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
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Department of Clinical Nutrition, Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Osaka, Japan.
Am J Physiol Endocrinol Metab. 2022 May 1;322(5):E436-E445. doi: 10.1152/ajpendo.00439.2021. Epub 2022 Mar 28.
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 G. 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 G and other signaling pathways. Therefore, the contribution of MC4R/G signaling to energy metabolism and appetite remains unclear. To study the effect of G signaling activation in MC4R cells on whole body energy metabolism and appetite, we generated a novel mouse strain that expresses a G-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 G signaling in MC4R-expressing cells increases energy expenditure and locomotor activity and suppresses appetite. We report that G signaling in melanocortin 4 receptor (MC4R)-expressing cells regulates energy expenditure, appetite, and locomotor activity. These findings shed light on the mechanism underlying the regulation of energy metabolism and locomotor activity by MC4R/cAMP signaling.
黑皮质素4受体（MC4R）在人类和啮齿动物的食欲及能量消耗调节中发挥着重要作用。MC4R信号受损会导致严重肥胖。MC4R主要与G蛋白G偶联。配体与MC4R结合会激活腺苷酸环化酶，导致细胞内cAMP水平升高。cAMP作为第二信使，调节各种细胞过程。MC4R也可与G及其他信号通路偶联。因此，MC4R/G信号对能量代谢和食欲的贡献仍不清楚。为研究MC4R细胞中G信号激活对全身能量代谢和食欲的影响，我们构建了一种新型小鼠品系，该品系在表达MC4R的细胞中选择性地表达一种仅由设计药物激活的与G偶联的设计受体[Gs - DREADD（GsD）]（GsD - MC4R小鼠）。在表达MC4R的细胞中，通过设计药物[去氯氯氮平（DCZ）；0.01∼0.1 mg/kg体重]对GsD进行化学遗传激活，可显著增加耗氧量和运动活性。此外，GsD激活显著降低呼吸交换率，促进脂肪酸氧化，但不影响核心（直肠）温度。低剂量的DCZ（0.01 mg/kg体重）不抑制食物摄入，但高剂量的DCZ（0.1 mg/kg体重）可抑制MC4R - GsD小鼠的食物摄入，尽管这两种DCZ剂量（0.01或0.1 mg/kg体重）均不影响对照小鼠的食物摄入。总之，当前研究表明，在表达MC4R的细胞中刺激G信号可增加能量消耗和运动活性，并抑制食欲。我们报告称，在表达黑皮质素4受体（MC4R）的细胞中，G信号调节能量消耗、食欲和运动活性。这些发现揭示了MC4R/cAMP信号调节能量代谢和运动活性的潜在机制。
