. 1999 Jun;103(11):1489-98 .     stimulates fatty acid oxidation to Acetyl CoA in the liver and further into ketone bodies (acetoacetate and betahydroxybutyrate). Since fatty acids are ligands for PPAR α, fatty acids themselves can up-regulate PPAR α and facilitate their own metabolism. Note that PPAR α deficient mice have defective fatty acid oxidation and ketogenesis with resultant elevation of plasma free fatty acids, and hypoglycaemia.  

Obesity & adipokines Obesity & adipokines Presentation Transcript

  • Isfahan University of Medical Science, School of Pharmacy Department of Clinical BiochemistryJune 25, 2012 1 Total slides : 51
  • AdipokinesThe link between obesity and its complications Supervised by: Dr. Mohsen Ani Presented by: A.N. Emami Razavi
  • O u t lin e s  A d ip o s e t is s u e  O b e s it y & r e la t e d c o m p lic a t io n s  A d ip o c y t e s a s a n e n d o c r in e c e lls  A d ip o k in e sJune 25, 2012 3 Total slides : 51
  • Adipose tissue An overview
  • Adipose tissue Adipose tissue or fat is loose connective tissue composed of adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body.
  • Two types of adipose tissue exist: white adipose tissue (WAT)and brown adipose tissue (BAT). WAT Characteristics of brown and white adipocytes Multilocular adipocyte Brown adipocyte Lipid storage and mobilization (++) Mitochondria (+++) Fatty acid oxidation (+++) Respiratory chain (+++) UCP1 (+++) PGC-1α (+++) White adipocyte BAT Unilocular adipocyte ( 200µm) Lipid storage and mobilization (+++) Mitochondria (+) Fatty acid oxidation (+) Respiratory chain (+) UCP1 (0) PGC-1α (+) For letter symbols, see slide 36
  • Anatomical features In humans, adipose tissue is located beneath the skin (subcutaneous fat), and is also found around internal organs (visceral fat). Adipose tissue is found in specific locations which are referred to as adipose depots.
  • Fat cells  Adipose cells store majority of the body’s fat, vary in size and number  Increase in body fatness is due to:  Fat cell hypertrophy  Fat cell hyperplasiaJune 25, 2012 8 Total slides : 51
  • Fat Cell DevelopmentDuring growth, When energy intake After fat cells have enlarged and With fat loss, the size of thefat cells increase exceeds expenditure, energy intake continues to exceed fat cells shrinks, but not thein number. fat cells increase in size. expenditure, fat cells increase in number. number again.
  • Fat cell number  Fat cell develop:  Last trimester of pregnancy  First year of life  During adolescent  Average non-obese person: 25-30 bill.  Moderately obese: 60-100 bill.  Massively obese: 300 bill.+  Number of fat cells appears to be biggest factor in determining risk for obesity.June 25, 2012 10 Total slides : 51
  • Adipose tissue as an endocrine organ  Adipose tissue has been recognized as the quantitatively most important energy store of the human body for many years, in addition to its functions as mechanical and thermal insulator. During the last 10 years, adipose tissue has come into focus as an endocrine organ important for development of many diseases related to obesity including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular disease. Adipose tissue secretes a variety of bioactive peptides that play important roles in insulin action, energy homeostasis, inflammation, and cell growth. These secretory proteins from the adipose organ are named adipokines and have many physiological effects on different organs including the brain, bone, reproductive organs, liver, skeletal muscles, immune cells and blood vessels. Adipokines may locally regulate fat mass by modulating adipocyte size/number or angiogenesis and inversely increased fat mass leads to dysregulation of adipocyte functions.June 25, 2012 11 Total slides : 51
  • The Fat Cell Is a Veritable Endocrine Factory Cytokines Proteins of the Proteins involved in alternative glucose homeostasis complement system Fa t c e l l Proteins for Proteins involved in regulation of blood homeostasis pressure Proteins involved in Acute phase and lipid metabolism stress response proteins Fat cells are continually absorbing or releasing substances in response to the body’s energy needs
  • Adipokines from adipose tissue CytokinesTNF-α Leptin IL-1β IL-10 IL-6 IL-8
  • Adipokines from adipose tissue Proteins involved in glucose homeostasis Adiponectin Resistine
  • Adipokines from adipose tissue Proteins of the alternative complement system Acylation Adipsin stimulating protein
  • Adipokines from adipose tissue Proteins involved in homeostasis Plasminogen activator Tissue factor inhibitor-1 (PAI-1)
  • Adipokines from adipose tissue Proteins for regulation of blood pressure Angiotensinogen
  • Adipokines from adipose tissue Proteins involved in lipid metabolism Retinol binding Cholesterol ester protein transfer protein (RBP) (CETP)
  • Adipokines from adipose tissue Acute phase and stress response proteins Haptoglobin Metallothionein
  • Cellular origin of the peptides secreted by human adipose tissue Adipocytes  Adipokines Stromavascular fraction cells  cytokines & chemiokines Monocyte chemoattractant protein 1 (MCP1)Leptin Macrophage inflammatory protein (MIP)Adiponectin Tumor necrosis α (TNFα)Serum amyloids Interleukins 1β, 6, 8, 10, ….Retinol binding protein 4 (RBP4) ChemiokinesApelin ResistinFIAF/PGAR Apelin …
