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

Abstract

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 Protein79–129 (AgRP79–129), 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 Signaling in the Brainstem Influences Vagal Outflow to the Stomach

“…We used MT-II, a drug widely used to assess the effect of MC4-R activation on food intake and body weight (Baird et al, 2011;Blevins et al, 2012;De Jonghe et al, 2012;Mul et al, 2012;Roseberry, 2013). We found its predominant effect at the DMV was to decrease the amplitude of gastric phasic contractions.…”

Melanocortin 4 receptor distribution in the human hypothalamus

“…AVP release is driven by serum osmolality, and inappropriately low plasma levels as seen in central diabetes insipidus lead to a hyperosmolar state with polydipsia and polyuria (38). Interestingly, the Mc4r K314X mutation in the rat described by Mul et al (39) induces polydipsia. In view of the currently reported co-localization of AVP and MC4R, it is tempting to hypothesize that a deficient AVP release in the Mc4r K314X rat may be involved in the pathogenesis of the reported polydipsia.…”

Exome sequencing in Thai patients with familial obesity

“…This is the first study to use the exome sequencing approach to identify exonic variant(s) related to the BMI in an obese Thai (Farooqi et al, 2003;Begriche et al, 2011;Dubern and Clement, 2012;Loos, 2012;Mul et al, 2012;Tsou et al, 2012), did not differ significantly between obese and normal subjects. Subsequently, 65 variants in 60 genes predicted to negatively affect the protein structure and function were chosen for further analyses.…”

“…Previous studies have identified a correlation between several genes, such as LEP, LEPR,POMC,PCSK1,FTO,MC3R,MC4R,GNPDA2,TMEM18,QPCTL/GIPR,BDNF,ETV5,MAP2K5/SKOR1,SEC16B,SIM1, TNKS/MSRA, and obesity, using a candidate gene approach or a genome-wide association study (GWAS) (Farooqi et al, 2003;Begriche et al, 2011;Dubern and Clement, 2012;Mul et al, 2012;Tsou et al, 2012). Most of these variants were in the intronic region; therefore, the mechanism leading to the development of disease could not be determined (Dorajoo et al, 2012;Loos, 2012).…”