Stimulation of Gs signaling in MC4R cells by DREADD increases energy expenditure, suppresses food intake, and increases locomotor activity in mice

• Published in: American journal of physiology: endocrinology and metabolism 2022-05, Vol.322 (5), p.E436-E445
• Main Authors: Matsumura, Shigenobu, Miyakita, Motoki, Miyamori, Haruka, Kyo, Satomi, Shima, Daisuke, Yokokawa, Takumi, Ishikawa, Fuka, Sasaki, Tsutomu, Jinno, Tomoki, Tanaka, Jin, Goto, Tsuyoshi, Momma, Keiko, Ishihara, Kengo, Berdeaux, Rebecca, Inoue, Kazuo
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Appetite; Cell activation; Cyclic AMP; Energy expenditure; Energy metabolism; Fatty acids; Food; Food intake; Locomotor activity; Melanocortin; Melanocortin MC4 receptors; Metabolism; Oxidation; Oxygen consumption; Receptors; Signaling; Stimulation
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00439.2021

The melanocortin 4 receptor (MC4R) plays an important role in the regulation of appetite and energy expenditure in humans and rodents. Impairment of MC4R signaling causes severe obesity. MC4R mainly couples to the G-protein Gs. Ligand binding to MC4R activates adenylyl cyclase resulting in increased intracellular cAMP levels. cAMP acts as a secondary messenger, regulating various cellular processes. MC4R can also couple with Gq and other signaling pathways. Therefore, the contribution of MC4R/Gs signaling to energy metabolism and appetite remains unclear. To study the effect of Gs signaling activation in MC4R cells on whole body energy metabolism and appetite, we generated a novel mouse strain that expresses a Gs-coupled designer receptors exclusively activated by designer drugs [Gs-DREADD (GsD)] selectively in MC4R-expressing cells (GsD-MC4R mice). Chemogenetic activation of the GsD by a designer drug [deschloroclozapine (DCZ); 0.01∼0.1 mg/kg body wt] in MC4R-expressing cells significantly increased oxygen consumption and locomotor activity. In addition, GsD activation significantly reduced the respiratory exchange ratio, promoting fatty acid oxidation, but did not affect core (rectal) temperature. A low dose of DCZ (0.01 mg/kg body wt) did not suppress food intake, but a high dose of DCZ (0.1 mg/kg body wt) suppressed food intake in MC4R-GsD mice, although either DCZ dose (0.01 or 0.1 mg/kg body wt) did not affect food intake in the control mice. In conclusion, the current study demonstrated that the stimulation of Gs signaling in MC4R-expressing cells increases energy expenditure and locomotor activity and suppresses appetite.