  • Obesity  Obesity results from an imbalance between lipogenesis (fat synthesis) and lipolysis (fat destruction ). Lipogenesis which occurs in liver and adipose tissue involves fatty acid synthesis followed by triglyceride synthesis.  Differentiation of the pre- adipocytes to mature fat cells is referred to as adipogenesis and should not be confused with lipogenesis.June 25, 2012 22 Total slides : 51
  • June 25, 2012 23 Total slides : 51
  • Musculoskeletal Cardiovascular Problems Problems Gastrointestinal Complications Respiratoryand Liver Problems Problems of obesity Diabetes Mellitus Cancer
  • Cardiovascular Problems  Obesity is a significant risk factor for predicting cardiovascular disease  Risks  ↑ Low-density lipoproteins (LDLs)  ↑ Triglycerides  ↓ High-density lipoproteins (HDLs)  Hypertension  ↑ Circulating blood volume  Abnormal vasoconstriction  ↓ Vascular relaxation  ↑ Cardiac outputJune 25, 2012 25 Total slides : 51
  • Respiratory Problems  Severe obesity may be associated with  Sleep apnea  Obesity hypoventilation syndrome  ↓ Chest wall compliance  ↑ Work of breathing  ↓ Total lung capacity and functional residual capacityJune 25, 2012 26 Total slides : 51
  • Diabetes Mellitus  Hyperinsulinemia  Insulin resistance  Type 2 diabetes  80% of patients with type 2 diabetes are obese  Weight loss and exercise improve glucose controlJune 25, 2012 27 Total slides : 51
  • Musculoskeletal Problems  Osteoarthritis  Trauma to weight-bearing joints  Hyperuricemia  GoutJune 25, 2012 28 Total slides : 51
  • Gastrointestinal and Liver Problems  Gastroesophageal reflux disease (GERD)  Gallstones  Nonalcoholic steatohepatitis (NASH)  Can eventually lead to cirrhosis  Weight loss can improve NASHJune 25, 2012 29 Total slides : 51
  • Cancer  Obesity is one of the most important known preventable causes of cancer  Women  Breast, endometrial, ovarian, cervical  Possibly from ↑ estrogen postmenopause  Men  Prostate  Both genders: ColonJune 25, 2012 30 Total slides : 51
  • History of adipose derived hormones Communication between adipose and other tissues has been hypothesized since at least the 1940s to be bidirectional. However, the importance of adipose tissue as an endocrine organ was only fully appreciated in 1994 with the discovery of Leptin, the protein product of the Ob gene.
  • leptin Leptin is a 16 kDa polypeptide product of the obese (ob) gene. Leptin, expressed and secreted primarily by adipocytes, acts via a family of receptor (ob-R) isoforms to mediate an ever growing wide range of physiological effects. These receptors have divergent signaling capabilities, regulating pathways which include JAK/STATs and MAP kinases.
  • Leptin expression Leptin expression is influenced by energy stores in fat. Leptin levels increase within hours after a meal in rodents and after several days of overfeeding in humans. Insulin stimulates leptin expression and secretion in primary adipocytes. Other factors, such as dexamethasone, thyrotrophin (TSH) , TNF-α and IL-6 also regulate leptin release.
  •  Leptin concentrations in the blood are in the range of several ng/ml, both as an active free form and as an inactive bound form which occurs by its association with plasma proteins and the leptin receptor isoform. Leptin receptors (OB-R) are expressed in variety of tissues, which suggested that it has a wide range of actions. However, leptin receptor mutations cause early onset obesity in rodents. This is consistent with measurements of high leptin concentration and low leptin receptor expression in most diabetic patients.
  • Signalling Pathway of Leptin Action Leptin binding to the leptin receptor leads to the formation of a Ob-R/JAK2 (Janusactivated kinase) complex that triggers phosphorylation. JAK2 phosphorylation leads to activation of the PI3K and MAPK pathways that regulate apoptosis, energy homeostasis and gene transcription. Leptin signaling occurs mainly through signal transducers and activators of transcription (STAT3). Phosphorylation of STAT3 triggers dimerization and translocation to the nucleus which leads to activation of gene transcription. The targets include: genes of suppressors of the cytokine signaling family (SOCS3). Therefore, leptin regulates various signaling pathways and impacts gene transcription.
  • Physiological effects of Leptin Regulation of food intake ,energy expenditure and body weight . Thermo genesis . Reproductive function . Suppressed bone formation . Directly act on the cells of liver and muscles . Related to inflammatory response . Contribute to early hematopoiesis.
  • Role of leptin in regulation of food intake and body weight Decrease hunger and food consumption - inhibition of neuropeptide Y synthesis . Food intake linked to its ability to regulate the neuroendocrine system .
  • Neuropeptide Y 36 a.a residue produce in the arcuate nucleus of the hypothalamus . Rich in tyrosine residues . Appetite stimulating hypothalamic peptide
  • Neuropeptide Y Found in many organ, high level of NPY are found in brainstem and hypothalamus . Stimulates leptin production in adipose tissue by increasing food intake and insulin secretion. Action through the parasympathetic nervous system.
  • Leptin and food intake
  • Mice with and without LeptinWithout leptin, this mouse With leptin treatment, this mouseweighs almost three times as lost a significant amount of weight,much as a normal mouse. but still weighs almost one and a half times as much as a normal mouse.
