1. ADIPONECTIN: THE MOLECULE OF MILLENNIUM
Presented By:-
Dr. Ayush Kumar, PGT-1
Dept. Of General Medicine
2. Introduction
• Adiponectin, also known as adipocyte complement-related protein of 30 kDa
(Acrp30), was identified by different groups.
• Adiponectin is an adipokine abundantly produced and secreted by adipose tissues
and widely recognized for its antidiabetic, anti-inflammatory, antiatherogenic, and
cardioprotective effects.
• Adiponectin is a protein hormone of 244 amino acids that circulates in high
concentrations (5–30 μg/mL) accounting for 0.01% of total serum proteins.
Adiponectin expression and serum levels are decreased in obese patients, pigs, and
rodents.
3. Adiponectin Receptors
• Adiponectin acts through two major functionally distinct and ubiquitously
expressed receptors, AdipoR1 and AdipoR2; the former is the most abundant form
in skeletal muscle, whereas the latter is the most abundant form in the liver.
• In addition, AdipoR1 has a very strong affinity for gAdiponectin whereas
AdipoR2 has a very strong affinity for fAdiponectin.
• The adiponectin pathway depends on the molecular form of adiponectin, on the
relative abundance of its receptors, and on the target tissue.
4. Adipocyte-derived proteins with anti-diabetic actions include leptin, adiponectin, omentin and visfatin; other
factors tend to raise blood glucose including resistin, Tumor necrosis factor-α and Retinol-binding protein 4.
(Adapted from Mohamed-Ali et al and Rosen et al. LPL: Lipoprotein lipase; HSL: Hormone-sensitive lipase;
NEFA: Non-esterified fatty acids; ASP: Acylation stimulating protein; TAG: Triacylglycerol; TNF-α: Tumor necrosis
factor α; RBP4: Retinol-binding protein; IL6: Interleukin 6.
6. In Energy Metabolism
Adiponectin exhibits key metabolic functions on skeletal muscle and liver :
• In muscle, the insulin sensitivity functions of adiponectin are mediated via AMP kinase (AMPK) and peroxisome
proliferator-activated receptor α (PPARα).
• In liver, adiponectin activates glucose transport and inhibits gluconeogenesis via AMPK, whereas adiponectin
activates fatty acid oxidation and decreases inflammation through the PPARα pathway. Interestingly, activation of
AMPK seems to be mediated mainly by AdipoR1, whereas activation of PPAR-α seems to be mediated by
AdipoR2.
• In addition, adiponectin, in liver, enhances insulin sensitivity promoting phosphorylation of the insulin receptor and
of the adaptor protein insulin receptor substrate 1.
• In pancreas, adiponectin acts on cell proliferation stimulating insulin secretion. In adipose tissues, adiponectin
increases basal glucose uptake and enhances insulin-stimulated glucose uptake through AMPK activation .
7. In Inflammation
• Adiponectin exhibits protective activity in several inflammatory diseases including atherosclerosis,
CVDs.
• Moreover, adiponectin attenuates inflammation in endothelial, muscle, epithelial cells, and
macrophages mainly by AMPK and cyclic AMP-protein kinase A (cAMP-PKA) activation.
8. On Cell Proliferation
• Adiponectin, in fact, inhibits cell growth and induces apoptosis in dose-dependent manner both in
vitro and in vivo through different molecular pathways.
• Through AMPK stimulation, adiponectin counteracts carcinogenesis by p21 and p53 that in turn
regulate growth arrest and apoptosis in colon cancer cells.
• Moreover, tumor suppressor effects of adiponectin are mediated via AKT and ERK signaling
pathways in lung and pancreatic cell lines.
• In fact, in patients affected by breast and endometrial cancer, adiponectin levels are
decreased; inversely, in patients affected by lung, prostate, gastric, liver, pancreatic and
hematological, colon, and renal cancers adiponectin levels are increased.
9. Adiponectin and Obesity-Related Diseases
• The expansion of adipose tissues results in oxidative stress and inflammatory
responses.
• Moreover, through a cross talk between adipocytes and the immune system, a
significant infiltration in adipose tissue of immune and inflammatory cells is
generated increasing local and successively systemic levels of various
inflammatory cytokines.
• The dysregulation of cytokines and adipokines production strongly contributes to
the onset of several obesity complications as MetS, CVDs, respiratory disorders,
diabetic retinopathy, and cancer.
• We will focus on the role of adiponectin.
10. Metabolic Syndrome
• Metabolic syndrome (MetS), an emerging public health problem, is multiplex metabolic risk
factors associated with a 5-fold risk of T2DM and a 2-fold risk of CVDs.
• Recently, chronic low-grade inflammation has been implicated among the major factors in the
development of the MetS.
• The inflammatory state in MetS is represented by elevated concentrations of a variety of
inflammatory regulators such as C-reactive protein, TNF-α, resistin, IL-6, IL-8, visfatin, and
adiponectin. The latter is inversely related to both adiposity and proinflammatory cytokines.
• In addition, it was demonstrated that low HMW adiponectin levels are independently associated
with the development of MetS.
11. Hypertension
• The relationship between obesity and hypertension is well established and attributed to many
factors among which are sympathetic nervous system activation, endothelial dysfunction (caused
by increase in free fatty acids, oxidative stress), and an aberrant adipokine production.
• In fact, lower adiponectin levels are detected in adults with hypertension. Accordingly, total
adiponectin levels have been found to be lower in obesity-associated hypertensives than in lean
hypertensives or lean normotensives.
