Neurobiology of food intake in health and disease

Abstract

Under normal conditions, food intake and energy expenditure are balanced by a homeostatic system that maintains stability of body fat content over time. However, this homeostatic system can be overridden by the activation of 'emergency response circuits' that mediate feeding responses to emergent or stressful stimuli. Inhibition of these circuits is therefore permissive for normal energy homeostasis to occur, and their chronic activation can cause profound, even life-threatening, changes in body fat mass. This Review highlights how the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions.

Figure 1. CNS regulation of energy homeostasis

The CNS integrates input from long-term energy stores (for example, leptin) and short-term meal-related signals (nutrients and gut-derived satiety signals) to regulate food intake and energy expenditure in a manner that maintains stable body fat stores over time. Positive energy balance induced by overfeeding inhibits the rewarding properties of food while enhancing meal-induced satiety, thereby reducing food intake. In response to energy deprivation, CNS adaptive responses are engaged that both increase the rewarding properties of food and reduce the response to satiety signals, collectively resulting in increased food consumption until deficient fat stores are replenished. CCK, cholecystokinin; FFAs, free fatty acids; GLP1, glucagon-like peptide 1. Modified from Marx, J. Cellular warriors at the battle of the bulge. Science 299, 846-849 (2003). Reprinted with permission from AAAS.

Figure 2. Integration of long-term homeostatic and short-term satiety signals

A model describing homeostatic control of body adiposity proposes that regulation of food intake on a meal-to-meal basis is adjusted in response to changes in body fat content. Through actions in both the forebrain and hindbrain, the adiposity negative feedback signal leptin enhances responsiveness to gut-derived satiety signals such as cholecystokinin (CCK), which are released upon food ingestion. In addition to direct effects on hindbrain areas such as the nucleus of the solitary tract (NTS), leptin stimulates pro-opiomelanocortin (POMC) neurons but inhibits neurons that express agouti-related protein (AGRP) and neuropeptide Y (labelled as just AGRP) in the hypothalamic arcuate nucleus (ARC). These neurons project to second-order neurons in adjacent hypothalamic nuclei, including the paraventricular nucleus (PVN) and lateral hypothalamic area (not shown), which, in turn, project to the NTS, where satiety signals are processed. Satiety signals activate vagal afferents that terminate in the NTS to promote the termination of a meal. The NTS response to the satiety response is amplified both by direct input to the NTS from leptin and indirectly through the action of leptin in the hypothalamus. Consequently, reduced leptin action (for example, following weight loss) increases meal size by reducing the hindbrain response to satiety signals. GI, gastrointestinal. Figure from REF. , Nature Publishing Group.

Figure 3. Integration of homeostatic and reward-related inputs

Homeostatic signals modulate the perception of food reward (for example, the hedonic value and the motivation to work for food). Mesolimbic dopaminergic neurons in the ventral tegmental area (VTA) project to the nucleus accumbens (NAc) and other brain areas to heighten the reward value of palatable food. Neurons in the lateral hypothalamic area (LHA) integrate reward-related input from the NAc with information related to energy homeostasis from arcuate nucleus (ARC) neurons. In turn, LHA neurons project to and influence the mesolimbic dopaminergic system while also influencing satiety perception through projections to the hindbrain (not shown). Weight loss lowers plasma insulin and leptin levels while increasing plasma ghrelin levels. Working in concert, these responses increase the rewarding properties of food and hence the motivation to eat through either direct effects in the ventral striatum or indirect effects in the hypothalamus through the LHA. Conversely, following periods of positive energy balance, body weight is returned to its biologically defended level through both a decrease in the rewarding properties of food and an increased response to input from satiety signals. AMY, amygdala.

Figure 4. Neurocircuits involved in the homeostatic regulation of feeding

Neurons in the hypothalamic arcuate nucleus (ARC) and nucleus of the solitary tract (NTS) sense and respond to peripheral energy signals to promote energy homeostasis. Neuropeptides such as neuropeptide Y (NPY) and neurotransmitters such as GABA, among others, are released onto downstream neurons including those in the paraventricular nucleus (PVN). In the PVN, oxytocin and other neurons tonically inhibit feeding and, during energy deficit, are inhibited by orexigenic input from the ARC, thereby stimulating feeding. The same agouti-related protein (AGRP) neurons (which co-express GABA and NPY) that are involved in short-term feeding also contribute to long-term energy balance through the release of AGRP, an inverse agonist of melanocortin receptor 4 (MC4R) and, through GABA release, inhibit neighbouring pro-opiomelanocortin (POMC) neurons. POMC neurons are stimulated by input from leptin, and the release of α-melanocyte stimulating hormone (α-MSH) activates MC4R, thereby inhibiting food intake. In addition, recent evidence also implicates leptin-responsive GABAergic neurons that express neuronal nitric oxide synthase (nNOS) in the regulation of energy homeostasis. These neurons are found in the ARC and dorsomedial nucleus (not shown) and are hypothesized (dashed line) to inhibit downstream neurocircuits that drive feeding. Collectively, this input is relayed to the PVN and lateral hypothalamic area (not shown) and integrated to modulate the rewarding properties of food and the response to satiety signals. GABA_AR, type A GABA receptor; GHSR, growth hormone secretagogue receptor (ghrelin receptor); LRb, leptin receptor; NPY1R, NPY receptor type 1.

Figure 5. Activation of emergency neurocircuits that inhibit feeding

Neurocircuits exist that, when activated, can override the homeostatic control of food intake. Recent work from the Palmiter laboratory suggests that calcitonin gene-related peptide (CGRP) neurons expressed in the parabrachial nucleus (PBN) are an ‘off switch’ that can trigger anorexia in the context of emergency conditions (that is, illness, trauma or injury). The activity of this neurocircuit is constrained by inhibitory GABAergic input from agouti-related protein (AGRP) neurons in the arcuate nucleus (ARC), but this inhibition can be overcome in response to trauma, illness or stress. Some PBN neurons express NMDA receptors (NMDARs) that are activated by glutamatergic input from neurons in the rostral nucleus of the solitary tract (NTS), which in turn are regulated by serotonergic input from neurons located in the raphe magnus (RMg) and raphe obscurus (ROb). The net effect of activating this circuit is to activate CGRP neurons and thereby inhibit feeding. AMY, amygdala; GABA_AR, type A GABA receptor; 5-HT, 5-hydroxytryptamine (serotonin); 5-HT₃R, 5-HT₃ receptor.