Neuroendocrine, metabolic and pharmacological control of feeding behaviour – closing in on antiobesity treatment

Abstract

One of the largest challenges in medicine today is to break the curve of the increasing prevalence of obesity and its deleterious effects on health including type 2 diabetes, cardiovascular disease and cancer in most societies across the world. Although feeding behaviour and exercise habits to a large extent are considered to be deliberate and voluntary choices of human beings, research conducted over the last couple of decades has unravelled a significant and non-voluntary contribution of peripheral appetite regulating hormones like leptin, ghrelin, serotonin, glucagon like peptide-1 (GLP-1) and peptide YY on feeding behaviour, and thereby on risk of development of obesity. Genetic or non-genetic permanent changes in secretion or action, or in the ‘set point control’, of these hormones may provide the clue to understand why behaviour changes are most often unsuccessful to prevent, or in particular to revert, obesity. While appetite may be controlled in different areas of the brain, the hypothalamic arcuate, ventromedial and paraventricular nuclei as well as the lateral hypothalamic area seems to take centre stage in the hormonal and metabolic control of feeding behaviour. Interestingly, the metabolic actions of most appetite controlling hormones goes far beyond hypothalamic regulation of feeding behaviour per se, and may influence other direct and indirect obesity and diabetes related functions including energy expenditure (leptin, peptide YY), sleep (serotonin), insulin secretion (GLP-1, leptin) and insulin action (leptin, peptide YY). To this end, metabolic substrates including glucose and fatty acids exhibit more direct effects on central neuronal activities and functions than previously thought, all together unmaking a complex scenario of metabolic and hormonal cross-talk(s) between peripheral tissues, including adipose tissue and gut, on one side, and the central nervous system on the other side, with potential utmost importance for understanding the molecular mechanisms causing obesity and diabetes. In this issue of The Journal of Physiology, we focus on novel aspects of hormonal and metabolic effects on neuronal and CNS functions relevant to appetite, feeding behaviour, and ultimately to the understanding of the mechanisms causing – as well as the potentials to treat – obesity and type 2 diabetes. The discovery of the appetite regulating gut hormones glucagon like peptide-1 (GLP1), peptide YY and ghrelin has created increased awareness of the gut being perhaps the largest endocrine organ, with metabolic and behavioural effects going far beyond food digestion and dissemination. GLP1 and peptide YY are both produced and secreted form specialized enteroendocrine L-cells within the distal gastrointestinal tract in response to food intake, and they share the effect on a hypothalamic level to reduce appetite and food intake. Hypothalamic Y2-receptors seems to mediate the anorectic effect of peptide PYY, and as reviewed by Karra et al. (2009), plasma levels of PYY have been reported to associate negatively with obesity in humans, and knock-out experiments have documented a hyperphagic and obese phenotype in mice lacking PYY. Most interestingly, the surprising almost complete normalization of glucose metabolism in obese patients with type 2 diabetes occurring the first day(s) after gastric bypass surgery may be caused by significantly elevated PYY levels due to a more rapid passage of food through the gut after operation. Altogether, pharmacological targeting of the PYY system represents a promising strategy to treat obesity in the future. As for GLP1, analogues mimicking its documented metabolic and appetite reducing effects have in fact already been approved and launched as drugs to treat obese patients with type 2 diabetes. Native GLP1 is cleared rapidly after secretion by the enzyme dipeptidyl-peptidase, and native GLP1 therefore cannot be used clinically as a drug without some kind of prolongation of action. The GLP1 analogues have primarily been approved due to their incretin effects to enhance insulin secretion, and they are not (yet) approved to treat obesity per se. However, despite increased insulin secretion, treatment with GLP1 analogues does result in less weight gain as compared with antidiabetic drugs with the same potency, and it may be a question of time before GLP1 analogues may be used to treat obesity per se. In the review by Tolhurst et al. (2009), they focus on cellular and physiological mechanisms, as well as on nutritional effects, of GLP1 production and release from the intestinal L-cells. Obviously, the development of tools to increase endogenous GLP1 secretion and plasma levels represent yet another way to reduce appetite in obesity, and to increase insulin secretion in type 2 diabetes. Hypocretin (Hcrt) peptides are produced in neurones in the lateral hypothalamus playing a key role in the control of sleep and in the diurnal variation of a number of metabolic functions including appetite, basal metabolic rate, insulin action as well as insulin secretion. The role of Hcrt neurons in metabolism has become a topic of increased interest with the awareness of sleep deprivation as a significant cause of increased appetite, possibly due to reduced leptin and increased ghrelin levels, as well as insulin resistance and decreased insulin secretion. Recent evidence suggest that Hcrt neurones my act as ‘primary’ sensors responding to various different changing neuroendocrine and metabolic signals including leptin, ghrelin and glucose levels. In the review by Adamantidis & de Lecca (2009), they discuss the intriguing potential role of Hrct neurones in coordinating metabolic and physiological inputs into appropriate goal-orientated behaviour. Gonzalez et al. (2009) review the physiological significance of hypothalamic glucose sensing neurones on appetite and sleep regulating circuits. Hypothalamic neuronal firing rates may either decrease or increase in response to extracellular glucose influencing wakefulness-promoting hypocretin/orexin related signalling, as well as appetite-regulating neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) biological functions. Interestingly, dissociation between sensing and metabolism of glucose represents a homeostatic mechanism allowing the brain rapidly to respond to changes in extracellular glucose without adverse effects on the vital and fine tuned flow of intracellular fuel in the brain. It has long been known that increased availability of serotonin (5-hydroxy-tryptamine, 5-HT) in the CNS attenuate food intake. However, induction of tolerance and side-effects of serotonin raising compounds including fenfluramine and dexfenfluramine has limited their clinical usefulness. In the review by Garfield & Heisler (2009), they discuss the molecular mechanism of action of serotonin to reduce appetite by modulating firing of pro-opiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) as well as agouti related protein (AgRP)/neuropeptide Y (NPY) neurones in the arcuate nucleus of the hypothalamus. Serotonin activates a number of different receptors in different tissues, some of them being responsible for the undesirable side-effects, and therefore the potential selectively to target the most central appetite regulating serotonin receptors including the 5HT1b and 5HT2c receptors may represent a promising way forward to reduce appetite in obesity. After reading the reviews on recent progress in knowledge concerning neuroendocrine and metabolic hypothalamic – as well as gut – control of feeding behaviour in this issue of The Journal of Physiology, it is difficult not to become somewhat less defaitistic regarding the possibility to develop more effective and safe tools and drugs to combat obesity in the future.