21. CORRELATION CLINIC: OBESITY AND FUEL METABOLISM

Appetite regulation: central and peripheral signaling

*2 neurons:* *(a) POMC (anorexigenic) -- Leptin feeds into the POMC. Insulin activates POMC. POMC generates MSH. MSH is involved in repressing appetite and stimulating energy expenditure*. *(b) NPY (orexigenic) -- stimulated by ghrelin. stimulating appetite, decreasing energy expenditure* The hypothalamus contains two major types of neurons that regulate appetite and energy utilization, each with opposite actions.

*The role that AMPK plays in regulating energy status*

*AMPK Regulates Glucose -- Conserves ATP* *It prevents energy consuming anabolic pathways* *Increases catabolic pathways* *Decreases Insulin (major anabolic hormone) -- BUT INCREASES insulin sensitivity* *AMPK is increased when ATP is low and AMP is high* *Induced by LOW glucose* AMPK is a downstream target for many hormones including ghrelin, adiponectin and leptin AMPK activity is regulated both centrally and peripherally Peripheral activation of AMPK --> inhibition of energy consuming anabolic pathways Peripheral activation AMPK --> promotion of energy-generating catabolic pathways Exercise and adipokines (leptin and adiponectin) result in activation of AMPK --> phosphorylates and inhibits acetyl CoA carboxylase (ACC) activity --> reduces malonyl CoA synthesis --> activates carnitine palmitoyl transferase (CPT1) --> increases mitochondrial import and oxidation of long-chain acyl-CoA fatty acids in muscle. Leptin activates AMPK in muscle through two distinct mechanisms: 1. A direct effect through the leptin receptor in muscle 2. Mediated by the hypothalamic-sympathetic nervous system (SNS) axis through α adrenergic receptors in muscle.

Role of AMPK in the regulation of whole-body glucose homeostasis

*Fuel gauge of the cell. A cytoplasmic protein kinase, activated allosterically by AMP.* *AMPK is active during periods of low energy in the cell. Leads to the inhibition of anabolic pathways. Increases insulin sensitivity* AMPK is a downstream target for many hormones including ghrelin, adiponectin and leptin AMPK regulated centrally and peripherally Peripheral activation of AMPK leads to inhibition of energy consuming anabolic pathways Peripheral activation AMPK leads to promotion of energy-generating catabolic pathways

Congenital leptin deficiency

*Severe hyperphagia* -- hunger, food centered bx Extreme fat deposition (early onset) Significantly reduced 24 hr energy expenditure Impaired T-cell immunity Mild hyperinsulinemia Hypogonadotrophic hypogonadism

Model for the stimulatory effect of AMPK on fatty-acid oxidation in muscle

Exercise --> adipokines (leptin and adiponectin) --> activate of AMPK --> phosphorylates and inhibits acetyl CoA carboxylase (ACC) activity --> reduces malonyl CoA synthesis --> activates carnitine palmitoyl transferase (CPT1) --> increases mitochondrial import and oxidation of long-chain acyl-CoA fatty acids in muscle. Leptin activates AMPK in muscle through two distinct mechanisms: 1. A direct effect through the leptin receptor in muscle 2. Mediated by the hypothalamic-sympathetic nervous system (SNS) axis through α adrenergic receptors in muscle.

Change in BMI in US males and females since 1960

F as in Fat: How Obesity threatens America's Future By 2030 all 50 states could have adults obesity rates at least 44% with 13 states > 60%. Treatment costs for preventable obesity-related diseases predicted to add $48 to $66 billion to current costs estimated as $147 - $210 billion by 2030 Economic loss by 2030 predicted to be between $390 - $580 billion Obesity could contribute to more than 6 million cases of type 2 diabetes, 5 million cases of coronary heart disease and stroke, and more than 400,000 cases of cancer in the next two decades.

