Feeding Behavior/Obesity

1. Feeding Behavior/Obesity Stefany Primeaux, PhD Dept of Internal Medicine-Endocrinology Office: MEB, 7159D Phone: 568-2733 Email: sprime@lsuhsc.edu

2. Reading for this lecture Physiol Rev 85: 1131-1158; 2005

3. Why are we interested in learning about Feeding Behavior and Obesity? • The overconsumption of diets high in calories and fat are major contributors to the current rate in obesity. • Approximately 75 million adult Americans are considered OBESE. • In 2009, 33% of adults in Louisiana were considered OBESE. • Obesity is a major risk factor for cardiovascular disease, certain types of cancers and Type II Diabetes. Medical costs approximately $147 billion/year

4. Outline • Background • Energy Balance Equation • Obesity rates • Health Consequences • Peripheral Mechanisms • Adiposity Factors • Gut Hormones • Central Mechanisms • Hypothalamic Circuitry

5. Energy Balance Equation Energy IN Energy Intake Food/calories Consumed Energy expenditure Physical Activity Resting Metabolic Rate Energy OUT • ENERGY IN (calories consumed) = ENERGY OUT (calories burned) = weight same • Energy IN > Energy OUT= weight gain • Energy IN < Energy OUT = weight loss

6. Estimated Daily Calorie Requirements • Sedentary means a lifestyle that includes only the light physical activity associated with typical day-to-day life. • Moderately active means a lifestyle that includes physical activity equivalent to walking about 1.5 to 3 miles per day at 3 to 4 miles per hour • Active means a lifestyle that includes physical activity equivalent to walking more than 3 miles per day at 3 to 4 miles per hour HHS/USDA Dietary Guidelines for Americans, 2005

7. Obesity is a chronic metabolic disease resulting from an imbalance between energy intake and energy output • Obesity is caused by the interaction of multiple genetic and environmental factors. • Among these are: • Excessive calorie and food intake • Insufficient physical activity • Genetic predisposition • Family history of obesity • Individual metabolism • Behavioral factors • The defining feature is excess body fat

8. Percentage of individuals that are considered overweight or obese. Overweight = Body Mass Index (BMI) >25 Obesity = BMI >30 = 5’5” and 180lbs Louisiana: 1990 (10-14%) 1999 (20-24%) 2009 ( > 30%)

9. Health Consequences of Obesity • Coronary heart disease • Type 2 Diabetes • Cancer (endometrial, breast, colon) • Hypertension • Dyslipidemia • Stroke • Liver & gallbladder disease • Sleep apnea & respiratory problems • Gynecological problems • (abnormal menses, infertility)

10. Regulation of Food Intake • Due to the numerous health consequences of obesity, there is an emphasis on determining causes of and potential treatments for obesity. In order to understand and provide treatments for obesity and its comorbidities, we must understand the mechanisms which regulate feeding behavior.

11. Control of Food Intake Brain Many factors control appetite and influence food intake

12. Absorptive vs. Post-Absorptive State Gastrointestinal Tract We eat for energy! • Absorptive State • Ingested nutrients enter the blood from the GI tract • Break down of food provides nutrients • Some nutrients provide energy (carbohydrates) • Up to 4 hours after a meal • Post-absorptive State • GI tract is empty of food and nutrients • Body’s cells must supply energy (liver, adipose tissue) • When are we in the post-absorptive state?

13. Nutrient Metabolism During the Absorptive Period • Absorbed carbohydrate is primary energy source (converted to glucose) • Net uptake of glucose by the liver. • Some carbohydrate stored as glycogen in liver and muscle • Excess carbohydrate stored as fat in adipose tissue • Fat is stored in adipose tissue. • Some amino acids used to synthesize body protein. • Excess amino acids converted to fat. What is the primary source of energy during the absorptive period? Excess carbohydrates, fat and amino acids are stored as????

14. Nutrient Metabolism During the Post-absorptive Period • Glycogen, fat, and protein synthesis slow, net breakdown occurs • Formation of glucose in the liver • Gluconeogenesis in kidneys with prolonged fast. • Utilization of glucose by muscle and other non-neural tissues is reduced • Fatty acids released (lipolysis). • Fatty acids and ketones provide most of the body’s energy supply. • Brain uses glucose and starts using ketones as they build up in the blood. What is the primary source of energy during the post-absorptive period? Major goal is to maintain blood glucose levels

15. How is feeding behavior regulated? We might ask ourselves…. - Why do we feel hungry? - How do we know when to start eating? -How do we know when to stop eating? - Does being overweight/obese alter our eating behavior? Central and Peripheral mechanisms regulating feeding behavior

16. Peripheral Mechanisms regulating Feeding Behavior • Energy balance is regulated by central and peripheral signals • The central nervous system responds to signals from the periphery…adipose tissue, pancreas, liver and gastrointestinal tract What do these peripheral signals communicate?

