Hunger: The carrot and the stick

Figure 1: Regulation of food intake by negative valence and positive valence appetitive systems, visceral aversive pathways, and the relationship with homeostatic deficit. Negative valence appetitive systems (e.g., AGRP neurons) are under homeostatic control, but AGRP neurons are rapidly inhibited by cues that predict food, thus consumption is associated with the positive valence system. Positive valence-driven eating (e.g., via the lateral hypothalamus) is modulated by energy deficit but also maintains appetite irrespective of a homeostatic need state. Aversive visceral signals, with different motivational properties than negative valence AGRP neurons, are activated by visceral and hormonal satiety signals and lead to cessation of food consumption. Interactions between these systems exist but are not shown. The distinction between feeding driven by homeostatic energy deficit versus non-homeostatic reward is a frequently heard dichotomy in the neurobiology of appetite. Although oversimplified, the underlying idea is that there are multiple appetitive systems. One important homeostatic system is mediated by Agouti related protein (Agrp)-expressing neurons, a hypothalamic cell type that is activated by conditions of homeostatic energy deficit. Optogenetic [1] or chemogenetic [2] activation of AGRP neurons rapidly elicits intense food intake, and transient inhibition of these neurons reduces appetite [2,3]. Recently, this population has also been found to transmit a signal with negative valence, and this may serve as a motive for mice to consume food, which consequently reduces AGRP neuron activity [3]. In fact, 96% of AGRP neurons have been shown by in vivo calcium imaging to rapidly reduce activity upon just the sight of food, such that the neurons have low activity during food consumption [3]. This indicates that AGRP neurons are involved in food-seeking but not food consumption. However, sustained reduction of AGRP neuron activity requires food consumption, which is consistent with a homeostatic role [3]. Conversely, a population of inhibitory neurons in the lateral hypothalamus increases feeding, is active during food consumption, and shows rewarding characteristics [4]. These neurons preferentially elicit palatable food consumption and interact with the ventral tegmental area (VTA), a brain region associated with incentive (reward)-based learning [5]. Notably, lateral hypothalamic neurons and VTA dopamine neurons have also been demonstrated to have receptors for key homeostatic hormones such as ghrelin [6] or leptin, indicating that positive valence (i.e., ‘hedonic’) systems are also homeostatically sensitive. Taken together, these systems mediate appetite regulation by both the ‘carrot and the stick’, where the positive valence of lateral hypothalamic/dopamine circuits associated with food consumption or the expectation of consumption pulls an animal towards incentives, and the negative valence AGRP neurons push an animal to attend to physiological needs. Both positive and negative valence systems are homeostatically sensitive, but the positive valence system also operates in the absence of homeostatic need if the reward value of the food is high enough (Figure 1). A new report in Cell Metabolism by Denis et al. examines the food consumption characteristics of mice that lack AGRP neurons [7]. This work builds on prior studies showing that permanent ablation of AGRP neurons in adult mice leads to short-term anorexia [8] due to visceral malaise [9]; however, when AGRP neurons are ablated in neonatal mice,