Mechanism of the anti‐obesity effects induced by a novel Melanin‐concentrating hormone 1‐receptor antagonist in mice

Abstract

Background and purpose: Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists. Experimental approach: To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions. Key results: Treatment with the MCH1 receptor antagonist at 30 mg·kg -1 for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis. Conclusions and implications:Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.

Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin‐concentrating Hormone Receptor 1 Antagonist

“…Furthermore, based on the assumption that AZD1979 mainly targets EI and not EE, the mathematical model15, 16 also predicted a linear relationship (dashed line in Figure 3 E ). The shift of the observed data compared to the model prediction (dashed line in Figure 3 E ) indicates a minor drug effect on EE in line with previously reported data 10, 42, 43…”

Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet‐induced obese mice

“…Huang et al showed that rats treated with a MCHR1 antagonist (1-(4-Amino-phenyl)-pyrrolidin-3-yl-amine and 6-(3-aminopyrrolidin-1-yl)-pyridin-3-yl-amine) lost significantly more weight than pair-fed matches (19). Acute administration of a highly selective and potent MCHR1 antagonist (20) that has high brain penetrability and oral bioavailability increased metabolic rate in DIO mice (20). Moreover, mice chronically treated with this antagonist exhibited a significantly higher body temperature compared to pair-fed controls (20).…”

Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

“…We conclude that drug effects on T b can be a useful and efficient pharmacodynamic marker. (18) were synthesized at Merck Research Laboratories or Banyu Pharmaceutical, as described. Sibutramine, AM251, and CL-316243 were purchased from Sigma-Aldrich (St. Louis, MO).…”