Differential effects of hunger and satiety on insular cortex and hypothalamic functional connectivity.

The insula cortex and hypothalamus are implicated in eating behaviour, and contain receptor sites for peptides and hormones controlling energy balance. The insula encompasses multi-functional subregions, which display differential anatomical and functional connectivities with the rest of the brain. This study aimed to analyse the effect of fasting and satiation on the functional connectivity profiles of left and right anterior, middle, and posterior insula, and left and right hypothalamus. It was hypothesized that the profiles would be altered alongside changes in homeostatic energy balance. Nineteen healthy participants underwent two 7-min resting state functional magnetic resonance imaging scans, one when fasted and one when satiated. Functional connectivity between the left posterior insula and cerebellum/superior frontal gyrus, and between left hypothalamus and inferior frontal gyrus was stronger during fasting. Functional connectivity between the right middle insula and default mode structures (left and right posterior parietal cortex, cingulate cortex), and between right hypothalamus and superior parietal cortex was stronger during satiation. Differences in blood glucose levels between the scans accounted for several of the altered functional connectivities. The insula and hypothalamus appear to form a homeostatic energy balance network related to cognitive control of eating; prompting eating and preventing overeating when energy is depleted, and ending feeding or transferring attention away from food upon satiation. This study provides evidence of a lateralized dissociation of neural responses to energy modulations.

The effect of Korean pine nut oil (PinnoThin) on food intake, feeding behaviour and appetite: a double-blind placebo-controlled trial.

Certain free fatty acids have been shown to have potent effects on food intake and self-reported changes in appetite; effects associated with increases in the release of endogenous cholecystokinin (CCK) and glucagon like peptide-1 (GLP-1). In the current study, the effects of a Korean pine nut oil product, PinnoThin, at doses 2 g, 4 g and 6 g triglyceride (TG) and 2 g free fatty acid (FFA), on food intake and appetite were examined in a cross-over double-blind placebo-controlled randomised counter-balanced design in 42 overweight female volunteers. 2 g FFA PinnoThin, given 30 minutes prior to an ad-libitum buffet test lunch, significantly reduced food intake (gram) by 9% (F(4,164) = 2.637, p = 0.036) compared to olive oil control. No significant effect of PinnoThin on macronutrient intake or ratings of appetite were observed. Given the recent data showing that the TG form of PinnoThin may also reduce appetite by increasing CCK release, the lack of any effect of the TG form found in this study could be attributed to the timing of the dosing regime. Collectively, these data suggest that PinnoThin may exert satiating effects consistent with its known action on CCK and GLP-1 release, and previously observed effects on self-reported appetite ratings.

Autoradiographic analysis of ghrelin receptors in the rat hypothalamus.

Ghrelin exerts potent stimulatory effects on food intake. It is assumed to increase feeding by binding at growth hormone secretagogue receptors (GHS-R), the only sites of action for this gastric hormone identified to date. Initially, the distribution of ghrelin binding sites could only be determined from expression patterns of GHS-R mRNA or the use of immunohistochemical techniques to examine c-fos expression. However, the characterisation of a novel radioligand ([(125)I-his(9)]-ghrelin), has enabled the distribution of GHS-R receptor protein to be directly demonstrated. Here, using quantitative autoradiography, we investigate the distribution and density of ghrelin receptors in the rodent hypothalamus. Specific binding was identified in the appetite-regulating arcuate nucleus, ventromedial hypothalamic nucleus, paraventricular nucleus, dorsomedial hypothalamic nucleus and the lateral hypothalamic area corresponding to the previously reported distribution pattern of GHS-R mRNA. Surprisingly, variations in receptor density were not identified in any of these binding sites upon a change in nutritional status, despite relevant alterations in plasma ghrelin levels being identified. We suggest that this may relate to the paradigm employed to modify nutritional status in the study or could indicate that peripheral ghrelin is unlikely to be the major source of ghrelin that acts in many hypothalamic sites.

Melanocortin-4 receptors, beta-MSH and leptin: key elements in the satiety pathway.