  • Role of leptin in thermogenesis
  • Role of leptin in lipid metabolism Leptin activated lipid oxidation, at least partially by inducing the expression of enzymes involved in lipid metabolism. Activate 5 –AMP-activated protein kinase (AMPK) Inhibits acetyl coenzyme-A carboxylase (ACC) Increase insulin sensitivity Inhibits intracellular lipid concentration Leptin also stimulated apoptosis of adipocytes through activation of caspase-8.
  • Leptin resistance The ability of leptin to decrease body fat content suggests leptin is an anti-obesity hormone. However, high leptin levels have been found in obese and diabetic mice and humans, which is defined as “leptin resistence”. Sometimes it is combined with low-level expression of leptin receptors. Another mechanisms are:  Mutation of the gene for leptin receptors in the brain  Post receptor abnormalities in leptin signal transduction  Impaired leptin transport across blood- brain barrier
  • Leptin, obesity and diabetes Disruption of leptin action is thought to play a role in development of diabetes. This hypothesis is supported by data showing that mutations of the ob gene cause early onset obesity and type II diabetes in mice and humans. A frameshift/premature stop mutation, c.398delG (Delta133G mutation) caused a congenital leptin deficiency and led to severe early-onset obesity. A homozygous frameshift mutation (delta133) in the human leptin (ob) gene was associated with undetectable serum leptin and extreme obesity.
  • Leptin effects on immune system Leptin stimulates the proliferation of stem cells and regulates hematopoiesis. It participates in innate immunity by promoting the maturation and survival of dendritic cells (DC) and stimulates macrophage proliferation, phagocytosis, and production of proinflammatory cytokines. Leptin plays a direct role in adaptive immunity by regulating the expression of Ob-R on both T and B cells and promoted the suvival of T and B cells by suppressing Fas-mediated apoptosis. Leptin increase the production of IL-2 and IFN-γ by T lymphocytes.
  • Adiponectin A protein is also called ADIPOQ, gelatine-binding 28, Acrp30, discovered in 1995. A peptide hormone made by adipocytes in response to high fat reserves:  Increases FA uptake by myocytes and the rate of FA oxidation.  Slows FA synthesis in the liver.  Slows gluconeogenesis in the liver.  Acts through AMP-dependent protein kinase (AMPK). Humans who are obese or who suffer from Type II diabetes show reduced levels of adiponectin. Drugs (thiazolidinediones) used to treat Type II diabetes elevate expression of adiponectin.
  • Plasma concentration Adiponectin is abundant in human plasma, with concentrations ranging from 5 to 30mg/ml, thus accounting for approximately 0.01% of total plasma protein This concentration is three orders of magnitude higher than concentrations of most other hormones
  • Adiponectin and Fat Mass There seems to be a clear relationship between adiponectin and fat mass in humans. However, in contrast to leptin, adiponectin levels are significantly reduced among obese subjects in comparison with lean control subjects. Arita et al showed that mean plasma adiponectin levels were 3.7 mg/ml in a group of obese patients, whereas in non-obese subjects these values reached a mean of 8.9 mg/ml In a recent longitudinal study, plasma adiponectin concentrations decreased with increasing adiposity in a group of children evaluated at 5 and 10 years of age
  • Adiponectin and Fat Mass Adiponectin is the only adipose-specific protein known to date that is negatively regulated in obesity In a group of normal weight and obese women plasma adiponectin was negatively correlated not only with body mass index and body fat mass, but also with serum leptin concentration, fasting insulin and calculated insulin resistance Another study, performed in 967 Japanese subjects with normal weight, has shown that plasma adiponectin is negatively correlated with body mass index, systolic and diastolic blood pressure, fasting plasma glucose, insulin, insulin resistance, total and LDL-cholesterol, TG and uric acid, and positively correlated with HDL-cholesterol
  • Adiponectin and DM, CAD Like plasma leptin levels, adiponectin concentrations seem to be gender-dependent, being higher among women than men plasma adiponectin levels are reduced not only among obese patients but also among patients with some of the disease states frequently associated with obesity, such as type 2 DM and CAD Multivariate analysis demonstrated that hypoadiponectinemia was more intensively related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity or glucose intolerance
  • Adiponectin and DM, CAD first degree relatives of type 2 diabetic patients have reduced adiponectin mRNA expression in adipose tissue compared with controls, although they have normal levels of circulating adiponectin Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (apM1) is located Evidence of an association between type 2 diabetes and single nucleotide polymorphisms at positions 45 and 276, and in the proximal promoter and exon 3 of the adiponectin gene has been reported Some missense mutations in the globular domain have been also associated with low adiponectin levels and type 2 diabetes
  • Adiponectin and Serum lipid concentrations In a large number of non-diabetic women with dyslipidemia, Matsubara et al. have shown that plasma adiponectin is negatively correlated with serum triglyceride, atherogenic index, apo B or apo E, and positively correlated with serum HDL-cholesterol or apo A-I levels. These data suggest that low adiponectin concentrations are associated with some of the well-known risk factors for atherosclerosis, such as low HDL-cholesterol levels or hypertriglyceridemia. A relationship between hypoadiponectinemia and the metabolic syndrome seems likely
  • Adiponectin and Body Weight loss Recent evidence also suggests that weight loss induces an increase in adiponectin levels in obesity. In a group of 22 obese patients, who were treated by gastric partition surgery, a 46% increase in mean plasma adiponectin level was accompanied by a 21% reduction in mean body mass index Changes in plasma adiponectin were related to changes in body mass index, waist and hip circumferences, and steady-state plasma glucose levels These data suggest the existence of a negative feedback mechanism between adipose mass and the production of adiponectin in humans
