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 obesity Bari Siddiqui M A Shyam Prasad B R

2. Energy Metabolism Obesity 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 Obesity 3 Obesity results from increased intake of energy or decreased expenditure of energy, as required by the first law of thermodynamics. Energy Intake Energy Expenditure Adipose 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 TEE Energy expended in physical activity – includes both volitional activity like exercise and non volitional activity like muscle contractions, maintaining posture- 20% of TEE Thermic 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 obesity Diet induced weight loss reduces REE by 15 to 30%

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

7. Adipocyte formation Obesity 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 storage The major function of adipocytes is storage of triglycerides Triglycerides stored within adipose tissue constitute the body’s major energy reserve Triglycerides yield 9.3 kcal/g upon oxidation Stored as oil inside the fat cell Most of the triglycerides in adipocytes is derived from chylomicrons and VLDL

9. Regulation of storage Lipo 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. Testosterone Growth hormone Catecholamines Tumor necrosis factor Insulin cortisol LIPO PROTIEN LIPASE Circulating chylomicrons and VLDL Free fatty acids ADIPOCYTES

11. LIPOLYSIS Alterations in adipocyte lipolysis (triglyceride breakdown) is observed in obesity and results in increased release of fatty acids into the circulation by 1. 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 LIPASE insulin catecholamines adipocytes free fatty acids Esterification Beta Oxidation

14. Dysregulation of fatty acid metabolism in obesity

15. ENDOCRINE FUNCTION The 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. Ghrelin 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)

20. Ghrelin is secreted mainly by the stomach, Has paracrine or endocrine effects on GI motility Circulate 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 pathway 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.

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 feeding Both 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 Hypothalamus Arcuate Nucleus Paraventricular Nucleus FEEDING CENTER Orexin MCH + NPY/ AgRP a-MSH CART Peripheral Adiposity Signals Appetite LECTIN NPY/ AgRP a-MSH CART CRH Oxytocin SATIETY CENTER

28. SUMMARY 28

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

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

31. Genetics Leptin gene mutations Leptin receptor mutations Prohormone convertase1 gene mutation Pro-opiomelanocortin gene mutation Melanocortin 4 receptor gene mutation SIM1 gene mutation

32. Medical Complications of Obesity Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome 32 Stroke Cataracts CHD Diabetes Dyslipidemia Hypertension Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Severe pancreatitis Gall bladderdisease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Gynecologic abnormalities abnormal menses infertility PCOS Osteoarthritis Phlebitis venous stasis Gout