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Obesity is caused by an imbalance between energy intake and expenditure and has become a major health‐care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional  Mc4r  knockout model in the rat, resulting from an  N ‐ethyl‐ N ‐nitrosourea mutagenesis–induced point mutation.  In vitro  observations revealed impaired membrane‐binding and subsequent nonfunctionality of the receptor, whereas  in vivo  observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti‐Related Protein 79–129  (AgRP 79–129 ), an MC4R inverse agonist, or Melanotan‐II (MTII), an MC4R agonist, did affect feeding behavior in wild‐type rats but not in homozygous mutant rats, confirming complete loss of MC4R function  in vivo . Finally, ICV administration of MTII induced excessive grooming behavior in wild‐type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII‐induced grooming behavior is exclusively regulated  via  MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function.

Melanocortin Receptor 4 Deficiency Affects Body Weight Regulation, Grooming Behavior, and Substrate Preference in the Rat