  • Adiponectin and TZD Thiazolidinedione treatment enhances endogenous adiponectin production In a group of mildly overweight subjects with glucose intolerance the administration of troglitazone for 12 weeks significantly increased the plasma adiponectin concentration in a dose-dependent way In a recent randomized double-blind placebo controlled trial performed in 64 type 2 diabetic patients, rosiglitazone therapy for 6 months was accompanied by a more than 2-fold increase in plasma adiponectin levels
  • Adiponectin and TZD Similar results have been reported with pioglitazone Furthermore, circulating adiponectin levels were found to be suppressed 5-fold in patients with severe insulin resistance in association with dominant-negative PPAR-g mutations thus suggesting that adiponectin may be a biomarker of in vivo PPAR-g activation
  • Adiponectin and CRF, Type 1 DM, Anorexia Norvosa In a study, performed in 227 hemodialysis patients, plasma adiponectin levels were 2.5 times higher among dialysis patients than among healthy subjects, and they were higher among women than among men Plasma adiponectin concentrations have been found to be significantly elevated in a group of 46 type 1 diabetic patients in relation to healthy controls Insulin replacement therapy did not affect adiponectin levels in a subgroup of seven patients. A preliminary report also showed that adiponectin levels were moderately elevated in 26 female patients with anorexia nervosa
  • Control of the synthesis of Adiponectin The only hormone implicated in the regulation of adiponectin expression has been insulin TNF-a is one of the candidate molecules responsible for causing insulin resistance The expression and secretion of adiponectin from adipocytes are significantly reduced by TNF-a Therefore, increased TNF-a might be partially responsible for the decreased adiponectin production in obesity adiponectin itself may increase insulin sensitivity through an inhibition of both the production and action of TNF-a It has also been hypothesized that adiponectin and TNF-a may antagonize each other or perform opposite functions locally in adipose tissue or in the arterial wall
  • Adiponectin as a Biomarker of the Metabolic syndrome The metabolic syndrome:  common basis for the development of atherogenic cardiovascular diseases. Decreased plasma concentrations of adiponectin:  plays a significant role in the development of the MS. the plasma concentration of adiponectin was significantly correlated with each component of the metabolic syndrome.
  • Definition of the Metabolic Syndrome The presence of at least 3 of the following abnormalities;2. Abdominal obesity: WC>=85cm in men or >=90cm in women3. Hypertriglyceridemia: a serum triglyceride concentration>=150mg/dl4. Low HDL cholesterolemia: a serum HDL cholesterol concentration<40mg/dl5. Hypertension: SBP>=130mmHg, DBP>=85mmHg and/or having received antihypertensive medication6. High fasting glucose: serum glucose concentration>=110 mg/dl
  • Potential therapeutic applications Evidence reported so far suggests that adiponectin possesses antihyperglycemic, anti-atherogenic and anti-inflammatory properties. Increased serum adiponectin levels are associated with increased insulin sensitivity and glucose tolerance adiponectin – or drugs that stimulate adiponectin secretion or action –might play a role in the therapeutic armamentarium against disease states associated with insulin resistance, mainly type 2 diabetes mellitus and obesity Low levels of adiponectin have also been implicated in the severe insulin resistance that accompanies lipoatrophy Therapy with adiponectin may also play a role in reversing insulin resistance in lipodystrophic disorders.
  • Potential therapeutic applications The anti-inflammatory effects of adiponectin indicate that it is an interesting protective factor for atherosclerosis development, especially in those clinical situations associated with low plasma levels of adiponectin. It is conceivable that the use of recombinant adiponectin may become beneficial in the prevention of cardiovascular disease in selected patients. The recent finding that adiponectin deficiency aggravates neointimal thickening, and that supplementation with adiponectin attenuates neointimal thickening in mechanically injured arteries, suggests that increasing plasma adiponectin might be useful in preventing vascular restenosis after vascular intervention
  • Adiponectin - structure
  • Adiponectin action : activation AMPK
  • Molecular Mechanisms of Adiponectin Action Kadowaki et al. Endocrine Reviews 26 (3): 439 - 451, 2005
  • Adiponectin R1 and R2 are Expressed in Heart, Liver, Kidney, Skeletal Muscle and Other Tissues  Brain  Heart  Kidney  Liver  Lung  Skeletal Muscle  Spleen  TestisYamauchi T., et al Nature 423, 762-769
  • Resistin Resistin has been named for the fact that it conveys the resistance to insulin Resistin is a cysteine-rich protein secreted by adipose tissue of mice and rats. In other mammals, at least primates, pigs and dogs, resistin is secreted by immune and epithelial cells.
  • Resistin Resistin is a 114 amino-acid peptide present in humans most likely in the form of a few splice variants. Monomeric peptides may create oligomeric structures It is secreted as a disulfide-linked homodimer via disulfide bonds at cysteine residue (Cys26)
  • Resistin and obesity Circulating resistin levels are increased in mouse models of obesity and in obese humans and are decreased by the anti- diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity Administration of anti-resistin antibody has been shown to improve blood sugar and insulin action in mice with diet- induced obesity. Similarly resistin has been implicated in the pathogenesis of diabetic complication and diabetes. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin- stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment.
