Muscarinic receptors in energy homeostasis: Physiology and pharmacology

Abstract

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. K E Y W O R D Sacetylcholine, energy metabolism, GPCR, muscarinic, obesity, pharmacology, type 2 diabetes | 67 FALK et AL.

The dialog between neurons and microglia in Alzheimer's disease: The neurotransmitters view

“…The mAChR subtype M1 is extensively expressed in the brain, and is highly abundant in the hippocampus (Falk et al., 2019). M1 is greatly involved in learning and spatial memory (Aronstam & Patil, 2009; Jiang et al., 2014), which had been shown to be restored following its activation in AD animal models (Fisher et al., 2003).…”

“…The mAChR M3 has also been suggested to play a role in AD. The receptor has been shown to be involved in a variety of processes (Aronstam & Patil, 2009; Falk et al., 2019), and as is evident from experiments in M3 KO mice, it is also important for fear conditioning and memory (Falk et al., 2019). Similar to mAChR M1, activation of M3 subtype has been shown to promote the elevation of the favorable sAPPα, instead of Aβ.…”

Cevimeline co-treatment attenuates olanzapine-induced metabolic disorders via modulating hepatic M3 muscarinic receptor: AMPKα signalling pathway in female rats

“…Molecular cloning studies have revealed five subtypes of acetylcholine muscarinic receptors (M1R-M5R), all of which are G protein coupled receptors (Falk et al, 2019). The M3Rs are widely expressed throughout the brain and peripheral organs, including the liver and pancreas (Eglen, 2005; Falk et al, 2019).…”

G protein‐coupled receptor pharmacology—The next generation

“…Another interesting MiniReview from the Kellendonk group reviews the latest data on the highly relevant topic of how the dopamine D2 receptor modulates motivated behaviour through regulation of neuronal activity in the striatal indirect pathway . Finally, the Clemmensen group has taken an exciting new look at muscarinic acetylcholine receptors and written a MiniReview about their role in energy homoeostasis . They outline that the receptors both play a direct role in energy homoeostasis via canonical brain circuits regulating appetite and indirect roles via neurocircuits regulating motivated behaviours and emotional stress.…”

“…They outline that the receptors both play a direct role in energy homoeostasis via canonical brain circuits regulating appetite and indirect roles via neurocircuits regulating motivated behaviours and emotional stress. Muscarinic acetylcholine receptors might thus be novel drug targets for treatment of obesity and type 2 diabetes …”