بسم الله الرحمن الرحيم

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 universityMember of North American Association For The Study Of Obesity

Perfect survivor

• 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.

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-R1300Woods, 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

CCKserotonin

GLP-1PYY(3-36) Ghrelin

Glucagon Amylin

NTS AP

Arc

NPY-AGRP

↑Feeding

Vegally dependent

↑Satiety ↑Satiety

Leptin NTS

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

Rationale Barry E. Levin . (2006) Central Regulation of Energy Homeostasis Intelligent Design:

How to Build the Perfect Survivor Obes Res. 14:192S-196S

• 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

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

What happens with prolonged fasting ?

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

In genetically programmed susceptible patients

Hyperinsulinemia and hyperliptinemia

The role of insulin at fat cells

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 cellsInsulin inhibits hormone sensitive lipase that releases the fat from fat cells into the blood

The Early Event is

Increased intracellular triglyceridesShulman, 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

Is the adipose tissue an endocrine organ ?

The answer is

Defect in adenosine monophosphate –activated protein kinaseRuderman, 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

Disinhibition of the HSL

Release of the FFA

Increased Hepatic gluconeogesisDeFronzo, RA, Bonadonna, RC, Ferrannini, E. (1992) Pathogenesis of NIDDM: a balanced overview Diabetes Care 15,318-368

Reduced glucose uptake by musclesBoden, 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

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

Home message

• 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