17. Energy homeostasis is controlled by peripheral signals. Peripheral signals have a positive (+) or negative (-) effect on energy balance What does a negative effect mean? How do these signals affect feeding behavior? Positive effect? Figure 1 Stanley S et al. Physiol Rev 2005;85:1131-1158

18. Peripheral Signals-Adiposity signals Leptin • One of the most important hormones is leptin. • Leptin is expressed predominately in adipocytes • Leptin levels are highly correlated with adipose tissue mass • Food restriction decreases circulating leptin Considine, 2002 Leptin signals energy stores

19. Leptin • The more fat the more circulating leptin! KO Mice do not express the leptin gene Wildtype ob/ob Leptin Food Intake Ob/ob mice are hyperphagic and obese White et al., 2009

20. Leptin Resistance • The majority of obese animals and humans have raised plasma leptin. • Administration of leptin in rats with high fat diet-induced obesity does not reduce food intake • Circulating levels of leptin are higher in rats eating high fat diet Leptin resistance occurs when there is no response to leptin Low fat diet High fat diet White et al., 2009

21. Leptin Deficiency in Humans • Congenital leptin deficiency • Hyperphagia • Severe obesity • Hypogonadism • Impaired immunity Leptin treatment reduced food intake up to 80% Farooqi & O’Rahilly, 2009

22. Peripheral Signals: Gut Hormones Ghrelin • Endogenous agonist of the growth hormone receptor • Produced and released primarily by the stomach • Orexigenic hormone • Regulated by diurnal rhythms and food intake The only orexigenic gut hormone! What does this mean???

23. Ghrelin • Plasma ghrelin levels are highest during fasting and fall after a meal • Postprandial reduction in ghrelin is regulated by caloric intake and circulating nutritional signals (glucose) • Circulating ghrelin is inversely related to adiposity. Obese < ghrelin • Ghrelin administration increases food intake in rodents and humans Humans Druce et al., 2005

24. Energy homeostasis is controlled by peripheral signals. Peripheral signals have a positive (+) or negative (-) effect on energy balance How do these peripheral signals influence the brain???

25. Central Control of Feeding Behavior • Brain plays a critical role in the regulation of energy homeostasis • CNS circuits instantly assess and integrate peripheral metabolic, endocrine and neuronal signals • CNS coordinates a response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements • Two main types of afferent inputs to the brain from the peripheral organs that are relevant for energy homeostasis: Hormones & Neurons

26. Communication between the peripheral signals and the brain Brain Neuronal Vagus Nerve Fig. 4 Periphery—Hormones in circulation Stanley et al. 2005

27. The central control of appetite and feeding behavior • Hypothalamus is considered the main integrator and processor of peripheral metabolic information • Brain stem plays an important role in these processes • Other brain regions that influence feeding Interconnected regions Lesions of specific regions of the hypothalamus induce starvation (LH) or obesity (VMH) J Endocrinol. 2005 Feb;184(2):291-318

28. Hypothalamic Lesion Studies Lateral Hypothalamus Lesions Ventromedial Nucleus of the Hypothalamus Rat decreased food intake, also have sensory and motor deficits Rat continues to eat as long as it is provided with palatable food

29. Arcuate Nucleus of the Hypothalamus PYY Insulin Leptin Ghrelin • Arcuate Nucleus plays pivotal role in integration of signals regulating appetite • Contains receptors for peripheral hormones • Contains two key peptidergic systems: Neuropeptide Y and POMC (α-MSH) Stanley S et al. 2005

30. Central Signals: Neuropeptide Y • One of the most abundant and widely distributed neuropeptides in the CNS • ARC is the major site of NPY expression • NPY mRNA and release increase with fasting and decrease with feeding • Binds to g-protein coupled receptors Y1—Y6, which are located throughout the brain Ventromedial /Arcuate Nucleus * Primeaux, unpublished

31. Neuropeptide Y • Most potent orexigen known!! • Administration of NPY increases food intake, inhibits thermogenesis, suppresses sympathetic nerve activity, reduces energy expenditure • Also involved in alcohol intake, anxiety, seizure activity Larsen et al., 1999 Rhesus monkeys

32. Central Signals: Melanocortin System • Comprised of the peptide products of POMC cleavage, their receptors • α-MSH is one of the most potent anorexigenic brain signals. • AgRP is an endogenous ligand of melanocortin receptors, acts as an inverse agonist • MC3R and MC4R play a role in energy balance • POMC gene mutations or abnormal POMC peptide processing result in early-onset obesity and red hair • Approximately 4% of cases of genetic obesity in humans Arcuate N.

33. Melanocortin System Notice Yellow Coat This 5-yr-old boy is heterozygous for a mutation in MC4R. In addition to early-onset obesity and hyperphagia, this child has increased lean mass, accelerated linear growth, and severe hyperinsulinemia. Daily energy intake in male mice receiving normal or high fat chow -/- POMC KO mouse

34. We have discussed: • Peripheral Regulation of feeding behavior • Adiposity Signals: Leptin • Gut Hormones: Ghrelin • Central Regulation of feeding behavior • How peripheral signals affect the brain • Hypothalamus • Major Neuropeptides involved in feeding • NPY • POMC

35. What other factors influence Feeding Behavior? Visual, olfactory, auditory Modulatory Factors Genetic & Epigenetic Taste Non-homeostatic consumption Morrison & Berthoud, 2007

36. Outline • Background • Energy Balance Equation • Obesity rates • Health Consequences • Peripheral Mechanisms • Adiposity Factors • Gut Hormones • Central Mechanisms • Hypothalamic Circuitry