Energy intake and storage/expenditure are largely governed by hormonal interactions with the hypothalamus. Although eating behavior is very complex (factors such as social environment and olfactory stimuli are also important), a clearer understanding of the neuroendocrine control of appetite may prove beneficial to those of us trying to lose a pound or two.
Although feeling hungry is “all in your head,” that’s not where the problem starts. Various hormones released from the periphery travel throughout the body and towards the brain where they can interact with vagus afferents, the nodose ganglia, and/or specific sites in the hypothalamus. Ultimately, this results in changes in hypothalamic (ie brain) activity leading to either increased or decreased hunger. Specifically, these hormones influence feeding behavior by potentiating or inhibiting the release of specific anorexigenic (makes you feel full) or orixigenic (makes you want to eat) peptides in the hypothalamus. Effects on metabolic rate due to sympathetic output are also attributable to these interactions (1).
With all the new research being done on leptin, it’s not surprising that much of our knowledge of hypothalamic function in the control of appetite and energy expenditure comes from leptin studies. However, as leptin has been extensively discussed in numerous previous issues, I will not concentrate on this hormone. Instead, I will focus on certain gut-hormones as well as some non-gut-hormones with respect to neuroendocrine control of appetite and energy expenditure.
If you’re trying to lose weight, ghrelin can be viewed as a powerful enemy. Ghrelin is an orixigenic peptide secreted by the stomach and functions by activating its receptor (GHS-R) on AGRP and NPY-producing neurons in the arcuate nucleus (ARC) of the hypothalamus (2). Simply put, when ghrelin levels are high, signals in the brain cause you to feel hungry. What’s worse, the longer you go without eating (or the longer you maintain a negative energy balance), the higher your ghrelin levels go. As one would expect, the inverse is true post-prandially (after you eat) and under positive energy balance (ie while bulking) (3;4).
Furthermore, apart from effects on feeding behavior, ghrelin stimulates gastric emptying by both central and local mechanisms (5). When the gastrointestinal tract is less full, distension-sensing cells reduce their rate of firing. This sends signals (via vagal afferents to the hypothalamus) that you are once again ready to eat. If you’re trying to lose weight, it’s not hard to understand why this is a bad thing. Additionally, evidence indicates that elevated ghrelin levels decreases sympathetic nervous system activity (6). This is also a bad thing if you’re trying to shed a few pounds.
There is much scientific evidence indicating the important role of ghrelin in controlling eating behavior and body weight. Levels are elevated in patients with Prader-Willi syndrome (7). This syndrome is a genetic obesity disease. Thus, a role for ghrelin in controlling body weight in humans is clear. Moreover, Administration of ghrelin increases food intake and body weight in rats (6) and humans (8), further illustrating the role of ghrelin in influencing feeding behavior.
With respect to reducing ghrelin concentrations, carbohydrates appear to be most beneficial (9;10). Thus, incorporating more carbohydrates in your diet may ameliorate the increase in ghrelin concentrations observed during energy restriction. Increased carbohydrates will also be beneficial for leptin and insulin plasma levels. However, the trick is incorporating them at appropriate times of the day. Early in the day and post-workout is probably the best. Additionally, consumption of 4g of psyllium fiber suppressed plasma ghrelin concentrations in healthy women equivalent to a 585-calorie meal (11). Thus, fiber-rich / low-energy meals could be a useful strategy to manage hunger… Imagine that.
Studies in mice showed that human ghrelin crosses the blood-brain barrier as an intact molecule by saturable transport (12). Thus, inhibiting the transport of ghrelin could be a possible mechanism to inhibit ghrelin signalling. Expect this in future appetite-limiting supplements or drugs.
CCK is secreted by enteroendocrine cells called I cells. These cells are primarily concentrated in the duodenal and jejunal mucosa and are stimulated primarily by dietary fat. Moreover, evidence indicates that to stimulate CCK release, fats must first be hydrolysed (broken down) and the fatty acid acyl chain must be at least 12 carbons in length (13). This may become an important consideration with new drugs designed to prevent fat hydrolysis such as pancreatic lipase inhibitors.
CCK induces satiety by acting on CCKA receptors on vagal afferents. This leads to suppression of NPY in the dorsomedial hypothalamus (13). As far back as 1973, it was demonstrated that administering CCK to rats dose-dependently reduced meal size (14). However, total daily caloric intake is unaffected due to a compensatory increase in meal frequency (15). This demonstrates a role for CCK in immediate satiety as opposed to long-term control of caloric intake, suggesting that CCK would be of questionable benefit in the treatment of obesity. Nevertheless, in combination with other interventions to decrease meal frequency, modulation of CCK levels could offer some benefit in controlling meal size.
Pharmaceutical interventions for weight loss targeting CCK could involve CCK administration or dietary/pharaceutical intervention. The addition of dietary fiber to a mixed meal increased CCK concentrations and also prolonged CCK elevations (16;17). Additionally, rats fed a high-fat / low carbohydrate diet have reduced satiety in response to CCK injection than rats maintained on a low-fat / high carbohydrate diet. This may be due to down-regulation of vagal CCKA receptors (18). This indicates that a high carbohydrate to fat ratio may prove beneficial in controlling meal size. However, it is possible that the effects are due to saturated fats (as these typically constitute high-fat diets in animal studies), so lowering saturated fats may suffice in restoring CCK signalling (ie keep downing the fish oil and sesamin). Nevertheless, I should mention that CCK has a negative effect on leptin concentrations (15), questioning its potential benefit in weight loss.
