WEEK 4 Lecture Homeostatic regulation of energy balance

1. WEEK 4 LectureHomeostatic regulation of energy balance Bonnie Beezhold, PhD, CHES Assistant Professor, Nutrition Benedictine University

2. Experimental obesity studies of Sims et al, 1973 Figure 1. Evidence from “Experimental Obesity in Man” studies (adapted from Sims et al. illustrating key aspects of the regulation of energy balance. After a baseline period, this subject was incentivized to overeat for a period of approximately 25 weeks, and experienced approximately a 20% body weight gain. By inference, his energy expenditure greatly increased at weight plateau, and once the monetary incentive was discontinued (at approximately week 25) his caloric intake approached zero until the time he returned to his pre-study body weight. The data demonstrate regulation of both appetite (suppressed) and energy expenditure (increased) in response to positive energy balance (achieved experimentally) and weight gain. Pediatric Blood & CancerVolume 58, Issue 1, pages 149-153, 23 SEP 2011 DOI: 10.1002/pbc.23376http://onlinelibrary.wiley.com/doi/10.1002/pbc.23376/full#fig1

3. Homeostatic energy regulation • Complex, many cues • Short-term processes control meal initiation and termination, also inter-meal interval • Long-term processes control stability of fat mass

4. Gut-brain axis http://scientopia.org/ Neural and endocrine signals from and to the brain and gut affect energy expenditure via the autonomic nervous system.

5. The hypothalamus in the diencephalon receives inputs from the nucleus of the solitary tract (NTS) in the medulla oblongata. This nucleus collects all of the visceral sensory information from the vagus nerve such as gut distension and relays it to the hypothalamus and other targets. The arcuate nucleus (ARC) is located in the mediobasal hypothalamus at the base of the brain and is an important relay center for inflow of energy regulatory signals.

6. Factors that affect homeostatic feeding Neural signals resulting from mechanical distension and chemical stimulation by nutrients present in the gut Bloodborne signals related to body energy stores resulting from nutrient or hormone levels such as low plasma glucose levels (stimulates hunger) Hormones and neurotransmitters circulating in the blood such as insulin (depresses hunger) and epinephrine (stimulates hunger) Orexigens and anorexigensare chemicals released that influence feeding behavior

7. Adiposity negative feedback signaling • Signal is circulating at levels proportional to body fat content • Signal is able to enter the CNS and regulate homeostatic neurons • Signal is able to reduce food intake and/or increase energy expenditure • If deficient, this signal leads to hyperphagia LEPTIN

8. Farooqi et al, 1999

9. Another adiposity signal • Very anabolic, stimulating macronutrient uptake and synthesis • Leads to energy storage • Deficiency does not lead to obesity but its presence reduces food intake INSULIN

10. Adiposity signaling and the arcuate nucleus (ARC) • Expresses NPY (anabolic), inhibited by leptin and insulin, becomes active when these hormones are low – stimulates feeding • Expresses POMC (catabolic), activated by elevated leptin and insulin, release α-MSH – stimulates satiety

11. Melanocortin system Neurons in the ARC produce two opposing types of peptides. One type produces NPY and AgRP which STIMULATE appetite. POMC (pro-opiomelanocortin) neurons in the ARC produce alpha-melanocyte-stimulating hormone (ά-MSH) which acts on the melanocortin-4 receptor (MC4R) and SUPPRESSES appetite and increases metabolism of fat and lean body mass.

12. Melanocortins POMC neurons (ά-MSH system) are inhibited; NPY promotes hunger, inhibits satiety  weight gain (endogenous antagonist of MC4 receptor) http://www.nature.com/nrn/journal/v5/n8/fig_tab/nrn1479_F2.html#figure-title

13. Satiety signaling • Satiety: the absence of hunger resulting from circulating nutrients and hormones • Determines length between meals • Satiation: the feeling of fullness resulting from the presence of food in the gut relayed by nervous and hormonal signals • Determines meal termination

14. Example: CCK • Secreted by enteroendocrine cells into the intestinal lumen of stomach and SI in response to chyme • Stimulates gallbladder contraction, pancreatic enzyme secretion, inhibition of gastric emptying • Stimulates fibers of vagus nerve that synapse in nucleus of the solitary tract (NTS)

15. Adiposity and satiety signaling • How are these integrated? • Melanocortin 4 receptors (MC4R) mediates the CNS actions of leptin to enhance the satiety effects of CCK • MC4R increases the CNS response to satiety signals in animal studies • So…leptin limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals (Blevins et al, 2008; Morton et al, 2005)

16. What happens when body mass rises? • Insulin and leptin go up and at high body mass circulate at high levels • No longer regulate energy intake/expenditure at high fidelity! • Hormones/peptides have attenuated effect • Without effective negative adiposity feedback signaling, weight loss efforts are not ultimately successful

17. Adaptations to the weight-reduced state (reduced- obese) • Reduced EE due to drop in REE, TEF, activity • Reduced fat oxidation • Increased energy intake due to changes in homeostatic signals and response to non-homeostatic signals

18. Changes in appetite with weight loss • Inappropriate sensing of changes in energy balance and failure to properly compensate • Adiposity signals are reduced, reducing satiety signaling and increasing hunger • Neuronal responses to food in the brain is similar in obese and non-obese

19. Hunger and satiety in the reduced-obese state Mean (± SEM) pre-meal hunger (A) and post-meal satiety (B) during eucaloric and overfeeding diet periods are shown. Overfeeding resulted in significant reductions in mean pre-meal hunger and increases in mean post-meal satiety in thin as compared to reduced-obese individuals. M.A. Cornier, G.K. Grunwald, S.L. Johnson and D.H. Bessesen, Effects of short-term overfeeding on hunger, satiety, and energy intake in thin and reduced-obese individuals. Appetite,  43  (2004), pp. 253–259

20. Oxyntomodulin • Released postprandially from the gut in proportion to kcals consumed • It binds to the GLP-1 receptor in ARC and inhibits gastric acid secretion, reduces food intake, and promotes energy expenditure

21. A double-blind, placebo-controlled study was performed in which 15 healthy overweight and obese volunteers were trained to give themselves oxyntomodulin injections under the skin, just before each meal, three times daily. Food intake and energy expenditure were measured over four days and compared with a similar period during which the same volunteers administered a saline placebo. Food intake was provided in excess and the volunteers ate until they felt full. Activity-related energy expenditure was calculated from combined heart rate and movement monitoring in the participant’s normal environment. REE was calculated using indirect calorimetry. A.After an injection of oxyntomodulin, volunteers ate on average 128 Kcal or 17.3% less without altering their enjoyment of food. B.The participants’ energy expenditure due to activity was markedly increased by 143 Kcal/day or 26.2% during the period of oxyntomodulin treatment. C. The increase in activity resulted in an increase in total energy expenditure of 9.4%, although REE was unchanged. D. These overweight and obese people started with expected low levels of physical activity, but oxyntomodulin administration increased physical activity back toward normal levels, resulting in more energy being used each day. These findings suggest that oxyntomodulin has a double effect of suppressing appetite and concurrently increasing physical activity toward normal levels. Wynne et al, 2005, 2006

22. Bottom line • After weight loss, energy balance-related biologic signals are powerfully enhanced to promote increased energy intake and reduced energy expenditure, setting up for weight regain • Therapies targeting appetite circuits and administering low doses of a combination of gut hormones appear more promising than therapies targeting the central nervous system