This paper reviews aspects of our research, focusing on the role of the melanocortin system in the central regulation of feeding and energy balance, which was begun in 1997. It describes data from successive physiological studies, concerning the identity of the appetite-regulating melanocortin receptor, melanocortin-4 receptor (MC4R) regulation with altered nutritional status, the role of MC4R in dietary obesity and the identity of the endogenous MC4R ligand.

The hypothalamus and obesity.

Obesity has reached epidemic proportions across the developed world. Even though there have been numerous scientific advances in terms of the understanding of the regulation of energy homeostasis, few novel anti-obesity drugs have emerged. Furthermore, those that are available have limited efficacy in producing and maintaining a weight loss beyond 10%. This is partly attributable to the complex neuronal circuitry at play within the central nervous system and periphery, which acts to regulate food intake and energy expenditure. This article will focus on a selection of the many products (peptides, neurotransmitters and others) such as endocannabinoids, Neuropeptide Y, Orexins, Melanin-Concentrating Hormone, Melanocortins, Cocaine and Amphetamine Regulated Transcript and Serotonin, expressed within the brain, that have been shown to influence energy balance. The true relevance of many of these to the regulation of human energy balance remains uncertain, but some novel anti-obesity drugs aimed at these targets are likely to emerge in the next few years.

Increases in melanin-concentrating hormone and MCH receptor levels in the hypothalamus of dietary-obese rats.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that stimulates feeding and increases body weight in rodents. We studied the role of the system in energy homeostasis and its regulation by the satiety signals, leptin and insulin. We used real-time PCR to measure the hypothalamic expression of MCH and its receptor (MCHR1) in two contrasting models of altered nutritional status, namely, obesity induced by 8 weeks' voluntary overeating and food restriction for 10 days. Diet-fed rats were stratified according to final total fat-pad mass into a 'high fat gain' group (HG) and 'low fat gain' group (LG). MCH mRNA levels were increased by 31% (p>0.05) and 49% (p<0.05) in the LG and HG, respectively, compared with controls. MCHR1 mRNA levels rose by 118% in the LG (p<0.01) and 85% in the HG (p<0.01). There were significant positive correlations (p<0.05) between plasma leptin concentration and both MCH and MCHR1 mRNA levels, and between plasma insulin and MCHR1 expression. A positive correlation was also observed between MCH and MCHR1 mRNA levels (p<0.05). Food-restricted rats showed no significant alterations in the levels of either MCH mRNA or MCHR1 mRNA. In a second experiment, we measured MCH peptide levels in five discrete hypothalamic areas of dietary-obese rats. MCH concentrations were significantly increased in the arcuate nuclei of the HG (p<0.05) and the paraventricular nuclei of both the LG (p<0.05) and HG (p<0.05), compared with their lean counterparts. These results suggest that the MCH system becomes more active in dietary obesity and could be involved in enhancing appetite for palatable food. The possibility that MCH and MCHR1 expression are positively regulated by leptin and insulin, which normally inhibit feeding, is a putative explanation for how appetite for palatable food is able to override mechanisms that prevent the development of obesity.

Leptin leads hypothalamic feeding circuits in a new direction.

A decade ago, leptin (from the greek lepto meaning 'thin') was identified as the product of the ob gene.1 This adipocyte-derived hormone was found to suppress feeding and stimulate thermogenesis, and was thus proposed as a mediator in a negative feedback loop that controls body adiposity. This discovery led to a rapid revolution in the understanding of neurobiological mechanisms regulating obesity. However, while leptin's first life was as an adipostat, it is now known to have a wide range of additional neuroendocrine, metabolic and behavioural functions in the CNS and periphery. Remarkably, the pleiotropic nature of the hormone continues to be extended with the recent publication of two papers that expand on leptin's neurobiological actions in the CNS.2,3 They indicate novel regulatory roles for the hormone in both synaptic plasticity and axon guidance. Crucially, in light of the rising incidence of obesity in modern society, both of the studies reveal leptin-mediated links between nutrition and neurodevelopment, findings that have further implications for leptin's role in the regulation of energy homeostasis.

Hypothalamic control of energy balance.

