Joanne A. Harrold

The hypothalamus and the control of energy homeostasis: Different circuits, different purposes

The hypothalamus regulates many aspects of energy homeostasis, adjusting both the drive to eat and the expenditure of energy in response to a wide range of nutritional and other signals. It is becoming clear that various neural circuits operate to different degrees and probably serve specific functions under particular conditions of altered feeding behaviour. This review will discuss this functional diversity by illustrating hypothalamic neurones that express neuropeptide Y (NPY), the melanocortin-4 receptor (MC4-R) and the orexins. NPY neurones in the arcuate nucleus (ARC) release NPY, a powerful inducer of feeding and obesity, in the paraventricular nucleus (PVN) and the lateral hypothalamic area (LHA). ARC-NPY neurones are inhibited by leptin and insulin and become overactive when levels of these hormones fall during undernutrition. They may function physiologically to protect against starvation. With disruption of the inhibitory leptin signals due to gene mutations, the NPY neurones are overactive, which contributes to hyperphagia and obesity in the ob/ob and db/db mice and fa/fa Zucker rat. The MC4-R is activated by alpha-melanocyte-stimulating hormone [alpha-MSH; a cleavage product of pro-opiomelanocortin (POMC), which is expressed in the other ARC neurones] and inhibits feeding. This effect is antagonised by agouti gene-related peptide (AGRP), which is coexpressed by the ARC-NPY neurones only. Activation of MC4-R, possibly mediated by blockade of AGRP release, appears to restrain overeating of a palatable diet. This response may be programmed by a transient rise in leptin soon after presentation of palatable food, and rats that fail to do this will overeat and become obese. Orexin-A and -B (corresponding to hypocretins 1 and 2) are expressed in specific LHA neurones. These have extensive reciprocal connections with many areas involved in appetite control, including the nucleus of the solitary tracts (NTS), which relays vagal afferent satiety signals from the viscera. Orexin neurones also have close anatomical connections with LHA glucose-sensitive neurones. Orexin-A induces acute feeding but does not cause obesity. Orexin neurones are stimulated by hypoglycaemia partly via the NTS and inhibited by food ingestion. These neurones may therefore be involved in the severe hyperphagia of hypoglycaemia and short-term control of feeding.

Serotonergic drugs : effects on appetite expression and use for the treatment of obesity.

Over 35 years of research suggests that endogenous hypothalamic serotonin (5-hydroxytryptamine) plays an important part in within-meal satiation and post-meal satiety processes. Thus, the serotonin system has provided a viable target for weight control, critical to the action of at least two effective anti-obesity treatments, both producing clinically significant weight loss over a year or more. Numerous serotonin receptor subtypes have been identified; of these, serotonin 5-HT1B and 5-HT2C receptors have been specifically recognised as mediators of serotonin-induced satiety.A number of serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), dexfenfluramine and 5-HT2C receptor agonists, have been shown to significantly attenuate rodent bodyweight gain. This effect is strongly associated with marked hypophagia and is probably mediated by the hypothalamic melanocortin system. Additionally, sibutramine, dexfenfluramine, fluoxetine and the 5-HT2C receptor agonist chlorophenylpiperazine (mCPP) have all been shown to modify appetite in both lean and obese humans, resulting in reduced caloric intake. Clinical studies demonstrate serotonergic drugs specifically reduce appetite prior to and following the consumption of fixed caloric loads, and cause a reduction in pre-meal appetite and caloric intake at ad libitum meals. Weight loss in the obese has also been produced by treatment with both the serotonin precursor 5-hydroxytryptophan and the preferential 5-HT2C receptor agonist mCPP.A new generation of 5-HT2C receptor selective agonists have been developed and at least one, lorcaserin (APD356), is currently undergoing clinical trials. In addition, 5-HT6 receptor antagonists such as PRX-07034 and BVT74316 have been shown to potently reduce food intake and bodyweight gain in rodent models and have recently entered clinical trials. However, the role of the 5-HT6 receptor in the expression of appetite remains to be determined. The hope is that these drugs will not only be free of their predecessors’ adverse effect profiles, but will also be equally or more effective at regulating appetite and controlling bodyweight.