Peripheral hormones participating in the regulation of feeding behavior

Ghrelin Peptide YY (PYY) Glucagon-like peptide 1 (GLP-1)

*The biochemical signals regulating feeding*

Ghrelin Peptide YY (PYY) Glucagon-like peptide 1 (GLP-1) CKK? Removed influences: Leptin

Peripheral hormones participating in the regulation of feeding behavior Ghrelin

Ghrelin Synthesized and released from the stomach, unique post-translational motif. Binds to growth hormone secretagogue receptor (GHS-R). Stimulates NPY/AgRP neurons; orexogenic pathway Levels increase 2-fold before a meal and decrease within 1 hr after eating. Obese individuals low levels, while loss of weight causes increase. (High in anorexia nervosa). Levels negatively correlate with BMI. Ghrelin inhibition by caloric intake is diminished in obese patients Increase appetite in cancer patients with cachexia.

*Differences between normal weight and obese individuals in hormone levels and physiological responsiveness to hormones*

Ghrelin Response Pre-and postprandial plasma ghrelin response in normal-weight subjects. Shows more fluctuations in the levels of ghrelin in lean individuals. Pre- and postprandial plasma ghrelin response in obese subjects. Ghrelin is fairly consistent regardless of condition. Gastric banding does not seem to affect hormones

Peripheral hormones participating in the regulation of feeding behavior Glucagon-like peptide 1 (GLP-1)

Glucagon-like peptide 1 (GLP-1) Synthesized and released from L cells in distal intestine. Release occurs rapidly after eating and proportionally to food intake, satiety factor (feeling full). Acts centrally and on peripheral targets, major one is pancreas *Incretin hormone; increases glucose-dependant insulin secretion while inhibiting glucagon secretion*. Acts as ileal brake; slows gastric emptying and intestinal motility.

*The interplay between peripheral and central signaling*

Hypothalamus: two major types of neurons regulate appetite, have opposite actions. *Appetite stimulating (orexigenic)* produce Neuropeptide Y and Agouti-related protein (NPY/AgRP). NPY stimulates the NPY receptors (Y1R and Y5R). AgRP is an antagonist for the Melanocortin Receptor (MC3/4). *Appetite surpressing (anorexigenic)* neurons producing POMC and Cocaine and Amphetamine-Regulated Transcript (CART) release α-melanocyte stimulating hormone, (αMSH ) and CART. αMSH suppresses appetite (anorexigenic) by acting as an agonist to the MC3/4 receptors.

Adiponectin

Increase in BMI --> decrease in Adiponectin *Adiponectin signaling actives AMPK, increases glucose uptake and fatty acid oxidation in muscle, decreases liver gluconeogenesis, and decreases blood glucose levels.* Primarily secreted by white adipose cells, circulates as a homomultimer Circulating levels (5 - 30 ug/mL) are 1000x fold higher than leptin in normal weight individuals Levels correlate inversely with fat stores. *They are also inversely correlated with visceral adiposity and insulin resistance*. AdipoR present on most cell types Adiponectin plasma levels are low in obese individuals but increase following prolonged caloric restriction or weight loss.

Central action of leptin

Leptin is stimulating POMC --> makes MSH --> binds to melanocortin 3 and 4 activtors Leptin is inhibiting the NPY --> preventing orexogenic effects of NPY

appetite suppressing (anorexigenic)

Neurons producing Proopiomelanocortin and Cocaine and Amphetamine-Regulated Transcript (POMC/CART) release α-melanocyte stimulating hormone, (αMSH ) and CART. αMSH suppresses appetite (anorexigenic) by acting as an agonist to the MC3/4 receptors.

appetite stimulating (orexigenic)

Neurons producing the peptide neurotransmitters Neuropeptide Y and Agouti-related protein (NPY/AgRP). NPY stimulates the NPY receptors (Y1R and Y5R) while AgRP is an antagonist for the Melanocortin Receptor (MC3/4).

Bariatric weight loss surgical procedures

Not just a small stomach, but also an increase in the feeling of fullness hormones and insulin sensitivity. Stomach volume is reduced by banding and gastroplasty and in the case of by-pass the the stomach volume is reduced and small intestine is attached proximal to the pylorus. Affects both volume and absorption and is the most effective treatment for morbid obesity. Approximately 60 to 70 percent excess body weight is lost in the first year following Roux-en-Y surgery.

