The Brain GutBrain Axis in the Regulation of Food Intake

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The Beta Switch Program by Sue Heintze

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The hypothalamic mechanisms regulating food intake and energy metabolism occur via interaction of the monoaminergic and the neuropeptidergic systems at various levels in the nervous system. The important components of these interactions include: (1) early satiety signals from the gut relayed via gastrointestinal afferent vagal fibres to

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Fig. 1. Pattern of changes in (a) food intake (g per 24 h), (b) meal number (meals per 24 h), and (c) meal size (g/meal). Anorexia developed 18 days after tumour inoculation in tumour-bearing rats on chow (TB-Chow). * p < 0.05 vs. non-tumour-bearing chow-fed rats (NTB-Chow), non-tumour-bearing rats fed rn-3 fatty acids (NTB-rn-3 FA) and tumour-bearing rats fed rn-3 fatty acids (TB-rn-3 FA). (From [15])

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Fig. 1. Pattern of changes in (a) food intake (g per 24 h), (b) meal number (meals per 24 h), and (c) meal size (g/meal). Anorexia developed 18 days after tumour inoculation in tumour-bearing rats on chow (TB-Chow). * p < 0.05 vs. non-tumour-bearing chow-fed rats (NTB-Chow), non-tumour-bearing rats fed rn-3 fatty acids (NTB-rn-3 FA) and tumour-bearing rats fed rn-3 fatty acids (TB-rn-3 FA). (From [15])

the liver and the dorsovagal nuclei (visceral relay nuclei) in the brainstem that project onto the hypothalamus [16]; (2) effects of changing circulating glucose, amino acid, and fatty acid concentrations on the activity of nutrient-related neurons in vis ceral relay nuclei and hypothalamus [17]; (3) hormone (ghrelin, cholecystokinin, polypeptide YY, insulin, and leptin) signals acting on the dorsal vagal complex and hypothalamus; hormones such as cholecystokinin (CCK) can also send messages to the brain via the gastric branch of the vagus nerve [18]; (4) changes in neurotransmitters and peptides in food-intake-related nuclei [19, 20], (5) control of the hypothalamic-pituitary-adrenal axis and sympathetic and parasympathetic output to immuno-endocrine organs, including the gastrointestinal tract, liver, adrenals, and pancreas; and (6) hypo-thalamic mechanisms regulating thyroid function, which is also important for energy expenditure [21].

Aspects of the gut-brain axis are discussed in Chap. 9.8. Gut hormones (Fig. 2) regulating food intake can be separated into short-term and long-term mediators. The former mediators are meal-related signals that act in accordance with the daily circadian rhythm of food intake and participate in a meal-to-meal control system. CCK and ghrelin have been implicated in the short-term and long-term (ghrelin) regulation of food intake, and have opposite actions on appetite. CCK is released from the gastrointestinal tract during eating and promotes a sense of fullness that encourages the end of

Fig. 2. Gut-brain hormonal axis. (Reproduced with permission from [22])

the meal [23]. Ghrelin is an appetite-stimulating hormone, blood concentrations of which rapidly increase just before a meal. At the end of the meal, ghrelin concentration falls rapidly, decreasing appetite [24]. Apart from insulin, whose role and actions are well defined, another long-term mediator of food intake is leptin, which is released into the blood by adipocytes. Leptin has sustained inhibitory effects on food intake and increases energy expenditure. When blood leptin concentrations decline, which occurs with a loss of adipose tissue, sensory neurons in the brain stimulate an increase in appetite [25]. Gut hormones, including pancreatic polypeptide and polypeptide Y3-36 are also involved in the intermediate-term regulation of food intake. Pancreatic polypeptide (PP) produces a rapid and prolonged reduction in food intake when injected peripherally while central administration increase food intake in animal models. Polypeptide Y3-36, which is secreted by endocrine cells of the small bowel and colon [26, 27], inhibits food intake for up to 12 h in humans and rodents [27]. Another well-known and well-characterised peptide is neuropeptide Y (NPY), which acts in the hypothalamus to increase food intake. PP, polypeptide Y, and NPY increase food intake when administered into the brain, while peripheral administration of PP produces inhibitory effects on feeding.

As shown in Fig. 3, the arcuate nucleus (ARC) synthesises NPY and agouti-related peptide (AgRP), which increase appetite. Adjacent neurons in the hypothalamus produce melanocortin peptides, which inhibit appetite. a-Melanocyte stimulating hormone (a-MSH) is a tridecapeptide melanocortin cleaved from pro-opiomelanocortin that acts to inhibit food intake [28]. This co-localisation has contributed to NPY, AgRP, and a-MSH currently being among the most-studied pep-tides. Immunohistochemical studies show a dense population of neurons producing a-MSH in the ARC, with projections to the dorsomedial nuclei, the medial preoptic area, and the anterior hypothalamus [29]. A moderately dense population of fibres also projects to the paraventricular nucleus (PVN), the lateral hypothalamic area (LHA), the posterior hypothalamus, and the central nucleus of the amygdala.

Fig. 2. Gut-brain hormonal axis. (Reproduced with permission from [22])

Fig. 3. Peripheral signals reach the arcuate nucleus of the hypothalamus, where they interact with two neuronal populations that project to second-order neuronal signalling pathways. NPY/Agouti-related peptide (AgRP) neurons stimulate food intake. Pro-opiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons inhibit food intake. (From [13])

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