• Adiponectin is a biologically relevant modulator of vascular remodeling linking obesity and
vascular disease.
• Adiponectin protectively regulates blood pressure via brain- and endothelium-mediated
mechanisms
12. Chronic Kidney Disease
• Chronic kidney diseases (CKD) and various functional/structural lesions of the kidney
(glomerulomegaly, glomerulosclerosis, diabetic nephropathy, carcinoma of the kidney, and
nephrolithiasis) are correlated to obesity.
• The factors that are linked to the development of obesity include, among the others, energy intake
and hyperinsulinemia; furthermore, adipokines as leptin and proinflammatory cytokines, as well as
adiponectin, may contribute to renal injury.
• Endothelial dysfunction has been described as the main pathogenic mechanism responsible for
CKD while weight loss and restoration of adipokine levels represent crucial factors to ameliorate
the progression of renal diseases.
13. Obstructive sleep Apnea Syndrome
• Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent condition characterized by
repeated disruptions of breathing during sleep.
• Obesity is a major risk factor for OSA.
• Systemic inflammation and oxidative stress are thought to play key roles in the activation of a
variety of pathological mechanisms that are involved in OSA, including increased cardiovascular
sympathetic tone, impaired regulation of coagulation, impaired glucose metabolism, and
endothelial dysfunction.
• Adiponectin levels are significantly lower in patients with OSAS being related to its severity and
arterial oxygen saturation.
14. Diabetic Retinopathy
• Obesity is a risk factor for diabetic microvascular complications.
• In fact, the glucose levels in T2DM are responsible for the increased risk of both
microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular
complications (ischaemic heart disease, stroke, and peripheral vascular disease).
• Diabetic retinopathy, the most frequent diabetic microvascular complication, affects 30–
50% of all diabetic patients.
• Circulating levels of adiponectin decrease both in obesity and in T2DM.
15. Cancer
• Obesity is a risk factor for many cancers. The cross talk between macrophages, adipocytes, and epithelial cells via
obesity-associated hormones may enhance cancer risk and/or progression.
• It is well established that adiponectin is able to activate several intracellular pathways including AMPK, MAPK,
and PI3K/AKT.
• AMPK interferes with cellular growth signaling through mTOR, thus inhibiting the promotion of carcinogenesis.
• On the other hand, adiponectin activates AMPK in several cell lines promoting growth arrest and apoptosis via
increased p53 and p21 expression.
• Furthermore, growth factors activate PI3K which results in the phosphorylation of AKT that promotes cellular
growth and proliferation.
16. • Adiponectin treatment of breast and colorectal cancer cell lines decreases the phosphorylation of
PI3K and AKT while the phosphorylation is increased in lung and pancreas cell lines, leading in
both cases to a suppression of tumor growth.
• Adiponectin treatment on hepatocellular carcinoma cell line resulted in increased JNK activation
while on a lung cell line in ERK1/2 activation and subsequent apoptosis and suppression of cell
growth.
• On the contrary, endometrial and breast cancer cell lines showed that adiponectin inhibited ERK1/2
signaling, resulting in decreased cellular viability.
17. Chronic Obstructive Pulmonary Disease
• Obesity in COPD is associated with increased symptoms of dyspnoea, poorer health-related quality of life,
increased levels of fatigue, and exercise performance limitations.
• Low BMI is an independent risk factor for mortality in subjects with COPD, and this association is strongest in
subjects with severe disease.
• In humans, adiponectin serum levels are elevated in COPD patients. It is known that levels of total adiponectin are
low in smokers without COPD, while high levels are observed in COPD patients.
• Total serum levels of adiponectin represent a significant diagnostic and prognostic marker of COPD.
• Adiponectin inhibits NF-κB nuclear transactivation and induces the expression of the anti-inflammatory
IL10 cytokine via ERK1/2 and AKT through the specific mediation of AdipoR1.
19. Treatment
• Today, available treatments include combination of diet, physical exercise, and pharmaceutical regimens where
monoagent therapy is not as effective as combination ones.
• Bariatric surgery is considered the most efficient treatment in severely obese patients (BMI ≥ 40 kg/m2).
• Adiponectin, showing antihyperglycemic, antiatherogenic, and anti-inflammatory properties, could have important
clinical benefits such as enabling the development of therapies for the prevention and/or for treatment of obesity
and its obesity-related diseases.
• Various therapeutic approaches are targeted to increase adiponectin expression or its activity with different
strategies:
(1) caloric restriction and physical exercise,
(2) administration of inducers - Drugs like rosiglitazone and pioglitazone, metformin.
(3) administration of recombinant adiponectin, and
(4) peptide mimetic approaches.
20. Summary
• Obesity is a pandemic condition that leads to health impairment by increasing the
risk of developing diseases such as T2DM, MetS, CVDs, respiratory disorders,
and several types of cancer.
• The molecular mechanism underlying the development and establishment of
obesity needs to be better understood. At present, it is well recognized that fat
accumulation in obesity results in an altered expression of several hormones,
growth factors, and adipokines.
• Adiponectin may act as a protective and safe endocrine/paracrine/autocrine factor
to prevent the establishment and/or progression of lethal conditions related to
obesity.
• In this context, expression enhancement of adiponectin and its AdipoRs may
represent a useful therapeutic approach against obesity and obesity-related
diseases.