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.

Pharmacological management of appetite expression in obesity

For obese individuals, successful weight loss and maintenance are notoriously difficult. Traditional drug development fails to exploit knowledge of the psychological factors that crucially influence appetite, concentrating instead on restrictive criteria of intake and weight reduction, allied to a mechanistic view of energy regulation. Drugs are under development that may produce beneficial changes in appetite expression in the obese. These currently include glucagon-like peptide-1 analogs such as liraglutide, an amylin analog davalintide, the 5-HT2C receptor agonist lorcaserin, the monoamine re-uptake inhibitor tesofensine, and a number of combination therapies such as pramlintide and metreleptin, bupropion and naltrexone, phentermine and topiramate, and bupropion and zonisamide. However, the effects of these treatments on eating behavior remain poorly characterized. Obesity is typically a consequence of overconsumption driven by an individuals natural sensitivity to food stimuli and the pleasure derived from eating. Intuitively, these processes should be effective targets for pharmacotherapy, and behavioral analysis can identify drugs that selectively affect desire to eat, enjoyment of eating, satiation or postmeal satiety. Rational interventions designed specifically to modulate these processes could limit the normally aversive consequences of caloric restriction and maximize an individuals capacity to successfully gain control over their appetite.

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.

Satiety-enhancing products for appetite control: science and regulation of functional foods for weight management

The current review considers satiety-based approaches to weight management in the context of health claims. Health benefits, defined as beneficial physiological effects, are what the European Food Safety Authority bases their recommendations on for claim approval. The literature demonstrates that foods that target within-meal satiation and post-meal satiety provide a plausible approach to weight management. However, few ingredient types tested produce the sustainable and enduring effects on appetite accompanied by the necessary reductions in energy intake required to claim satiety/reduction in hunger as a health benefit. Proteins, fibre types, novel oils and carbohydrates resistant to digestion all have the potential to produce beneficial short-term changes in appetite (proof-of-concept). The challenge remains to demonstrate their enduring effects on appetite and energy intake, as well as the health and consumer benefits such effects provide in terms of optimising successful weight management. Currently, the benefits of satiety-enhancing ingredients to both consumers and their health are under researched. It is possible that such ingredients help consumers gain control over their eating behaviour and may also help reduce the negative psychological impact of dieting and the physiological consequences of energy restriction that ultimately undermine weight management. In conclusion, industry needs to demonstrate that a satiety-based approach to weight management, based on single-manipulated food items, is sufficient to help consumers resist the situational and personal factors that drive overconsumption. Nonetheless, we possess the methodological tools, which when employed in appropriate designs, are sufficient to support health claims.

Effects of olanzapine in male rats: enhanced adiposity in the absence of hyperphagia, weight gain or metabolic abnormalities

Many of olanzapines (OLZ) actions in humans related to weight regulation can be modelled in female rats (Cooper et al., 2005). Such effects include weight gain, hyperphagia, enhanced visceral adiposity and elevated Levels of insulin and adiponectin. As sex differences have been reported in the effects of antipsychotic drugs, including OLZ, in rats, the current study extended our study in female rats by directly comparing the actions of OLZ in maLes using identical methodology. Individually housed male Han Wistar rats were administered OLZ twice daily (i.p.), at 0, 1, 2, and 4 mg/kg over 21 days. Both differences from, and simiLarities to, the data obtained in females were obtained. Males treated with OLZ showed reduced weight gain, enhanced visceral adiposity and reduced Lean muscle mass. There were no accompanying changes in food or water intake. OLZ did not induce changes in plasma Levels of insulin, Leptin or gLucose. Significant elevation of adiponectin was observed. OLZ-treated males dispLayed elevated prolactin and suppressed testosterone. OLZs effects in humans can very clearly be most validly modelled in female rats, although the cause(s) of the sex difference in OLZs actions in rats are not clear. However, the finding that significantly enhanced adiposity is seen in both male and female rats, in other animal species (mice and dogs) and in humans suggests that studies in male rats of OLZs effects may be of value, by highlighting the consistent ability of OLZ to increase visceral adiposity. It is hypothesized that such adiposity is a key, clinically relevant, common component of OLZs actions which may be, at Least partially, independent of both OLZinduced weight gain and hyperphagia, and which is induced reliably in male and female rats and other animal species. Possible mechanisms involved in the effects reported are discussed.

