Neural integration of satiation and food reward: role of GLP-1 and orexin pathways

Abstract

Central nervous system control of food intake involves detecting, integrating and responding to diverse internal and external signals. For maintenance of energy homeostasis, the brain uses long-term signals of metabolic status and short-term signals related to the nutrient content of individual meals. Feeding is also clearly influenced by hedonic, reward-related factors: palatability, motivation, and learned associations and cues that predict the availability of food. Different neural circuits have been proposed to mediate these homeostatic and hedonic aspects of eating. This review describes research on neural pathways that appear to be involved in both, integrating gastrointestinal satiation signaling with food reward. First, the glucagon-like peptide 1 projections from the nucleus of the solitary tract to the nucleus accumbens and ventral tegmental area are discussed as a mechanism through which meal-related gut signals may influence palatability, motivation for food, and meal size. Second, the orexin projection from lateral hypothalamus to the nucleus of the solitary tract and area postrema is discussed as a mechanism through which cues that predict rewarding food may act to increase motivation for food and also to suppress satiation. Additional potential integrative sites and pathways are also briefly discussed. Based on these findings, it is suggested that the brain circuitry involved in energy homeostasis and the circuitry mediating food reward are, in fact, overlapping and far less distinct than previously considered.

Keywords: Food reward; Glucagon-like peptide 1; Orexin; Satiation.

Figure 1

(A) Simplified model of brain control of homeostatic eating. Leptin acts on hypothalamic (HYP) nuclei and the hindbrain NTS. Neurons within these nuclei and interactions between hypothalamus and hindbrain promote satiation. (B) Simplified model of brain control of hedonic eating. Leptin can act on the VTA, which sends projections to NAc. Output of the NAc includes mPFC, VP, and LH, and changes in activity within these nuclei can enhance or reduce the rewarding value of food. (C) This review focuses on 2 specific circuits that link the models described in (A) and (B). GLP-1 neurons of the NTS detect satiation signals from the GI tract and project to NAc and VTA, where GLP-1R activation promotes satiation and reduces food reward. Orexin-A neurons in the LH are activated by cues that predict highly rewarding food. These neurons project to NTS, where we OX1R activation dampens satiation and enhances food reward.