Regulation of Body Weight

1. Regulation of Body Weight Regulation of body weight and set point theory. Leptin and body weight regulation. Melanocortin system: anorexigenic signaling. NPY and AGRP: orexigenic signaling. Putting it all together.

2. Theories of Obesity • Can BW be regulated in the face of high or low caloric consumption (Jules Hirsch, early 1970’s)??? • Subjects • 100 healthy male volunteers with stable body weight for at least 6 months • three groups: thin, healthy weight, and overweight • confined to a sedentary life in a metabolic ward of a hospital • Design • food availability was systematically varied to promote: • a 10% BW gain • a 10% BW loss • measurements: • body weight, body mass index • food intake • feelings of hunger/satiety • mood

3. 165 lbs + 10% 150 lbs - 10% 135 lbs “Fattening Phase” • forced to increase intake • hi fat diet • hi carbohydrate diet “Slimming Phase” • caloric restriction • low fat diet • low carbohydrate diet

4. 165 lbs + 10% 150 lbs - 10% 135 lbs • Results – Following a 10% body weight loss • increase in appetite • food obsessions • felt sluggish • decrease in metabolic rate • When given free access to food, subjects • consumed larger meals • consumed more frequent meals • re-gained the weight lost during the “slimming phase”

5. 165 lbs + 10% 150 lbs - 10% 135 lbs • Results – Following a 10% body weight gain • decrease in appetite • food aversions • bloating, gastrointestinal distress • increase in metabolic rate • When given free access to food, subjects • consumed smaller meals • consumed less frequent meals • chose foods that were low in fat content • lost the weight gained during the “fattening” phase

6. 165 lbs + 10% 150 lbs - 10% 135 lbs • Conclusions • body weight is a regulated variable • transient behavioral changes • (i.e., over/under-eating) induces • behavioral (appetite) and physiological • (metabolic) changes that help to “defend” • a person’s body weight increased satiety signaling • The Big Question…. • Well, there are actually 2…. • How does the brain sense the body’s • level of adiposity stores? • If our body weights are regulated, how does • one become overweight/obese or maintain • a significant weight loss? increased orexigenic signaling

7. leptin leptin brain Factors that Regulate Body Weight • Leptin • protein product of the ob gene (also called OB protein) • synthesized in white adipose tissue • secreted in proportion to body adiposity • functions as a hormone • binds to leptin receptor (OB-R) in the brain • acts on multiple brain regions (ARC, VMH, DMH) • expression is sexually dimorphic

8. Melanocortin System • family of peptides cleaved from the proopiomelanoocortin (POMC) precursor • POMC neurons are expressed solely in the arcuate nucleus (ARC) • one product of POMC neurons is aMSH aMSH POMC protein • aMSH • alpha-melanocyte-stimulating hormone • synthesized within POMC neurons; secreted from the PVN • binds with melanocortin receptors in the PVN (MC4 receptor) • decreases food intake • release of aMSH is regulated by leptin • POMC neurons contain leptin receptors (OB-R) • melanocortin receptor knockout mice

9. NPY • neuropeptide Y • neurotransmitter; widespread expression in the brain • multiple biological actions • suppress reproductive function • causes smooth muscle to relax • decreases grooming behavior (in rats!) • anxiolytic effects • increases food intake • synthesized in the arcuate nucleus (ARC) • secreted from the paraventricular nucleus (PVN) in • response to a decline in energy stores • central administration of NPY • increases food intake • increases fat storage • decreases metabolic energy expenditure • increases body weight

10. AGRP • agouti-related protein • synthesized in the ARC (co-localized with NPY) • secreted in the PVN • endogenous antagonist of MC-4 receptor • stimulates food intake and weight gain • also regulated by leptin

11. Activation of the Melanocortin System Inhibits Food Intake Satiety Signal Decrease in Food Intake PVN MC4-R ARC

12. + + Melanocortin System Is Modulated by Leptin Increased Satiety Signal Decrease in Food Intake PVN MC4-R OB-R Increased Leptin Secretion ARC

13. Melanocortin System Is Modulated by Leptin Decreased Satiety Signal Increase in Food Intake PVN - MC4-R OB-R + Decreased Leptin Secretion ARC

14. Orexigenic Signal Increase in Food Intake • AGRP • agouti-related protein • synthesized in the ARC (co-localized with NPY) • secreted in the PVN • endogenous antagonist of MC-4 receptor • stimulates food intake and weight gain • also regulated by leptin PVN ARC

15. Satiety Signal Decrease in Food Intake PVN + - ARC Dual Systems Function to Keep Body Weight Stable

16. How Does Leptin Regulate Body Adiposity? % body fat A)Healthy BW:Leptin secretion is stable and supports energy balance (FI = EE). B)Healthy BW:Decrease in leptin secretion signals a decrease in adipose stores and produces a positive energy balance (FI > EE). C)Healthy BW:Increase in leptin secretion signals an increase in adipose stores and produces a negative energy balance (FI < EE). D)Obese:Set point is elevated. Increase in leptin secretion fails to signal an increase in adipose stores and, thereby, fails to produce a negative energy balance (FI = EE). ** WHY ???

17. OVEREAT brain senses rise in plasma leptin 1) appetite is suppressed 2) metabolism increases Increased Leptin Secretion In an Individual with a Healthy Body Weight….

18. In an Overweight Individual…. OVEREAT brain senses rise in plasma leptin 1) appetite is not suppressed 2) metabolism doesn’t change Increased Leptin Secretion

19. In an Individual with a Healthy Body Weight…. Increased release of a-MSH Decreased release of AGRP Decreased release of NPY OVEREAT brain senses excessive calories 1) appetite is suppressed 2) metabolism increases Increased Leptin Secretion