1. بسم الله الرحمن الرحيم

2. Perfect survivor versus Ideal survivor By Dr Amr Abdelmonem,MD. Assistant professor of cardiothoracic anesthesia,surgical intensive care and clinical nutrition in faculty of medicine, Cairo university Member of North American Association For The Study Of Obesity

3. Perfect survivor

4. The perfect survivor must be able to eat and store as many calories as possible when food is readily available as a buffer against periods of scarcity. He must also reduce energy expenditure when food is scarce and efficiently and accurately restore lost adipose stores when food is again available.

5. Question 1: What Are the Signals from the Periphery and How Are They Sensed and Integrated Within Systems that Regulate Energy Homeostasis? Levin, BE. (2004) The drive to regain is mainly in the brain Am J Physiol Regul Integr Comp Physiol. 287,R1297-R1300 Woods, SC, Seeley, RJ. (2002) Understanding the physiology of obesity: review of recent developments in obesity research Int J Obes Relat Metab Disord. 26(Suppl 4),S8-S10 Horvath, TL, Diano, S. (2004) The floating blueprint of hypothalamic feeding circuits Nat Rev Neurosci. 5,662-667

6. CCK serotonin GLP-1 PYY(3-36) Ghrelin Glucagon Amylin NTS AP Arc NPY-AGRP ↑Feeding Vegally dependent ↑Satiety

7. Leptin NTS

8. Question 2: Why Do Some Individuals Eat Beyond Their Metabolic Needs? Levin, BE, Keesey, RE. (1998) Defense of differing body weight set-points in diet- induced obese and resistant rats Am J Physiol. 274,R412-R419 Clegg, DJ, Benoit, SC, Reed, JA, Woods, SC, Levin, BE. (2005) Reduced anorexic effects of insulin in obesity-prone rats and rats fed a moderate fat diet Am J Physiol Regul Integr Comp Physiol. 288,R981-R986 Levin, BE, Dunn-Meynell, AA. (2002) Reduced central leptin sensitivity in rats with diet-induced obesity Am J Physiol Regul Integr Physiol. 283,R941-R948 Levin, BE, Dunn-Meynell, AA, Banks, WA. (2004) Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling prior to obesity onset Am J Physiol Regul Integr Physiol. 286,R143-R150

9. Rationale Barry E. Levin. (2006) Central Regulation of Energy Homeostasis Intelligent Design: How to Build the Perfect Survivor Obes Res. 14:192S-196S

10. Inborn elevation in the threshold of the metabolic neurones located in the brain for detecting or responding to the inhibitory signals from the GIT,pancreas or adipose tissue These are present before they become obese Diet-induced obese is genetically programmed so that they can increase the adipose stores far above the metabolic needs when energy dense foods are abundant

11. Question 3: do perfect survivors overeat or eat in improper timing?

12. What happens with prolonged fasting ?

15. What happens when we eat? When we eat,our bodies break down the food into its basic components ( protein- carbohydrates- fat), and absorbs them into blood stream  rise in blood sugar  pancreas will release insulin  moves sugar into cells either burned for energy or stored away as fat in fat cells or glycogen in liver and muscles

16. In genetically programmed susceptible patients Hyperinsulinemia and hyperliptinemia

17. The role of insulin at fat cells

18. Lets walk through the fat metabolism pathway and follow the flow of fat molecules: Fat travels in the form of triglycerides  at cells  ezymatic breakdowen  fatty acids enter the cells mitochondria  breakdowen fat  in order to enter mitochondria,fats need carnitine  insulin inhibits Fat- carnitine shuttle system  fats move back into blood Insulin stimulates lipoprotein lipase that transports fatty acid into fat cells Insulin inhibits hormone sensitive lipase that releases the fat from fat cells into the blood

19. The Early Event is Increased intracellular triglycerides Shulman, GI. (2000) Cellular mechanisms of insulin resistance J Clin Invest. 106,171-176 Boden, G, Shulman, GI. (2002) Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction Eur J Clin Invest. 32(Suppl 3),14-23 Increased adipose tissue

20. Is the adipose tissue an endocrine organ ? The answer is

21. Defect in adenosine monophosphate –activated protein kinase Ruderman, N, Prentki, M. (2004) AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov. 3,340-351 No phosphorylation of the insulin receptors No intracellular signaling No translocation of glucose Insulin resistance

22. Disinhibition of the HSL Release of the FFA

24. Increased Hepatic gluconeogesis DeFronzo, RA, Bonadonna, RC, Ferrannini, E. (1992) Pathogenesis of NIDDM: a balanced overview Diabetes Care 15,318-368 Reduced glucose uptake by muscles Boden, G, Chen, X, Ruiz, J, White, JV, Rossetti, L. (1994) Mechanisms of fatty acid-induced inhibition of glucose uptake J Clin Invest. 93,2438-2446 Arner, P. (2002) Insulin resistance in type 2 diabetes: role of fatty acids Diabetes Metab Res Rev. 18(Suppl 2),S5-S9 [Santomauro, AT, Boden, G, Silva, ME, et al (1999) Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects Diabetes 48,1836-1841 Peterson FK,Shulman IG. new insights into the pathogenesis of insulin resistance in humans using magnetic resonance spectroscopy.Obes Res 2006;14s:34s Hyperinsulinemia and insulin resistance

25. Role of free fatty acid Beta cells Insulin Reduction of FFA Persistent drive IR 11 β-hydroxysteroid dehydrogenase 1 Cortisol Cytokines 1.Inhibition of insulin receptors 2.Suppression of secretion of adiponectin

27. Home message

28. Meals are the biological units of eating behavior in humans,and the gut – brain axis is a critical neural network in the control of energy intake and meal size Survival of species is dependant on the development of systems that drive the individual to seek and ingest food and to conserve energy stores during times of low food availability This is an excellent survival strategy when food is only intermittently available but would promote the development of obesity in such individuals in our modern human society Understanding the neurobiological, pathophysiological and biochemical natures of the perfect survivors will enable physicians and scientists to switch them to be ideal survivors