PYY (Peptide YY)
PYY has had little attention thus far. However, this may soon change. Post-prandially, PYY is secreted from endocrine L cells of the distal GI track (19). Conflicting evidence indicates that either fat- (19) or protein-rich (20) meals produce the highest post-prandial PYY concentrations. PYY induces satiety (makes you feel full) by binding to the Y2R receptor on vagal afferents, resulting in reduced NPY secretion in the ARC (21).
Targeting PPY has potential benefit in weight loss. Administration of PYY reduces fasting ghrelin concentrations (a good thing) in obese and lean individuals (22). Moreover, obese individuals are not resistant to PYY but have lower fasting and post-prandial PYY concentrations despite consuming more calories than lean individuals (22). This indicates that increasing PPY signalling could prove beneficial in reducing caloric intake in both lean and obese individuals. This is rather interesting since increases in leptin (ie with leptogen) are mostly beneficial to relatively lean individuals.
Insulin may become your friend for weightloss. Insulin has similar effects on feeding behavior as the aforementioned anorexigenic gut hormones. These effects are due to effects in the ARC and subsequent effects in the paraventricular nucleus (PVN). Specifically, reduced leptin/insulin signalling increases expression and release of neuropeptide Y (NPY) and agouti-related peptide (AgRP), while decreasing expression and release of pro-opiomelanocortin (POMC) and cocaine amphetamine-regulated transcript (CART). POMC and CART release act directly on the hypophysis to regulate the release of ACTH, TSH, LH/FSH and GH. This explains the effects of leptin/insulin on cortisol (see note), thyroid hormones, and sex steroids. Additionally, increased NPY and AgRP release from the ARC enhances melanin-concentrating hormone (MCH) release from the PVN. This exacerbates the effects of NPY and AgRP on the hypophysis. Additionally, NPY, AgRP and MCH have key roles in enhancing caloric intake (reviewed in 1).
Infusing insulin into the brain near the ARC inhibited NPY production (23). Additionally, knock out of protein-tyrosine phosphatase 1B (PTP1B) – an enzyme responsible for inhibiting insulin and leptin signalling – resulted in animals gaining less weight when fed a high-calorie diet (24). Although this may mainly be due to peripheral effects, effects on the CNS (especially with respect to leptin – which mainly functions centrally), may be important. Thus, reducing PTP-1B action in the brain (as well as in the periphery) could be beneficial for weight loss. It is feasible to obtain small-molecule PTP1B inhibitors with the requisite potency and selectivity (25). The challenge for the future will be to incorporate these inhibitors into orally available drugs. I expect such drugs to surmount in the not-so-distant future, especially since effects on insulin-resistance are also probable.
Histamine also has effects on the CNS and has a role in controlling food consumption (26). Central effects are mainly attributable to H3 receptors, which are predominantly expressed in the brain. Antagonism of these receptors was shown to cause weight loss or prevent weight gain in response to a high-fat diet (26). Histamine H3 receptor antagonists are currently in development for use as potential antiobesity agents (25).
Ever wonder why pot makes you hungry? Exogenous cannabinoids (such as THC) and endocannabinoids (derived from membrane phospholipids) stimulate appetite and promote weight gain (27) by activating G-coupled type 1 CB (CB-1) receptors in the brain (28;29). Interestingly, CB-1 knockout mice are lean and resistant to diet-induced obesity (30). Furthermore, hypothalamic endocannabinoids are increased in obese rodents such as ob/ob mice, db/db mice and fa/fa rats (31;32). This indicates their potential role in the development of obesity.
High-fat feeding has been shown to increase intrahepatic (liver) endocannabinoid levels, even before the onset of obesity (33). This indicates that dietary intervention, specifically reducing dietary fat, could have beneficial effects on weight with respect to endocannabinoid concentrations.
Pharmacological treatments for obesity targeting the CB-1 receptor are in development. Rimonabant (SR141716) reduces food intake and body weight (27;34). This drug has been successfully tested in phase III trials as an adjunctive obesity treatment (35;36). Additionally, agonists of CB-1 may prove beneficial in the treatment of diseases complicated by undereating, such as AIDS and anorexia nervosa. Furthermore, endocannabinoids are degraded by the enzyme fatty acid amide hydrolase (FAAH), so pharmaceutical intervention targeting this enzyme may also prove beneficial.
Controlling appetite can be extremely beneficial in maintaining a calorie-restriction diet… if for no other reason, to maintain your sanity. For this reason, the neuroendocrine control of appetite is worthy of our attention. Furthermore, effects on energy expenditure (highly controlled by sympathetic output) are also highly attributable to the interaction of specific hormones with the brain (specifically the hypothalamus).
Control of this system can be attained either by ‘drugs’ (in which I will include supplements, such as LeptoGen) or dietary means. Overall, a diet higher in carbohydrates seems more beneficial than one higher in fat. I know this is a very complex issue, especially with theories about ketogenic diets and whatnot, but due to effects on gut-hormones / leptin / insulin ect., and their peripheral and central effects, I (and many others much smarter than me) advocate a moderate carbohydrate diet. Additionally, a diet higher in fiber should offer significant benefit (as if we all didn’t know fiber makes you feel full).
Finally, I would like to say that none of this is cut and dry. Neuroendocrine control of body weight constitutes numerous hormonal interactions, many of which we may be currently unaware. This, combined with the fact that many hormones that partake in this ‘system’ also have significant peripheral effects on metabolism, makes it even more difficult to fully understand the brain’s role in weight management. Still, it’s an interesting subject that should stimulate some interesting debate.
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