Metabolic abnormalities in obesity are caused by an imbalance between energy intake and expenditure over time. There are three main components of total energy expenditure - resting energy expenditure, the energy expended during physical activity, and the thermic effect of food. In obesity, resting energy expenditure is increased due to more adipose tissue, but the thermic effect of food is reduced. Adipose tissue stores triglycerides and also functions as an endocrine organ secreting hormones that influence metabolism. Dysregulation of lipid metabolism and adipokine secretion in obesity can lead to medical complications.

1. Metabolic abnormalities in obesityBari Siddiqui M AShyam Prasad B R

2. Energy MetabolismObesity is caused by excessive intake of calories in relation to energy expenditure over a long period of time.The gastro intestinal tract has the capacity to absorb large amounts of nutrients.Large increases in body fat can result from even minor but chronic differences between energy intake and energy expenditure

3. Nutrient and Energy Model of Obesity3Obesity results from increased intake of energy or decreased expenditure of energy, as required by the first law of thermodynamics.Energy IntakeEnergy ExpenditureAdipose tissue

4. Total energy expenditure(TEE) Resting energy expenditure(REE)- represents the energy expended for normal cellular and organ function under post absorptive resting conditions- 70% of total TEEEnergy expended in physical activity – includes both volitional activity like exercise and non volitional activity like muscle contractions, maintaining posture- 20% of TEEThermic effect of food(TEF) – the energy expended in digestion, absorption and sympathetic nervous system activation after a meal

5. Obese individuals have a greater rate of REE due to increased adipose tissue cell mass.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.There is reduction in thermic effect of food due to insulin resistance and blunted sympathetic nervous system activity in obesityDiet induced weight loss reduces REE by 15 to 30%

6. Adipose tissueEnergy depots that store triglycerides during feeding and release fatty acids during fastingFunctions as endocrine organ and secretes - leptin - resistin - estrogens - tumor necrosis factor α

7. Adipocyte formationObesity is associated with increased number of adipocytes.Adipocytes are formed from fibroblast precursor by extra nuclear factors and signal transduction pathways for differentiation Very early – Lipo protein lipase(LPL)Early - Methyl Isobutyl Xanthine(MIX) - Dexamethasone - Insulin - Enhancer Binding Protein(EBP)Intermediate – Peroxisome Proliferator Activated Receptor(PRAR)Late – EBPand adipocyte specific gene expression

8. Triglyceride storageThe major function of adipocytes is storage of triglycerides Triglycerides stored within adipose tissue constitute the body’s major energy reserveTriglycerides yield 9.3 kcal/g upon oxidation Stored as oil inside the fat cellMost of the triglycerides in adipocytes is derived from chylomicrons and VLDL

9. Regulation of storageLipo protein lipase(LPL) – is a key regulator of fat cell triglyceride uptake from circulating triglycerides.LPL is synthesized by adipocytes.The interaction of LPL with chylomicrons and VLDL release fatty acids from plasma triglycerides, which are then taken up by local adipocytes

10. TestosteroneGrowth hormoneCatecholaminesTumor necrosis factorInsulincortisolLIPO PROTIEN LIPASECirculating chylomicrons and VLDLFree fatty acidsADIPOCYTES

11. LIPOLYSIS Alterations in adipocyte lipolysis (triglyceride breakdown) is observed in obesity and results in increased release of fatty acids into the circulation by1. Hormone sensitive lipase (HSL)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

12. HORMONE SENSITIVE LIPASEinsulincatecholaminesadipocytesfree fatty acidsEsterificationBeta Oxidation

14. Dysregulation of fatty acid metabolism in obesity

15. ENDOCRINE FUNCTIONThe adipocyte produces and secretes a wide variety of hormones and cytokines (termed ‘adipokines’) that influence many biological processes, including substrate metabolism. 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.

16. LEPTIN 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).

17. Leptin acts on receptors in the hypothalamus of the brain where it inhibits appetite by 1. counteracting the effects of neuropeptideY (a potent feeding stimulant secreted by cells in the gut and in the hypothalamus)

18. 2. Counteracting the effects of Anandamide (another potent feeding stimulant that binds to the same receptors as THC, the active ingredient of marijuana); and 3. promoting the synthesis of α-MSH, an appetite suppressant. This inhibition is long-term, in contrast to the rapid inhibition of eating by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36.

19. GhrelinGhrelin 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)

20. Ghrelin is secreted mainly by the stomach, Has paracrine or endocrine effects on GI motilityCirculate in the blood and act on CNS growth hormone secretagogue receptors (GHS-Rs) inside and outside the blood–brain barrier. 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. 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.

22. Central pathwayWhile 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.

23. There are several circuits within the hypothalamus that contribute to its role in integrating appetite.The melanocortin pathway being the most well understood. 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.

24. The Arcuatenucleus contains two distinct groups of neurons. 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

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

26. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feedingBoth groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group

27. Lateral HypothalamusArcuate NucleusParaventricular NucleusFEEDING CENTEROrexinMCH+NPY/AgRPa-MSH CARTPeripheralAdipositySignalsAppetiteLECTINNPY/AgRPa-MSH CARTCRHOxytocinSATIETY CENTER

28. SUMMARY28

29. Hedonic CNS PathwaysMorton G.J., et.al., Nature 443:289-295, 2006

30. Homeostatic CNS PathwaysMorton G.J., et.al., Nature 443:289-295, 2006

31. GeneticsLeptin gene mutationsLeptin receptor mutationsProhormone convertase1 gene mutationPro-opiomelanocortin gene mutationMelanocortin 4 receptor gene mutationSIM1 gene mutation

32. Medical Complications of ObesityPulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome32StrokeCataractsCHDDiabetesDyslipidemia HypertensionNonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosisSevere pancreatitisGall bladderdiseaseCancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostateGynecologic abnormalitiesabnormal mensesinfertilityPCOSOsteoarthritisPhlebitisvenous stasisGout