Metabolic abnormalities in obesity

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Metabolic abnormalities in obesity

  1. 1. Metabolic abnormalities in obesity<br />Bari Siddiqui M A<br />Shyam Prasad B R<br />
  2. 2. Energy Metabolism<br />Obesity is caused by excessive intake of calories in relation to energy expenditure over a long period of time.<br />The gastro intestinal tract has the capacity to absorb large amounts of nutrients.<br />Large increases in body fat can result from even minor but chronic differences between energy intake and energy expenditure <br />
  3. 3. Nutrient and Energy Model of Obesity<br />3<br />Obesity results from increased intake of energy or decreased expenditure of energy, as required by the first law of thermodynamics.<br />Energy Intake<br />Energy Expenditure<br />Adipose tissue<br />
  4. 4. Total energy expenditure(TEE) <br />Resting energy expenditure(REE)- represents the energy expended for normal cellular and organ function under post absorptive resting conditions- 70% of total TEE<br />Energy expended in physical activity – includes both volitional activity like exercise and non volitional activity like muscle contractions, maintaining posture- 20% of TEE<br />Thermic effect of food(TEF) – the energy expended in digestion, absorption and sympathetic nervous system activation after a meal<br />
  5. 5. Obese individuals have a greater rate of REE due to increased adipose tissue cell mass.<br />During non weight bearing activities obese individuals spend the same amount of energy as lean individuals but during weight bearing activities obese individuals spend greater energy on physical activity.<br />There is reduction in thermic effect of food due to insulin resistance and blunted sympathetic nervous system activity in obesity<br />Diet induced weight loss reduces REE by 15 to 30% <br />
  6. 6. Adipose tissue<br />Energy depots that store triglycerides during feeding and release fatty acids during fasting<br />Functions as endocrine organ and secretes<br /> - leptin<br /> - resistin<br /> - estrogens<br /> - tumor necrosis factor α<br />
  7. 7. Adipocyte formation<br />Obesity is associated with increased number of adipocytes.<br />Adipocytes are formed from fibroblast precursor by extra nuclear factors and signal transduction pathways for differentiation <br />Very early – Lipo protein lipase(LPL)<br />Early - Methyl Isobutyl Xanthine(MIX)<br /> - Dexamethasone<br /> - Insulin<br /> - Enhancer Binding Protein(EBP)<br />Intermediate – Peroxisome Proliferator Activated <br />Receptor(PRAR)<br />Late – EBPand adipocyte specific gene expression<br />
  8. 8. Triglyceride storage<br />The major function of adipocytes is storage of triglycerides <br />Triglycerides stored within adipose tissue constitute the body’s major energy reserve<br />Triglycerides yield 9.3 kcal/g upon oxidation <br />Stored as oil inside the fat cell<br />Most of the triglycerides in adipocytes is derived from chylomicrons and VLDL <br />
  9. 9. Regulation of storage<br />Lipo protein lipase(LPL) – is a key regulator of fat cell triglyceride uptake from circulating triglycerides.<br />LPL is synthesized by adipocytes.<br />The interaction of LPL with chylomicrons and VLDL release fatty acids from plasma triglycerides, which are then taken up by local adipocytes<br />
  10. 10. Testosterone<br />Growth hormone<br />Catecholamines<br />Tumor necrosis factor<br />Insulin<br />cortisol<br />LIPO PROTIEN LIPASE<br />Circulating chylomicrons and VLDL<br />Free fatty acids<br />ADIPOCYTES<br />
  11. 11. LIPOLYSIS<br /> Alterations in adipocyte lipolysis (triglyceride breakdown) is observed in obesity and results in increased release of fatty acids into the circulation by<br />1. Hormone sensitive lipase (HSL)<br />2. Adipose triglyceride lipase (ATGL)-ATGL is highly expressed in white adipose tissue with less expression in skeletal muscle, accounts for 60-70% of triglyceride lipase activity in adipose and appears to be essential for the control of normal weight<br />
  12. 12. HORMONE SENSITIVE LIPASE<br />insulin<br />catecholamines<br />adipocytes<br />free fatty acids<br />Esterification<br />Beta Oxidation<br />
  13. 13.
  14. 14. Dysregulation of fatty acid metabolism in obesity<br />