Over the last decade, understanding of the circuits and molecules involved in the regulation of energy balance has expanded dramatically. A complex system has evolved which allows the brain to read, interpret and integrate a wide range of signals and to elicit appropriate changes in food intake and energy expenditure as a result of the information. A series of short-term signals derived from the gastrointestinal tract, such as cholecystokinin, govern meal size. Other hormones e.g. insulin and leptin, and circulating nutrients offer long-term regulation. These signals act at a variety of central nervous system sites, but the majority of pathways converge on the hypothalamus, which itself contains numerous peptides and neurotransmitters that influence feeding and energy expenditure. Mutations in key components of these circuits underlie some of the syndromes of genetic obesity in rodents, but are responsible for only a small percentage of human obesity--which is largely attributed to an adverse lifestyle. However, various abnormalities have been identified in dietary-obese rodents, which is the closest model to 'common' human obesity. The relevance of these to energy homeostasis in humans remains uncertain, but some are likely to emerge as therapeutic targets for the treatment of both obesity and eating disorders.

The cannabinoid system: a role in both the homeostatic and hedonic control of eating?

Knowledge of the cannabinoid system and its components has expanded greatly over the past decade. There is increasing evidence for its role in the regulation of food intake and appetite. Cannabinoid system activity in the hypothalamus is thought to contribute to the homeostatic regulation of energy balance, under the control of the hormone leptin. A second component of cannabinoid-mediated food intake appears to involve reward pathways and the hedonic aspect of eating. With the cannabinoid system contributing to both regulatory pathways, it presents an attractive therapeutic target for the treatment of both obesity and eating disorders.

beta-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?

alpha-Melanocyte stimulating hormone (MSH) has generally been assumed to be the endogenous ligand acting at the melanocortin-4 receptor (MC4-R), activation of which in the hypothalamus leads to reduced feeding. However, beta-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that beta-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. We found that beta-MSH had significantly higher affinities than alpha-MSH at both human MC4-R transfected into CHO cells (K(i): beta-MSH, 11.4+/-0.4 nmol/l versus alpha-MSH, 324+/-16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates (K(i): beta-MSH, 5.0+/-0.4 nmol/l versus alpha-MSH, 22.5+/-2.3 nmol/l, P<0.001). Incubation of brain slices with 5 microM beta-MSH significantly increased [35S]GTPgammaS binding by 140-160% (P<0.001), indicating activation of G-protein-coupled receptors (GPCRs), in the hypothalamic ventromedial (VMH), dorsomedial (DMH), arcuate (ARC) and paraventricular (PVN) nuclei. These sites match the distribution of beta-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased beta-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst alpha-MSH concentrations were unchanged. We propose that increased beta-MSH concentrations reflect blockade of the peptide's release in these sites, consistent with the increased hunger and the known up-regulation of MC4-R in the same nuclei. Thus, we conclude that (1). beta-MSH has higher affinity at MC4-R than alpha-MSH; (2). beta-MSH activates GPCR in these sites, which are rich in MC4-R; and (3). beta-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that beta-MSH rather than alpha-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of beta-MSH is one mechanism contributing to hunger in under-feeding.

Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?

Agonists at cannabinoid-1 (CB-1) receptors stimulate feeding and particularly enhance the reward aspects of eating. To investigate whether endogenous cannabinoids might influence appetite for palatable food, we compared CB-1 receptor density in the forebrain and hypothalamus, between rats fed standard chow (n=8) and others given palatable food (n=8) for 10 weeks to induce dietary obesity. CB-1 receptor density was significantly decreased by 30-50% (P<0.05) in the hippocampus, cortex, nucleus accumbens and entopeduncular nucleus of diet-fed rats. Furthermore, CB-1 receptor density in the hippocampus, nucleus accumbens and entopeduncular nucleus was significantly inversely correlated with intake of palatable food (r(2)=0.25-0.35; all P<0.05). By contrast, CB-1 receptor binding in the hypothalamus was low and not altered in diet-fed rats. CB-1 receptor down-regulation is consistent with increased activation of these receptors by endogenous cannabinoids. Acting in areas such as the nucleus accumbens and hippocampus, which are involved in the hedonic aspects of eating, cannabinoids may therefore drive appetite for palatable food and thus determine total energy intake and the severity of diet-induced obesity. However, cannabinoids in the hypothalamus do not appear to influence this aspect of eating behaviour.