Obesity results from the consumption of food in excess of bodily energy requirements, with the excess energy stored as adipose tissue. Sequelae of obesity, such as heart disease and type 2 diabetes, consistently rank among the top causes of death worldwide. The global prevalence of obesity highlights the urgency of understanding the mechanisms regulating hunger and satiety. Appetite, defined as the motivational drive to obtain food, is regulated by a complex neurocircuitry which integrates a variety of interoceptive signals to gauge nutritional state and guide appropriate levels of food-seeking. Here we review key recent developments in the identification of cell groups, neural circuits, endogenous and exogenous substances, and intracellular signaling pathways which drive hunger and satiety. We also consider particularly promising pharmacological targets for appetite modulation.
Obesity represents a substantial global health problem, with a burgeoning population of more than 400 million obese individuals worldwide. Its co-morbidities, such as the intricately etiologically linked metabolic disease diabetes mellitus, consistently rank within the World Health Organisation's top 10 causes of death. The high prevalence rate, severe health effects, and paucity of effective weight loss medications illustrates the substantial unmet clinical need for obesity treatment.
The brain represents the master coordinator of appetite and body weight. In 1940, Hetherington and Ranson proposed a dual-center model for regulation of ingestive behaviour based on lesion studies in which they defined the ventromedial hypothalamus as a region required for satiety and the lateral hypothalamic area (LHA) as a region essential for hunger [1]. Taking advantage of the latest technology, the recent advances reviewed here build on this early work in the hypothalamus and provide new insight into the neural underpinnings of appetite and body weight regulation.
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A number of brain regions, cell types, and even specific projections have been strongly implicated in the regulation of feeding. In this section, we describe important recent advances in the identification and characterisation of this circuitry.
Appetite is largely dependent on the interoceptive sense of whether energy levels are adequate. Thus, appetite has a major homeostatic component. When energy levels are perceived as adequate, the feeding drive is low, and when energy levels are perceived as inadequate, the feeding drive kicks into high gear.
A number of endocrine signals that modulate appetite neurocircuitry have been identified. One key hormonal signal is leptin, which is produced by adipose tissue. Leptin levels are
To appropriately regulate appetite and energy homeostasis over extended timescales, neural circuits must be capable of sustaining changes in activity. This is often achieved by changes in intracellular signaling cascades and transcriptional programs in response to neural and hormonal signals. For example, food deprivation elicits gastric ghrelin release. Ghrelin, acting via its receptor on neurons, recruits AMP kinase which then acts to liberate Ca 2+ from internal stores [41]. This response,
To date, pharmacological approaches to restrain (or promote) appetite have been frustrated by limited efficacy and specificity. Recent work has identified additional GPCRs and ion channels which are involved in appetite regulation. These types of targets are eminently more druggable than specific neuronal circuits and cell types. These recent discoveries include Nav1.7, a sodium channel involved in long-term signal integration in hypothalamic feeding circuits [15••], and the purinergic
The rapid pace of neurotechnological progress, including the ability to precisely bidirectionally modulate genetically defined projections and to record neural activity dynamics during naturalistic behaviour, has permitted an avalanche of insight into appetite neurocircuitry to be gleaned in recent years. This includes a much more precise dissection of brain regions implicated decades ago by relatively crude lesion studies. Taken together, these advances illuminate a complex and widely
Nothing declared.
Papers of particular interest, published within the period of review, have been highlighted as:
Work was supported by the Wellcome Trust (LKH: WT098012 ), Biotechnology and Biological Sciences Research Council (LKH: BB/K001418/1 , BB/NO17838/1 ), Medical Research Council (LKH: MC/PC/15077 ), and Deutsche Forschungsgemeinschaft (DDL: LA 3830/1-1 ).
