Bariatric Times

NOV 2017


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INTRODUCTION Regulation of appetite and food intake is mediated by the gut-brain axis, in which several gut hormones and neuropeptides travel, either directly through the blood brain barrier or indirectly via vagus nerve currents. This intricate circuitry between the gut and brain centers such as the dorsal vagal complex and the hypothalamus controls appetite, gastric motility, and satiety. Neuropeptide pathways originate from three systems/responses: 1) adipose tissue, 2) gut response to nutrient sensing from food, and 3) gut response to mechanical stretch from food. These pathways carry appetite- related signals to the brain. 1 Variations in levels of these neuropeptides between individuals with obesity and individuals with normal weight have been identified. This research has led to the development of drugs and devices that attempt to modulate various pathways in this interrelated neuropeptide signaling scheme in individuals with obesity. Bariatric surgery has been shown to have a variable, yet sometimes drastic and sustainable, impact on levels of key peptides, such as ghrelin, leptin, and glucagon-like peptide-1 (GLP-1). 2 To date, most research on the epigenetics of obesity has focused on peptide signaling that influences appetite and food intake rather than energy expenditure. The key appetite-regulating neuropeptides will be explored herein. HYPOTHALAMUS AND BRAINSTEM SIGNAL PROCESSING TO CONTROL FOOD INTAKE The hypothalamus is the major target for appetite regulating peripheral peptides released from adipose tissue and gastrointestinal tract organs. These peptides can travel through the blood stream, cross the blood brain barrier, and interact directly with the hypothalamus by stimulating the arcuate nucleus (ARC) or indirectly simulating the ARC upon delivery from vagus nerve afferents. During indirect communication, signals travel along the vagus nerve first to the dorsal vagal complex (DVC) in the brainstem, then to the ARC, paraventricular nucleus (PVN) of the hypothalamus, or to higher brain centers. Within the ARC, there are two groups of neurons: orexigenic (neuropeptide Y [NPY] and agouti-related peptide [AgRP] releasing neurons) and anorexigenic (pro- opiomelanocortin [POMC] and cocaine- amphetamine related transcript [CART] releasing neurons). Both groups of neurons within the ARC contain receptors for several different neuropeptides. When NPY/AgRP neurons are stimulated, they send signals to other regions of the hypothalamus, such as the PVN and the lateral hypothalamus, to induce appetite. When POMC/CART neurons are stimulated, they signal to the same secondary regions of the hypothalamus to suppress appetite. These messages are then translated to higher brain centers, such as the amygdala and cerebral cortex, and it is within this complex circuitry that eating behavior is ultimately driven (Figure 1). 3 Hedonic input is coordinated in higher brain centers, and a "reward" pathway is created with certain foods. Dopaminergic and NPY receptors appear to be most closely linked to eating for reward. It should be noted that food composition, particularly w hen high in sugar and fat, can trigger an altered response of these gut hormones, which might allow a strong connection with the reward pathway and promote continued f eeding beyond the point of satiation; 4 however, further discussion of this is beyond the scope of this article. SATIETY PEPTIDES AND RESPONSE TO INGESTION OF FOOD The ARC contains receptors for various peptides. Perhaps the most important receptor in terms of appetite regulation, however, are ghrelin, glucagon-like peptide 1 (GLP- 1), peptide YY (PYY), oxyntomodulin (OXM), and leptin. Ghrelin is the body's most well-known orexigenic hormone. Ghrelin peaks right before meals, decreases sharply postprandially, and accelerates gastric emptying. Ghrelin works in opposition of the anorexigenic/satiety peptides. Table 1 describes the various adipose a nd gastrointestinal secreted peptides, their sites of release, their target receptors, and their effects on appetite. When food enters the stomach, the p hysical tension is sensed by vagal nerve afferents. Signals are then sent to the brain that cause the stomach to expand to accommodate the meal and contract to empty the meal through the pyloric sphincter. As food or chyme passes into the small bowel, enteroendocrine cells start to release GLP-1, cholecystokinin (CCK), and PYY in response to physical distension or sensing of nutrients. Once the level of nutrients reaches a certain point in the intestine, these peptides, mostly via negative feedback action in the brain, slow gastric emptying. The release of these peptides is also influenced by meal composition. The 10 Review Bariatric Times • November 2017 by APRIL SMITH, PharmD, MA, BCPS Bariatric Times. 2017;14(11):10–14. Neurohormonal Influences on Obesity A BSTRACT This article provides an overview of key peripheral peptides secreted from gut and adipose tissue that influence appetite and satiety. The author explores how and where these peptides interact with the hypothalamus, dorsal vagal complexes, and higher brain c enters. By exploring this neurohormonal circuitry, readers should be able to identify target receptors that could influence treatment strategies for obesity. The role of neurohormonal peptides in weight regain and the impact of bariatric surgery on these peptides are also discussed. KEYWORDS Ghrelin, glucagon-like peptide-1, peptide YY, leptin, insulin, amylin, arcuate nucleus, dorsal vagal complex, neurohormone, obesity FIGURE 1. Gut brain axis and processing of neuropeptides

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