  • Resistin and inflammation Resistin mRNA has been found in human PBMC and was increased by pre-treatment with certain cytokines such as IL-6 and TNF-alpha, IL-1, IL-12 or lipopolysacharride. Interestingly resistin itself leads to increased release of numerous pro-inflammatory cytokines TNF-alpha and IL-12, from macrophages and monocytes. Resistin induce the nuclear translocation of NF-kappaB transcription factor and resistin pro-inflammatory effects are reduced in the conditions of NF-kappaB inhibition. Thus pro-inflammatory actions of resistin are related to the activation of NFkappaB pathway, which makes resistin’s actions on the immune system in a direct opposition to adiponectin’s. Finally an important effect of resistin on inflammation is related to it’s ability to induce vascular adhesion molecule expression, thus increasing leukocyte infiltration to tissues, including fat.
  • Glitozones and resistin Rosiglitazone and other glitazones lower glucose and lipid levels in patients with type 2 diabetes by activating the nuclear receptor peroxisome proliferator- activated receptor g (PPARg)1. Rosiglitazone treatment was shown to reduce resistin expression in 3T3-L1 adipocytes in vitro and in the white adipose tissue (WAT) of mice fed a high fat diet. These data raised the interesting possibility that decreases in resistin levels might be integral to the antidiabetic actions of PPARg agonists.
  • Visfatin Visfatin is the most recently identified adipocytokine (known previously as pre-B cell colony enhancing factor; PBEF) which appears to be preferentially produced by visceral adipose tissue, and has insulin- mimetic actions. Visfatin expression is increased in animal models of obesity and its plasma concentrations are increased in humans with abdominal obesity or type 2 diabetes mellitus.
  •  Visfatin binds to the insulin receptor at a site distinct from insulin and exerts hypoglycemic effect by reducing glucose release from hepatocytes and stimulating glucose utilization in peripheral tissues. The latter property could make this molecule very useful in the potential treatment of diabetes. Interestingly, known as PBEF, visfatin was also identified in inflammatory cells and it’s levels were increased in various inflammatory conditions
  • Angiotensinogen Angiotensinogen, a precursor to the major proatherogenic vasoconstrictor angiotensin II (AT-II), is expressed and produced in adipocytes. AT-II directly stimulates ICAM-1, VCAM-1, MCP-1 and M-CSF expression in vascular cells by activating NF-κΒ-regulated genes. AT-II also promotes the formation of free oxygen radicals from NO, thereby decreasing the availability of NO and incurring damage to the vascular tissue. Augmented angiotensinogen production by adipose tissue in obesity has been linked to angiogenesis and the development of hypertension, both of which are known to be associated with endothelial dysfunction.
  • Obesity and inflammationObesity has been suggested to be an inflammatory disease, or at least a disease with an inflammatory component to it. Pro-inflammatory molecules as CRP, IL-6, TNF-alpha, Nutrition. 2001 Nov-Dec;17(11-12):953-66; Intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1) Circulation. 2002 Feb 19;105(7):804-9 have been shown to be high in overweight or obese subjects.
  • TNFα TNF-α is now recognized as a multi-functional regulatory cytokine, involved in inflammation, apoptosis, cell survival, cytotoxicity, and insulin resistance. TNF-α is a 26-kDa plasma membrane-bound protein that is cleaved into a 17-kDa biologically active protein. There are two receptors for TNF-α, type I and type II that regulate different functions.
  • TNFα and obesity Both mRNA and TNFα protein were elevated in the adipose tissue of obese animals and humans. Adipose tissue also expressed both types of TNFα receptors. Long term exposure of cultured cells or animals to TNFα induced insulin resistance, characterized by hyperinsulinemia and an increased prevalence of obesity, hypertension, dyslipidemia and type 2 diabetes
  • TNFα and insulin resistance Several hypotheses have been proposed to explain how TNFα induces insulin resistance in adipocytes. For example, TNFα inhibited insulin-stimulated IRS-1 phosphorylation. Thus, it might inhibit PI3K and inhibit a pathway that regulates glucose uptake. In addition, TNFα up regulates transcription of many preadipocyte genes and proinflammatory cytokines, such as IL-6 and MCP-1. These proteins were elevated in the plasma or adipose tissue of diabetic patients. TNFα also inhibited adiponectin expression, which may impaire insulin action. Furthermore, TNFα directly stimulated lipolysis, which caused in increased plasma free fatty acids. This also caused hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis.
  • TNFα and inflammation TNFα, an inflammatory cytokine released in greater quantities by obese humans and patients with insulin resistance, not only initiates but also propagates atherosclerotic lesion formation. TNFα activates the transcription factor nuclear factor-κΒ (NFκΒ), which accelerates experimental atherogenesis, in part by inducing the expression of VCAM-1, ICAM-1, MCP-1 and E-selectin in aortic endothelial and vascular smooth muscle cells. TNFα reduces NO bioavailability in endothelial cells and impairs endothelium-dependent vasodilatation, promoting endothelial dysfunction. TNFα may also promote apoptosis in endothelial cells by dephosphorylating protein kinase B, or Akt, and thereby, contribute to endothelial injury, an effect counteracted by insulin.
