Melanin-Concentrating Hormone Receptor 1 Deficiency Increases Insulin Sensitivity in Obese Leptin-Deficient Mice Without Affecting Body Weight

Melanin-Concentrating Hormone Receptor 1 Deficiency Increases Insulin Sensitivity in Obese Leptin-Deficient Mice Without Affecting Body Weight Mikael Bjursell 1 2 , Anna-Karin Gerdin 2 , Karolina Ploj 4 , David Svensson 5 , Lennart Svensson 3 , Jan Oscarsson 1 4 , Michael Snaith 2 , Jan Törnell 1 2 and Mohammad Bohlooly-Y 1 2 1 Department of Physiology and Pharmacology, Gothenburg University, Gothenburg, Sweden 2 AstraZeneca Transgenics & Comparative Genomics, AstraZeneca, Mölndal, Sweden 3 Department of Molecular Pharmacology, AstraZeneca, Mölndal, Sweden 4 Department of Integrative Pharmacology, AstraZeneca, Mölndal, Sweden 5 Department of Biostatistic, AstraZeneca, Mölndal, Sweden Address correspondence and reprint requests to Mikael Bjursell, AstraZeneca, Mölndal S-43183 Mölndal, Sweden. E-mail: mikael.bjursell{at}astrazeneca.com Abstract The hypothalamic peptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis. Animals overexpressing MCH develop hyperphagia, obesity, and insulin resistance. In this study, mice lacking both the MCH receptor-1 (MCHr1 knockout) and leptin ( ob/ob ) double-null mice (MCHr1 knockout ob/ob ) were generated to investigate whether the obesity and/or the insulin resistance linked to the obese phenotype of ob/ob mice was attenuated by ablation of the MCHr1 gene. In MCHr1 knockout ob/ob mice an oral glucose load resulted in a lower blood glucose response and markedly lower insulin levels compared with the ob/ob mice despite no differences in body weight, food intake, or energy expenditure. In addition, MCHr1 knockout ob/ob mice had higher locomotor activity and lean body mass, lower body fat mass, and altered body temperature regulation compared with ob/ob mice. In conclusion, MCHr1 is important for insulin sensitivity and/or secretion via a mechanism not dependent on decreased body weight. BAT, brown adipose tissue CRH, corticotrophin-releasing hormone MCH, melanin-concentrating hormone MCHr1, MCH receptor-1 MSH, melanocyte-stimulating hormone RER, respiratory exchange ratio SCD-1, stearoyl-CoA desaturase-1 UCP-1, uncoupling protein-1 Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted December 16, 2005. Received October 6, 2005. DIABETES