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

Abstract

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-DREADD (Gs-coupled designer receptors exclusively activated by designer drugs: 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 BW) 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 BW) did not suppress food intake, but a high dose of DCZ (0.1 mg/kg BW) suppressed food intake in MC4R-GsD mice, although either DCZ dose (0.01 or 0.1 mg/kg BW) 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.

Neurochemical Basis of Inter-Organ Crosstalk in Health and Obesity: Focus on the Hypothalamus and the Brainstem

“…The MC4R/Sim1 neurons, located in the PVH, together with the POMC neuronal projections, arising from the ARC, form the melanocortin pathway in the hypothalamus. Stimulation of MC4R neurons in the PVH results in pronounced satiation effects and thereby can induce a negative energy balance and confer protection against obesity [ 50 , 89 , 90 , 91 ]. Interestingly, short-term administration of MC4R agonists can also increase resting energy expenditure and shift substrate utilization towards increased fat oxidation in obese individuals suggesting additional mechanisms through which the melanocortin pathway and Sim1 neurons induce a negative energy balance [ 92 ].…”

Hypothalamic melanocortin-4 receptors on astrocytes mediate inflammation and body weight homeostasis

“…MC4R signaling pathways play a multi-faceted role in regulating energy balance. Stimulating MC4R's within the brain has been shown to increase energy expenditure, locomotor activity and anorexigenic behaviors (26). We used promethion indirect calorimetry to investigate the effects of aMC4R deletion in the hypothalamus on these measures.…”

Deschloroclozapine exhibits an exquisite agonistic effect at lower concentration compared to clozapine-N-oxide in hM3Dq expressing chemogenetically modified rats

“…In our previous research, we employed CNO (1 mg/kg) to investigate the analgesic and anti-inflammatory properties of endogenous oxytocin (OXT) using OXT-hM3Dq-mCherry transgenic rats, which express hM3Dq and mCherry specifically in OXT neurons ( Nishimura et al, 2022 ). Although DCZ has shown promise in previous studies, most of them have been conducted in mice or monkeys ( Nagai et al, 2020 ; Matsumura et al, 2022 ; Perez et al, 2022 ). Hence, our objective was to assess the effectiveness of DCZ in our transgenic rat model.…”