  • file:///H:/files/seminar obesity/obesity sites/TNF-alpha_files/tnfpathway.gif
  • IL-6 IL-6 is another cytokine that has long been recognized for its effects on the immune system It is associated with obesity and insulin resistance, too Like TNF-o plasma IL-6 Adipocytes secretes 2 to 3 times more IL-6 than stromovascular cells
  • IL-6, obesity and inflammation The in vivo release of IL-6 from fat contributes more than one third of the basal circulating IL-6 and explains the positive correlation between serum levels of IL-6 and obesity. signals are passed either through (JAK-STAT) or (ERK- MAPK) pathways or both. IL-6 induces fever and the acute phase response, which is defined as the complex series of inflammatory reactions initiated in response to infection, physical trauma, or malignancy. Therefore, enlarged adipose tissue has the potential to exacerate both responses.
  • IL-6 and insulin resistance IL-6 induces SOCS3 transcription and inhibits JAK/STAT activation, which caused inhibition of insulin receptor (IR) phosphorylation and insulin receptor substrate (IRS) phosphorylation . Thus, increased glyconeogenesis and decreased gluconeogenesis decrease glycogen storage, a consequence of insulin resistance. IL-6 suppresses insulin-induced lipogenesis and reduces expression of GLUT4 via repressed PKB/ERK pathway. Furthermore, IL-6 decreased adiponectin gene expression and secretion in a dose- and time-dependent manner in 3T3L1 adipocytes. All of these changes contribute to a glucose intolerant state.
  • JAK-STAT signaling pathway The JAK-STAT signaling pathway takes part in the regulation of cellular responses to cytokines and growth factors. Employing Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs), the pathway transduces the signal carried by these extracellular polypeptides to the cell nucleus, where activated STAT proteins modify gene expression. Although STATs were originally discovered as targets of Janus kinases, it has now become apparent that certain stimuli can activate them independently of JAKs. The pathway plays a central role in principal cell fate decisions, regulating the processes of cell proliferation, differentiation and apoptosis. It is particularly important in hematopoiesis - production of blood cells.
  • Mechanism
  • Suppressor of cytokine signaling 3
  • CRP cAMP Receptor Protein (CRP) is a dimer of two identical subunits each of which is 209 amino acids in length.
  • CRP Circulating plasma CRP levels are elevated in obese subjects and the levels are also directly correlated with the amount of body fat, Elevated plasma levels of C-reactive protein (CRP) have become one of the strongest independent predictors of CHD CRP induces the expression of VCAM-1, ICAM-1, selectins, and MCP- 1 in cultured endothelial cells via increased secretion of ET-1, a potent endogenous vasoconstrictor, and IL-6 CRP downregulates eNOS mRNA and protein expression. The diminished NO activity may in turn inhibit angiogenesis, an important compensatory response in chronic ischemia
  • CRP Furthermore, in vascular smooth muscle cells, CRP upregulates angiotensin type 1 receptor (AT1-R) mRNA and protein levels and increased AT1-R expression on the cell surface. AT1-R is a key atherosclerotic switch that facilitates angiotensin-II induced reactive oxygen species production, vascular smooth muscle cell migration and proliferation, and vascular remodeling. The effect of CRP on endothelial dysfunction is potentiated by hyperglycemia and these effects are attenuated by rosiglitazone, an insulin sensitizing thiazolidinedione anti- diabetic drug.
  • CRP CRP may also play a coordinating role by amplifying the proinflammatory activity of other adipokines. For example, it increases the expression and activity of PAI-1 in endothelial cells Plasminogen activator inhibitor-1 (PAI-1) suppresses fibrinolysis by inhibiting plasminogen activation, and is an active contributor to atherogenesis by promoting thrombus formation. Plasma PAI-1 levels are positively correlated with cardiovascular risk and mortality, and recently, the development of diabetes
  • Elevated CRP Levels in Obesity: NHANES 1988-1994 Percent with CRP > 0.22 mg/dL 25 20 15 10 5 0 Normal Overweight ObeseVisser M et al. JAMA 1999;282:2131-2135.
  • Inflammation of coronary artery Inflammation in a coronary artery produces a cascade of events that can prove fatal. Pretreatment with the antithrombotic agent clopidogrel prior to angioplasty and stenting reduced rates of myocardial infarction and death in patients with the highest levels of C-reactive protein, a marker of inflammation.
  • Serum Amyloid A Serum amyloid A (SAA) proteins are a family of apolipoproteins found predominantly associated with high-density lipoprotein (HDL) in plasma, with different isoforms being unequally expressed constitutively and in response to inflammatory stimuli. Serum amyloid A (SAA) is an acute phase reactant like CRP, which has been associated with systemic inflammation, linked to atherosclerosis and used as a predictor for coronary artery disease and cardiovascular outcome. SAA levels correlate significantly with insulin resistance and obesity in type 2 DM patients. Adipose tissue has been shown to express SAA at low levels under normal conditions but expression in adipose tissue is dramatically upregulated in the diabetic state. The increase in acute phase reactant proteins may affect lipid metabolism and thus contribute to the dyslipidemia associated with diabetes. Serum amyloid A displaces apolipoprotein A1 from HDL cholesterol, increasing HDL binding to macrophages, and thus, decreasing cardioprotective HDL cholesterol.
