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

Abstract

Objective: The melanin-concentrating hormone (MCH) is a centrally acting peptide implicated in the regulation of energy homeostasis and body weight, although its role in glucose homeostasis is uncertain. Our objective was to determine effects of MCHR1 antagonism on energy budgets and glucose homeostasis in mice. Methods: Effects of chronic oral administration of a specific MCHR1 antagonist (GW803430) on energy budgets and glucose homeostasis in diet-induced obese (DIO) C57BL/6J mice were examined. Results: Oral administration of GW803430 for 30 days reduced food intake, body weight, and body fat. Circulating leptin and triglycerides were reduced but insulin and nonesterified fatty acids were unaffected. Despite weight loss there was no improvement in glucose homeostasis (insulin levels and intraperitoneal glucose tolerance tests). On day 4-6, mice receiving MCHR1 antagonist exhibited decreased metabolisable energy intake and increased daily energy expenditure. However these effects had disappeared by day 22-24. Physical activity during the dark phase was increased by MCHR1 antagonist treatment throughout the 30-day treatment. Conclusions: GW803430 produced a persistent anti-obesity effect due to both a decrease in energy intake and an increase in energy expenditure via physical activity but did not improve glucose homeostasis.

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…”

“…The shift of the observed data compared to the model prediction (dashed line in Figure 3E) indicates a minor drug effect on EE in line with previously reported data. 10,42,43 Data on BW reduction vs. trough RO (24 h) from several compounds of the chemical series indicated a linear relationship ( Figure 3G; Supplementary Figure S4 for model choice). A BW reduction of about 12% required RO of 62% at 24 h in the mouse (thick gray lines in Figure 3G).…”

Effects of a novel potent melanin‐concentrating hormone receptor 1 antagonist, AZD1979, on body weight homeostasis in mice and dogs

“…AZD1979 prevented HFD‐induced glucose intolerance and reduced fasting insulin levels and HOMA‐index in DIO mice, indicating improved insulin sensitivity. This is in line with the reduced insulin levels observed in Mchr1 KO mice compared with wild type mice when fed an HFD (Chen et al , ; Bjursell et al , ), but in contrast to the unchanged fasting insulin levels and glucose tolerance following administration of the MCH 1 receptor antagonist GW803430 to DIO mice (Zhang et al , ). Thus, different MCH 1 receptor antagonists seem to have different effects on glucose homeostasis even though they all lower body wt in rodents.…”

“…Brain penetration seems to be required for MCH 1 receptor antagonists to cause body weight loss (Eric Hu et al , ), and several small molecule MCH 1 receptor antagonists have been developed with the aim of treating obesity (reviewed in Macneil, ; Johansson and Lofberg, ). However, few studies have investigated the underlying mechanisms for the anti‐obesity effects of these molecules in rodents and the results are partly conflicting, showing either only effects on food intake or combined effects on both food intake and energy expenditure (Huang et al , ; Kowalski et al , ; Ito et al , ; Zhang et al , ).…”

Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone

“…Given that both the DRL and delay discounting tasks involve motivated responding for food, as well as accurate timing capabilities, it is possible that apparent outcomes of CA1v MCH signaling on impulsivity are secondary to one or both of these effects. Further, both global MCH knockout 34–36 and pharmacological MCHR1 blockade 37 are associated with hyperactivity, suggesting that DRL and delay discounting results may be secondary to changes in physical activity. To investigate food-motivated behavior (independent of impulsivity), we first tested whether CA1v MCH signaling affects normal, home cage feeding behavior.…”