Recent Developments in GPCR Signalling in Appetite Regulation

The balance between energy intake and energy expenditure determines whether we gain weight, and appetite regulatory circuits in the brain have a critical role in this energy balance. G protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, have an important role in appetite regulation. They function in the leptin-melanocortin pathway of the hypothalamic arcuate nucleus which plays a central role in the regulation of energy balance and appetite, integrating peripheral metabolic cues with central neural circuits to promote satiety. GPCRs also mediate the function of the orexigenic hormone ghrelin, the suppression of appetite and hedonic reward circuitry by serotonin, and the incretin receptors are targets for several drugs that currently dominate the weight loss market. Human genetic studies and animal models of obesity have revealed important physiological roles in appetite regulation and weight gain for several additional GPCRs, some of which are still classified as orphan receptors. In this review we discuss twelve GPCRs with roles in appetite regulation focussing on developments within the last 5-10 years where possible. We discuss evidence from animal models, proposed mechanisms of action, and relevance to human disease for each of these receptors. Finally, we evaluated, where applicable, the current position and future prospects for therapeutically targeting these receptors for use in treatments for weight loss or gain.