PowerPoint PresentationSlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Metabolic Integration 2:Energy balance, the “diabesity” epidemic, biochemistry of nutrition and exerciseBioc 460 Spring 2008 - Lecture 41 (Miesfeld)Leptin is released from visceral fat and controls neuronal signaling in the brain James Neel, M.D., proposed the term “thrifty gene” to explain the role of genes and lifestyle in “diabesity”MetforminMetformin•Energy balance refers to the metabolic state in which the Calories contained in the metabolic fuel you consume are equal to the Calories you expend as a result of chemical reactions in the body, muscle contraction, and thermogenesis. •Leptin is a peptide hormone that is secreted by visceral adipose tissue in proportion to the amount of stored lipid. Since leptin inhibits appetite and increases energy expenditure, it may represent a molecular “fat-o-stat.” •Choosing oils that low in saturated fats, and carbohydrates with a low glycemic index, can add value to your food. Metabolic regulation and signal transduction through AMPK and PPAR appear to be key components of this mechanism.•Studies have suggested that regular moderate to intense physical exercise can stimulate signaling pathways in muscle cells that reduce the risks of cardiovascular disease even if this regimen does result in significant weight loss.Key Concepts in Metabolic IntegrationThe “Diabesity” EpidemicAlmost two-thirds of adults in the United States are either overweight (BMI of 25-30) or obese (BMI >30), and nearly one-third of children ages 6-18 fit these same descriptions. Moreover, the incidence of type 2 diabetes in children has increased ten-fold in the last 15 years.Metabolic Energy BalanceThe concept of energy balance can be used to explain how energy input (food calories) and energy expenditure (basal metabolism, physical activity, exercise) alter metabolic homeostasis to bring about a measurable weight gain or weight loss as reflected in the amount of stored fat in the body. By consuming an extra ~115 calories/day for a month (total of ~3500 calories), you will add one pound of stored fat to your body.The Thrifty Gene HypothesisJames Neel, a University of Michigan physician scientist proposed his thrifty gene hypothesis to explain the genetic basis for obesity and diabetes. Neel proposed that humans contain gene variants (thrifty genes) that favor individuals with a capacity to store extra fat during times of feast as a way to prolong survival during times of famine.Pima Indians of southern Arizona have rates of obesity and type 2 diabetes that are among the highest in the world. However, a second population of Pima Indians in northern Mexico that are genetically similar and speak the same language, weigh on average 57 pounds less than their Arizona relatives and the incidence of diabetes is almost nine times lower.The Thrifty Gene Hypothesis Neel argued that while this genetic background was a good thing to have when humans depended on a hunter and gatherer lifestyle, these same thrifty gene variants become disease genes in a modern society where high fat foods and sedentary lifestyles are common.While it is still not clear what the most likely candidates are for these thrifty genes, key suspects include signaling proteins that control metabolic homeostasis and genes encoding glucose and lipid metabolizing enzymes.Leptin Controls Appetite and Energy ExpenditureA major breakthrough in obesity research came in 1994 when Jeffery Friedman and his colleagues at Rockefeller University identified a gene mutation in a strain of obese mice called OB (obese). The mutant gene was named leptin after the Greek word leptos which means thin. Friedman's lab demonstrated that the molecular defect in a second strain of obese mice called DB (diabetic), was in fact due to a mutation in the leptin receptor. The phenotypes of OB and DB mice are very similar in that both are grossly overweight and have elevated levels of glucose and insulin in the serum due to insulin-resistance.Leptin may be a type of“fat-o-stat”Following a period of positive energy balance, fat stores increase, which results in elevated serum levels of leptin and subsequent activation of neuronal signals that decrease appetite and increase energy expenditure. This returns the body to its normal set point weight.Leptin may be a type of “fat-o-stat”Leptin receptor activation in the hypothalamus controls appetite and energy expenditure through a complex hierarchical neuronal signaling scheme that involves first order and second order neurons. Basically, leptin activates neurons in the brain that relay the message to stop eating and start exercising, while at the same time, inhibiting neurons that normally relay the message to eat more and exercise less. Insulin has a similar effect on these same neurons.Two peptide hormones synthesized in the stomach (ghrelin), and small intestine (PYY3-36), also control appetite and energy expenditure. Ghrelin signals hunger when there is no food in the intestine, whereas, PYY3-36 signals full when food is in the intestine.Based on the function and localized secretion of ghrelin and PYY3-36, why is it good advice to eat slowly if you are trying to lose weight?Why does it make sense that leptin and insulin have the same effect on neuronal signaling, what signal are they each sending to the brain?Metabolic link between obesity and type 2 diabetesInsulin-resistant type 2 diabetes is distinct from type 1 diabetes in that type 1 diabetes is due to insufficient insulin production by the pancreatic cells, whereas, type 2 diabetes is characterized by desensitization of insulin receptor signaling. As shown by a glucose tolerance test, both type 1 and type 2 diabetes are associated with elevated serum glucose levels and abnormal glucose clearance kinetics, however, only type 1 diabetes has a normal response to insulin treatment.Metabolic link between obesity and diabetesResearch over that past twenty years have implicated that both genes and environment contribute to the development of obesity and type 2 diabetes. In many cases, obesity leads to prediabetic symptoms that are characterized by elevated levels of serum glucose (hyperglycemia) and over-production of insulin (insulinaemia). If this condition
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