Muscarinic receptors in energy homeostasis: Physiology and pharmacology.

Despite increased awareness and intensified biomedical research efforts, the prevalence of obesity continues to rise worldwide. This is alarming, because obesity accelerates the progression of several chronic disorders, including type 2 diabetes, cancer and cardiovascular disease. Individuals who experience significant weight loss must combat powerful counter-regulatory energy homeostatic processes, and, typically, most individuals regain the lost weight. Therefore, decoding the neural mechanisms underlying the regulation of energy homeostasis is necessary for developing breakthroughs in obesity management. It has been known for decades that cholinergic neurotransmission both directly and indirectly modulates energy homeostasis and metabolic health. Despite this insight, the molecular details underlying the modulation remain ill-defined, and the potential for targeting cholinergic muscarinic receptors for treating metabolic disease is largely uncharted. In this MiniReview, we scrutinize the literature that has formed our knowledge of muscarinic acetylcholine receptors (mAChRs) in energy homeostasis. The role of mAChRs in canonical appetite-regulating circuits will be discussed as will the more indirect regulation of energy homoeostasis via neurocircuits linked to motivated behaviours and emotional states. Finally, we discuss the therapeutic prospects of targeting mAChRs for the treatment of obesity and type 2 diabetes.