Discovery of melanin‐concentrating hormone receptor 1 in brown adipose tissue

Abstract

Although extensive research on brown adipose tissue (BAT) has stimulated optimism in the battle against obesity and diabetes, BAT physiology and organ crosstalk are not fully understood. Besides BAT, melanin-concentrating hormone (MCH) and its receptor (MCHR1) play an important role in energy homeostasis. Because of the link between hypothalamic MCH neurons and sympathetic BAT activation via β-adrenoceptors, we investigated the expression and physiological role of the MCHR1 in BAT. MCHR1 was detected in rodent and human BAT with RT-qPCR and western blot analyses. In vivo imaging in rats used the glucose analog [ 18 F]FDG and the MCHR1tracer [ 11 C]SNAP-7941. We found that the β3-adrenoceptor (ADRB3) agonist CL316,243 increased [ 11 C]SNAP-7941 uptake in BAT. Additionally, a pharmacological concentration of SNAP-7941-a low-affinity ADRB3 ligandstimulated [ 18 F]FDG uptake, reflecting BAT activation. In cultured human adipocytes, CL316,243 induced MCHR1 expression, further supporting a direct interaction between MCHR1 and ADRB3. These findings characterized MCHR1 expression in rodent and human BAT for the first time, including in vitro and in vivo data demonstrating a link between MCHR1 and the β3-adrenergic system. The presence of MCHR1 in BAT emphasizes the role of BAT in energy homeostasis and may help uncover treatment approaches for obesity.

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

“…Both receptors belong to the G protein-coupled receptor (GPCR) superfamily, with MCHR1 being common to all mammals and well-characterized in terms of its role in physiological processes. MCHR1 is primarily expressed in the central nervous system 14 , but can also be expressed in brown adipose tissue 15 , and is coupled by G i , G o , and G q 16 . The primary function of the MCH-MCHR1 system is in regulation of feeding behavior and energy homeostasis 4 .…”

Structural insights into ligand recognition and activation of melanin-concentrating hormone receptor MCHR1

“…Impaired synaptic function of the MCH-MCHR1 system has been observed in early-stage Alzheimer's disease patients and model mice, contributing to disturbances in sleep and neuronal homeostasis associated with Alzheimer's pathology and dementia risk 31 . MCHR1 is considered a potential therapeutic target for various diseases, including obesity, type diabetes, anxiety disorders, insomnia, narcolepsy, schizophrenia, Alzheimer's disease, ciliosis, osteoporosis, immune regulation, and impaired sense of smell 9,11,12,14,[16][17][18]21,[31][32][33][34][35][36] . Numerous MCHR1 antagonists, such as SNAP9471, AMG-076, NGD-4715, AZD1979, SNAP94748 and RGH-076, have been developed and some have shown therapeutic effects in clinical studies 37 .…”

“…Both receptors belong to the G protein-coupled receptor (GPCR) superfamily, with MCHR1 being well-characterized in terms of its role in behavior. MCHR1 is primarily expressed in the central nervous system 20 and adipocytes 21 , and can couple with multiple G proteins, including Gi, Go, and Gq 22 . The main function attributed to the MCH-MCHR1 system is the regulation of feeding behavior and energy homeostasis 5,10,23 .…”