  • Enzymatic and protein changes within high-density lipoprotein (HDL) during an acute phase reactionCopyright ©2005 American College of Cardiology Foundation. Restrictions may apply.
  • Cardiovascular Metabolic Syndrome (Syndrome X)Low grade inflammation Prothrombotic stateHyperglycaemia CVD Dyslipidemia Hypertension Genetics+ Lifestyle
  • ObesityI.c. TG accumulationFree radical production β cell damage Insulin deficiency
  • Role of obesity in insulin resistance ↑ Caloric intake ↑ Free OxidativeVisceral Sedentary fatty acids stress InsulinObesity lifestyle ↑ Glucose resistance Inflammation Genetic ↑ Lipids factors Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.
  • Fat Cell Products and Hypertension  Visceral l Portal  Hepatic  Plasma Insulin Fat Stores FFA Clearance Insulin Vascular  Renal Na+ Constriction Reabsorption Angiotensinogen Angiotensin II Angiotensin I HypertensionBray GA. Contemp Diagn Obes. 1998.
  • Clinical manifestations of insulin resistance Type 2 diabetes and glycemic disorders Atherosclerosis Dyslipidemia Insulin resistance – Low HDL – Small, dense LDLVisceral Glucotoxicity – HypertriglyceridemiaObesity Lipotoxicity Hypertension ↓ Adiponectin Endothelial dysfunction/ inflammation (hsCRP) Impaired thrombolysis ↑ PAI-1 Courtesy of Selwyn AP, Weissman PN.
  • Hypertension Hyperinsulinemia can enhance renal sodium reabsorption and vascular reactivity Angiotensinogen from fat cells can increase angiotensin II and thus blood pressure Both systolic and diastolic blood pressure increase with increasing body mass index
  • Metabolic Syndrome, Insulin Resistance, and Atherosclerosis Hyperinsulinemia/hyperproinsulinemia Insulin resistance Glucose Increased Decreased Increased BP intolerance triglycerides HDL cholesterol Endothelial dysfunction Increased Small, dense PAI-1 LDL Atherosclerotic cardiovascular diseaseMacFarlane S et al. J Clin Endocrinol Metab. 2001;86:713-718.
  • Effects of Thiazolidinediones Mediated via Adipose Tissue Thiazolidinediones Adipose tissue PPARγ Decreased FFA and TNFα release Decreased tissue triglycerides Increased adiponectin Muscle Liver β-cell Vascular Increased Decreased Increased Increased glucose glucose insulin endothelial utilization output secretion functionAdapted from Goldstein BJ. Am J Cardiol. Suppl 2002.
  • FFA and Adipokines in Endothelial Dysfunction Increased visceral fat Thiazolidinediones Increased lipolysis Increased TNFα Decreased adiponectin Increased FFA levels - - - Insulin NO production Shear stress Endothelium Vascular dilationAdapted from Steinberg H et al. Diabetes. 2000;49:1231.
  • Medical Complications of ObesityPulmonary disease Idiopathic intracranialabnormal function hypertensionobstructive sleep apnea Strokehypoventilation syndrome CataractsNonalcoholic fatty liver Coronary heart diseasedisease Diabetessteatosissteatohepatitis Dyslipidemiacirrhosis HypertensionGall bladder disease Severe pancreatitisGynecologic abnormalities Cancerabnormal menses breast, uterus, cervixinfertility colon, esophagus, pancreaspolycystic ovarian syndrome kidney, prostate Osteoarthritis Phlebitis Skin venous stasis Gout
  • Potential therapeutic strategies associated with Nicotinic acid fatty acid metabolism HM74a Inducers Ligands A C Gi PGC1α Nuclear Inhibitors cAMP receptors PKA Fat Lipid mass? utilization ATGL HSL Lipolysis A combination of PGC-1α inducers and nuclear receptor Antilipolysis as a strategy to combat the ligands may constitute a strategy to combat obesity metabolic syndromeTrends Endocrinol Metab 2006 ;17 :314-320. Trends Endocrinol Metab 2003;14 :439-441.
  • adipokines and cardiovascular diseaseBoth abdominal (visceral) fat and insulin resistance may contribute to cardiovascular disease in obesity.
  • Summary of “adipocyte-vascular axis” and role of major adipocyte - derived factors (leptin resistin and ghrelin) in in the regulation of vascular and immune functions. Detailed description is provided in individual sections in the text of the paper.
  • PPAR signaling pathway
  • Proposed mechanisms for obesity-related hypertension
  • ROLE OF ADIPONECTIN IN THE REGULATION OF CARBOHYDRATE AND LIPID METABOLISM
  • The potential effects of adiponectin (and resistin) on adaptive immunity Tilg and Moschen Nature Reviews Immunology 6, 772–783 (October 2006) | doi:10.1038/nri1937
  • The Role of Adipocytokines in Adipocyte- Related Pathological Processes
  • Effects of obesity on growth-factor production
  • Effects of obesity on hormone production
  • Obesity, hormones and endometrial cancer
  • Molecular links between Obesity and Atheroslcerosis Among the adipokines, CRP and IL-6 are the two most strongly associated with increased cardiovascular disease risk and the prediction of future cardiovascular disease or type 2 diabetes. The wide-ranging direct effects of CRP on endothelial and smooth muscle cells argue favorably for CRP as a key cellular mediator linking obesity, the metabolic syndrome of insulin resistance and type 2 diabetes, to increased atherogenesis. Emerging data suggest the beneficial effects of TZDs, and possibly statins and ACEIs, may in part be mediated via the reduction of the levels and the direct effects of the adipokines on atherogenesis. Further investigations into the molecular links between obesity and atherosclerosis will unravel innovative therapeutic strategies to improve cardiovascular health in people affected by obesity linked insulin resistance, the metabolic syndrome and type 2 diabetes.