  15. 15. ENDOCRINE FUNCTION<br />The adipocyte produces and secretes a wide variety of hormones and cytokines (termed ‘adipokines’) that influence many biological processes, including substrate metabolism. <br />Adipose tissue uses adipokines as a communication tool to signal changes in its mass and energy status to other organs that control fuel usage, such as skeletal muscle and liver. <br />
  16. 16. LEPTIN<br /> Leptin is produced by adipose tissue to signal fat storage reserves in the body, and mediates long-term appetitive controls (i.e. to eat more when fat storages are low and less when fat storages are high). <br />
  17. 17. Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by<br /> 1. counteracting the effects of neuropeptideY <br /> (a potent feeding stimulant secreted by cells <br /> in the gut and in the hypothalamus)<br />
  18. 18. 2. Counteracting the effects of Anandamide <br />(another potent feeding stimulant that binds to <br />the same receptors as THC, the active ingredient <br />of marijuana); and <br /> 3. promoting the synthesis of α-MSH, an appetite <br />suppressant. This inhibition is long-term, in <br />contrast to the rapid inhibition of eating by <br />cholecystokinin (CCK) and the slower suppression <br />of hunger between meals mediated by PYY3-36.<br />
  19. 19. Ghrelin<br />Ghrelin is produced by the stomach modulating short-term appetitive control (i.e. to eat when the stomach is empty and to stop when the stomach is stretched)<br />
  20. 20. Ghrelin is secreted mainly by the stomach, <br /> Has paracrine or endocrine effects on GI motility<br />Circulate in the blood and act on CNS growth hormone secretagogue receptors (GHS-Rs) inside and outside the blood–brain barrier. <br />Known target areas in the CNS include the hypothalamus, the ventral tegmentum and nucleus accumbens, the hippocampus and GHS-R populations in the brainstem area. <br />The actions of ghrelin in the CNS contribute to the control of food intake and co-regulate tissue-specific cellular pathways in the periphery, thereby governing glucose, lipid and energy metabolism. <br />
  21. 21.
  22. 22. Central pathway<br />While Leptin and Ghrelinare produced peripherally, they control appetite through their actions on the central nervous system. In particular, they act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure.<br />
  23. 23. There are several circuits within the hypothalamus that contribute to its role in integrating appetite.<br />The melanocortin pathway being the most well understood. <br />The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.<br />
  24. 24. The Arcuatenucleus contains two distinct groups of neurons.<br /> The first group co-expresses NeuropeptideY (NPY) and Agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH<br />
  25. 25. The second group coexpressespro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript(CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH<br />
  26. 26. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding<br />Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group<br />
  27. 27. Lateral Hypothalamus<br />Arcuate Nucleus<br />Paraventricular Nucleus<br />FEEDING CENTER<br />Orexin<br />MCH<br />+<br />NPY/<br />AgRP<br />a-MSH<br /> CART<br />Peripheral<br />Adiposity<br />Signals<br />Appetite<br />LECTIN<br />NPY/<br />AgRP<br />a-MSH<br /> CART<br />CRH<br />Oxytocin<br />SATIETY CENTER<br />
  28. 28. SUMMARY<br />28<br />
  29. 29. Hedonic CNS Pathways<br />Morton G.J., et.al., Nature 443:289-295, 2006<br />
  30. 30. Homeostatic CNS Pathways<br />Morton G.J., et.al., Nature 443:289-295, 2006<br />
  31. 31. Genetics<br />Leptin gene mutations<br />Leptin receptor mutations<br />Prohormone convertase1 gene mutation<br />Pro-opiomelanocortin gene mutation<br />Melanocortin 4 receptor gene mutation<br />SIM1 gene mutation<br />
  32. 32. Medical Complications of Obesity<br />Pulmonary disease<br />abnormal function<br />obstructive sleep apnea<br />hypoventilation syndrome<br />32<br />Stroke<br />Cataracts<br />CHD<br />Diabetes<br />Dyslipidemia<br /> Hypertension<br />Nonalcoholic fatty liver disease<br />steatosis<br />steatohepatitis<br />cirrhosis<br />Severe pancreatitis<br />Gall bladderdisease<br />Cancer<br />breast, uterus, cervix<br />colon, esophagus, pancreas<br />kidney, prostate<br />Gynecologic abnormalities<br />abnormal menses<br />infertility<br />PCOS<br />Osteoarthritis<br />Phlebitis<br />venous stasis<br />Gout<br />

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