Abstract

The identification of primary molecular targets for metabolic diseases has been confounded because such diseases typically develop over protracted time lines and ultimately are manifest in multiple organ systems. This review focuses on current understanding of a subset of G protein-coupled receptors (GPCRs) whose roles in nutrient and energy sensing, satiety, and associated feeding behaviors suggest that they may be modulated pharmacologically to affect glucose and energy homeostasis and ameliorate conditions such as type 2 diabetes and obesity. Receptor function will be examined at two levels: first, energy homeostasis by integration of neuroendocrine signals, primarily in the central nervous system (CNS), and second, fuel sensing and glucose homeostasis in the periphery.

6.1 INTRODUCTION

GPCRs play essential roles in establishing mechanisms that monitor energy expenditure, nutrient partitioning and metabolism, and ultimately determine body weight and composition. Energy homeostasis is, in large part, the outcome of a complex network of neural and hormonal signals exchanged between the gastrointestinal and nervous systems.

Although efferent signals can originate in a number of peripheral organs such as liver, stomach, intestine, skeletal muscle, and adipose tissue, their sites of action in the brain are more restricted. The hypothalamus serves as a center for integrating signaling events; responses are coordinated through GPCRs with discrete anatomical distribution, particularly in the arcuate nucleus (ARC) and the paraventricular nucleus (PVN). Such neuroendocrine signaling regulates metabolic events associated with both short-term (e.g., meal-to-meal) and long-term (e.g., body weight maintenance) ingestive behaviors. Ultimately, the imbalance between energy intake and expenditure determines excessive weight gain or loss.

6.2 CENTRAL MEDIATION OF FEEDING AND ENERGY HOMEOSTASIS

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