  • Anti- and proinflammatory adipokines
  • Effects of the metabolic syndrome of insulin resistance on endothelial dysfunction
  • Adipokines serve as the cellular mediators of the metabolic syndrome and endothelial dysfunction.
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceAdiponectin ↓ ICAM-1, VCAM-1, E-Selectin Plasma levels inversely correlated with obesity and insulin resistance ↓NFκB ↑ insulin sensitivity ↓transformation of macrophages to foam cells ↓ TNF-induced changes in adhesion molecule expression ↓ VSMC proliferation and migration
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin Resistance Adipokines Vascular action Insulin action and resistanceAngiotensinogen ↓ NO availability ↑ development of hypertension ↑ NFκB ↑ ICAM-1, V-CAM-, MCP-1 and M-CSF ↓ angiogenesis
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceCRP ↓ NO by destabilizing eNOS mRNA ↑ PAI-1 expression and activity and ↓ protein expression in endothelial cells ↑ ET-1 and IL-6 release ↑ VCAM-1, ICAM-1, selectins and CRP levels correlate with the MCP-1 in EC metabolic syndrome and predicts ↑ LDL uptake in EC future CHD ↓ angiogenesis ↑ apoptosis in EC predicts development of diabetes ↑ ROS ↑ SMC proliferation and migration Hyperglycemia potentiates and restenosis 73 proatherogenic action of CRP ↑ AT1-R on VSMC 11
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceIL-6 ↑ ICAM-1, E-Selectin, VCAM-1, ↑ preadipocyte differentiation MCP-1 ↓insulin receptor signal ↑ SMC proliferation and migration transduction ↑ systemic insulin resistance ↑ hepatic CRP production
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceLeptin ↑ NO by increasing eNOS ↑ glucose transport production ↑ ET-1 Reverses insulin resistance in ↑ proliferation and migration of EC lipodystrophy and VSMC ↑ ROS accumulation and oxidative ↑ sympathetic tone stress ↑ VSMC apoptosis ↑ blood pressure ↑ angiogenesis ↑ release of monocyte colony- stimulating factor ↑ cholesterol accumulation under hyperglycemia
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistancePAI-1 ↑ thrombus formation PAI-1 expression stimulated by TNF-α, ang II, FFAs ↑ restenosis
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceResistin ↑ ET-1 release ↑ insulin resistance in muscle and liver ↑ expression of adhesion molecules and chemokines ↓ glucose uptake and insulin action ↓ TRAF-3 TZD downregulates resistin expression
  • Effects of Adipokines on Vascular Homeostasis and the Metabolic Syndrome of Insulin ResistanceAdipokines Vascular action Insulin action and resistanceTNF-α NO bioavailability ↓ adipose cell differentiation ↓ insulin signal transduction ↓ vasodilatation ↑ systemic insulin resistance ↑ lipolysis ↑ NFκB via ROS ↑ FFAs ↑ VCAM-1, ICAM-1, E-selectin and MCP-1 in EC and VSMC ↑ apoptosis in EC
  • Peroxisomes proliferator activated receptors (PPAR) PPARs were originally cloned as nuclear receptors that mediate the effects of synthetic compounds called peroxisome proliferators on gene transcription. Three PPAR isotypes have been described: α, β, and γ. Binding of the ligands to these receptors results in activation of target gene transcription. Endocr Rev. 1999 Oct;20(5):649-88. The target genes of PPARs are involved in lipid transport and metabolism, including trans-membrane fatty acid uptake , fatty acid binding in cells, fatty acid oxidation in microsomes peroxisomes and mitochondria, as well as lipoprotein synthesis and transport. PUFA binds to all three receptors, while long chain unsaturated fatty acids (linoleic acid), branched chain fatty acids, Leukotriene B4 and eicosanoids bind mainly to PPAR α. Prostaglandin J2 and Prostaglandin 15-deoxy-D are the endogenous ligands for PPAR-γ.
  • PPAR isotypes PPAR-α is predominantly expressed in brown adipose tissue and liver as well as kidney heart and skeletal muscle. PPAR β has greatest expression in gut, kidney and heart. PPAR-β is linked to colon cancer . PPAR-β regulates the expression of acyl-CoA synthetase2 in the brain, thus playing a role in basic lipid metabolism. PPAR γ is mainly expressed in adipose tissue, and at lower levels in the colon, and immune system. No significant expression of PPAR-γ has been demonstrated in the skeletal muscle the main site of glucose disposal.
  • STAT The Signal Transducers and Activator of Transcription (STAT, also, called signal transduction and transcription) proteins regulate many aspects of cell growth, survival and differentiation. The transcription factors of this family are activated by the Janus Kinase JAK and dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
  • Janus kinase Janus kinase (JAK, or "Just another kinase") is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases[1]), but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of doorways, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity while the other negatively regulates the kinase activity of the first.
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