Peripheral hormones participating in the regulation of feeding behavior Peptide YY (PYY)

Peptide YY (PYY) Synthesized and released from the small bowel and colon. Inhibits the signaling of the NPY-AgRP neurons while stimulating the POMC neurons. Release occurs 15 min. after feeding (before arrival of nutrients) but continues with arrival of nutrients, potentiated by protein and fat, and increases as gut swells and by energy content of meal. Obese individuals have reduced levels but levels can increase following gastric bypass. Exogenous administration PYY increases satiety in obese individuals. Signals satiety, slows gut motility.

Adipokines: Leptin and Adiponectin

Primarily released from WAT

Interleulin-6 (IL-6)

Pro-inflammatory cytokine Released primarily by immune cells in adipose tissue but visceral adipocytes release more than sc adipocytes. Increases lipolysis and leptin secretion. Decreases lipoprotein lipase expression. Inhibits insulin signaling.

TNF-α

Pro-inflammatory cytokine. Released from visceral fat. Increases lipolysis and release of FFA. Decreases esterification of FA by down-regulating lipoprotein lipase and GLUT-4. Interferes with insulin receptor signaling. Inhibits adiponectin secretion.

Leptin

Product of the ob gene produced in adipocytes and binds to receptor similar to gp130 cytokine receptors. Circulating levels correlate with fat mass (BMI). Induces expression of α−MSH in POMC neurons and reduces the release of Neuropeptide Y (NPY), thereby suppressing appetite and stimulating energy expenditure. During starvation leptin levels decline thereby inducing appetite and reducing metabolic rates (no inhibition of NPY neurons). During weight gain levels increase repressing appetite and increasing metabolic rates. *Obese individuals exhibit leptin resistance* despite high levels of circulating leptin. Several possible mechanisms including poor transport across BBB, defective hypothalamic signaling and abnormal signaling in adipocytes. Loss of functional leptin results in severe hyperphagia, early onset obesity and hyperglycemia. In ob-deficient humans treatment with recombinant leptin reduces caloric intake and results in significant weight loss. Important in other physiological systems including both reproductive and the immune systems.

*The biochemical signals regulating feeding* GLP-1

Synthesized and released from L cells in distal intestine. Release occurs rapidly after eating and proportionally to food intake, satiety factor Acts centrally and on peripheral targets, major one is pancreas Incretin hormone; increases glucose-dependant insulin secretion while inhibiting glucagon secretion. Acts as ileal brake; slows gastric emptying and intestinal motility.

*The biochemical signals regulating feeding* PYY

Synthesized and released from the small bowel and colon. Inhibits the signaling of the NPY-AgRP neurons while stimulating the POMC neurons. Release occurs 15 min. after feeding (before arrival of nutrients) but continues with arrival of nutrients, potentiated by protein and fat, and increases as gut swells and by energy content of meal. Obese individuals have reduced levels but levels can increase following gastric bypass. Exogenous administration PYY increases satiety in obese individuals. Signals satiety, slows gut motility.

*The biochemical signals regulating feeding* Ghrelin

Synthesized and released from the stomach, unique post-translational motif. Binds to growth hormone secretagogue receptor (GHS-R). Stimulates NPY/AgRP neurons; orexogenic pathway Levels increase 2-fold before a meal and decrease within 1 hr after eating. Obese individuals low levels, while loss of weight causes increase. (High in anorexia nervosa). Levels negatively correlate with BMI. Ghrelin inhibition by caloric intake is diminished in obese patients Increase appetite in cancer patients with cachexia.

Chronic low level inflammation and obesity

TNF-α Interleulin-6 (IL-6)

Ghrelin response differs between normal weight and obese subjects

The level of ghrelin in the obese individuals is much reduced in obese individuals.

PYY and GLP-1 response is blunted in obesity

Try to replace hormones (PYY and GLP-1) to make obese people feel full --> caused nausea

*Weight reduction options*

https://www.youtube.com/watch?v=BOyebcrVWb4 Gastric Banding (Check out gastric bypass surgery)