The extent of food advertising to children on UK television in 2008.

OBJECTIVE To provide the most comprehensive analysis to date of the extent of food advertising on UK television channels popular with young people following regulatory reform of this type of marketing activity. METHODS UK television was recorded 06:00-22:00 h for a weekday and a weekend day every month between January and December 2008 for 14 of the most popular commercial channels broadcasting childrens/family viewing. Recordings were screened for advertisements, which were coded according to predefined categories including whether they were broadcast in peak/non-peak childrens viewing time. Food advertisements were coded as core (healthy)/non-core (unhealthy)/miscellaneous foods. RESULTS Food and drinks were the third most heavily advertised product category, and there were a significantly greater proportion of advertisements for food/drinks during peak compared to non-peak childrens viewing times. A significantly greater proportion of the advertisements broadcast around soap operas than around childrens programmes were for food/drinks. Childrens channels broadcast a significantly greater proportion of non-core food advertisements than the family channels. There were significant differences between recording months for the proportion of core/non-core/miscellaneous food advertisements. CONCLUSIONS Despite regulation, children in the UK are exposed to more TV advertising for unhealthy than healthy food items, even at peak childrens viewing times. There remains scope to strengthen the rules regarding advertising of HFSS foods around programming popular with children and adults alike, where current regulations do not apply. Ongoing, systematic monitoring is essential for evaluation of the effectiveness of regulations designed to reduce childrens exposure to HFSS food advertising on television in the UK.

Increased binding at 5-HT1A, 5-HT1B, and 5-HT2A receptors and 5-HT transporters in diet-induced obese rats

5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have studied changes in the regional density of binding to 5-HT receptors and transporters and the levels of tryptophan hydroxylase, in rats with obesity induced by feeding a palatable high-energy diet for 7 weeks. We mapped binding at 5-HT receptor subtypes and transporters using quantitative autoradiography and determined tryptophan hydroxylase protein levels by Western blotting. In diet-induced obese (DiO) rats, specific binding to 5-HT(1A) receptors ([3H]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P<0.01) and 132% (P<0.05), respectively, compared with chow-fed controls. 5-HT(1B) receptor binding sites ([125I]cyanopindolol) were significantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (58%; P<0.05), as were 5-HT(2A) receptor binding sites ([3H]ketanserin) in both the ARC (44%; P<0.05) and lateral hypothalamic area (LHA) (121%; P<0.05). However, binding to 5-HT(2C) receptors ([3H]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([3H]paroxetine) was significantly increased (P<0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%-165%. Tryptophan hydroxylase protein levels in the raphe nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-HT release and decreased activity of the 5-HT neurons. Reduction in the hypophagic action of 5-HT, possibly acting at 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, may contribute to increased appetite in rats presented with highly palatable diet.

Persuasive techniques used in television advertisements to market foods to UK children

The aim of this study was to quantify the nature and extent of use of persuasive marketing techniques in television advertisements (adverts) to promote foods to children. Popular UK commercial television channels broadcasting childrens/family viewing were recorded for 2 days (6 am-10 pm) every month in 2008 and recordings were screened for adverts. Eighteen thousand eight hundred and eighty eight adverts were for food and these were coded for peak/non-peak childrens viewing time and representation of core (healthy)/non-core (unhealthy)/miscellaneous foods. The analysis assessed use of persuasive appeals, premium offers, promotional characters (brand equity and licensed characters), celebrity endorsers and website promotion in food adverts. Promotional characters, celebrity endorsers and premium offers were used more frequently to promote non-core than core foods, even on dedicated childrens channels. Brand equity characters featured on a greater proportion of food adverts than licensed characters. A food brand website was promoted in a third of food adverts (websites are not covered by the statutory regulation on food advertising). This extensive analysis of television adverts demonstrated that the use of persuasive marketing techniques to promote unhealthy foods was extensive in broadcasting popular with children despite regulations. Further studies should incorporate an analysis of the content of websites promoted during food adverts.