Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications

Abstract

Significant comorbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease.

Figure 1. Canonical pathways that regulate stress responses (left; red arrows) and energy balance (right; blue arrows)

For the stress system, information from brainstem and limbic forebrain areas converges in the PVN, which directly activates the HPA axis and regulates autonomic nervous system responses via projections to brainstem. For energy balance, information from brainstem and limbic forebrain areas converges on the ARC, which regulates energy intake and expenditure via connections to the PVN, LHA and brainstem.

Figure 2. Schematic illustrating the complex functional interactions between homeostatic metabolic signaling, physiological responses to stress, and reward-driven food intake

These interactions likely occur, at least in part, as consequence of these systems’ largely overlapping anatomical circuitry. Metabolic signals including leptin and ghrelin, influence reward-driven food intake-which in turn alters energy balance. These metabolic signals also modulate HPA and autonomic responses to stress. Moreover, stress-mediators can override metabolic homeostasis to re-distribute fuels in the face of a challenge. Finally, stress mediators like glucocorticoids promote reward-driven food intake, which reciprocally reduces stress responses. All of these systems are profoundly influenced by stress exposure. In stress-prone individuals, this results in increased motivation for food reward and increased intake of highly palatable foods, that in turn limit uncomfortable psychological and physiological responses to stress. However, over the long term, chronic stress exposure can contribute to the development of metabolic disease.