Hypothalamic Regulation of Appetite

Katherine A. Simpson; Niamh M. Martin; Steve R. Bloom

Disclosures

Expert Rev Endocrinol Metab. 2008;3(5):577-592. 

In This Article

Abstract and Introduction

The prevalence of obesity is steadily rising and has huge health and financial implications for society. Weight gain is due to an imbalance between dietary intake and energy expenditure and research has focused on trying to understand the complex pathways involved in controlling these aspects. This review highlights the key areas of research in the hypothalamic control of appetite. The hypothalamus consists of several nuclei that integrate peripheral signals, such as adiposity and caloric intake, to regulate important pathways within the CNS controlling food intake. The best characterized pathways are the orexigenic neuropeptide Y/Agouti-related protein and the anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-related transcript neurons in the arcuate nucleus of the hypothalamus. These project from the arcuate nucleus to other key hypothalamic nuclei, such as the paraventricular, dorsomedial, ventromedial and lateral hypothalamic nuclei. There are also projections to and from the brainstem, cortical areas and reward pathways, all of which influence food intake. The challenge at present is to understand the complexity of these pathways and try to find ways of modulating them in order to find potential therapeutic targets.

Epidemiology. Globally, the WHO estimates that over 1 billion people are currently overweight and that over 300 million people are obese.[1] In the UK, the prevalence of obesity has more than tripled in the past 25 years, and obesity among children has tripled in a decade.[222] A weight gain of just 1kg has been shown to increase cardiovascular risk by 3.1% and diabetes risk by 4.5-9%.[2] As expected, obesity-related disorders have also increased, with 80% of obese adults having at least one or more comorbidities, including diabetes mellitus, hyperlipidemia, hypertension, cardiovascular disease and certain forms of cancer.[3,4] Deaths related directly to obesity have been estimated at 320,000 per year in Europe and 300,000 in the USA.[222] Governments in developed countries now recognize the potential social and financial burden that obesity will pose in the future. As a consequence, various reports and strategies have been suggested, particularly in children, in an attempt to tackle the problem.

Thrifty phenotype hypothesis. The increasing prevalence of obesity is partly attributable to a lack of exercise and the availability of high-calorie palatable food.[5] Some have also postulated that sleep deprivation and its effects on gut hormone secretion has a role in the development of obesity.[6] The concept of the 'thrifty phenotype' hypothesis was first coined almost 50years ago with the observation that, during the hunter-gatherer days of man, possession of genes that allowed one to survive despite famine, confered an evolutionary advantage.[7] Carriers of such genes would be able to store energy more efficiently during periods of abundant food supply to increase their odds of survival during famine. However, this 'thrifty genotype' becomes a disadvantage at times of abundant energy supply, such as that seen in our current Western civilization, resulting in obesity. Family, twin and adoption studies indicate that obesity is highly heritable, with the estimated genetic contribution ranging from 60 to 84%.[8] A series of complex systems regulate energy homeostasis so that sufficient energy is available and bodyweight remains stable.[9] Central circuits in the brain rely on peripheral signals indicating satiety levels and energy stores, as well as higher cortical factors, such as emotional and reward pathways. The hypothalamus is critical in the regulation of food intake and acts as a 'key controller' within neural circuitry to maintain energy homeostasis. As illustrated in Figure 1, the hypothalamus is an integral part of the processing of afferent signals, such as those from the gut and brainstem, as well as the processing of efferent signals that modulate food intake and energy expenditure. The hypothalamus is subdivided into interconnecting nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamic area (LHA). Early lesioning studies proposed a 'dual center' hypothesis, whereby the ventromedial hypothalamus acted as a satiety center and the lateral hypothalamus was a 'feeding center'.[10,11] The dual center hypothesis has now been replaced by the concept of discrete neuronal pathways, which are integrated into a complex neural network in which specific orexigenic and anorexigenic neurotransmitters are released from specific neurons to influence food intake and energy expenditure. The purpose of this review is to highlight the key players in the hypothalamic control of appetite, the brain circuitry involved and potential therapeutic targets for obesity.

Relationship between the brainstem, hypothalamus, cortical areas and reward circuitry known to modulate appetite control. Gut hormones acting via vagal afferents act on the NTS in the brainstem, which in turn signals to the hypothalamus. Some gut hormones may also act directly on hypothalamic nuclei via the circulation and across an incomplete blood-brain barrier. There are projections from hypothalamic nuclei to the prefrontal cortex, involved in conditioned taste aversion, as well as reward centers, such as the amygdala and nucleus accumbens. Leptin is also thought to act directly on the NTS as well as hypothalamic nuclei, suggesting that it can modulate appetite through different pathways. ARC: Arcuate nucleus; CCK = Cholecystokinin; GLP = Glucagon-like peptide; LHA = Lateral hypothalamic area; NTS = Nucleus tractus solitarius; OXM = Oxyntomodulin; PYY = Peptide YY; PVN = Paraventricular nucleus; VMN = Ventromedial nucleus.

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