Abstract
Melanocortin-3 and 4 receptors (MC3R and MC4R) can regulate energy homeostasis, but their respective roles especially the functions of MC3R need more exploration. Here Mc3r and Mc4r single and double knockout (DKO) rats were generated using CRISPR-Cas9 system. Metabolic phenotypes were examined and data were compared systematically. Mc3r KO rats displayed hypophagia and decreased body weight, while Mc4r KO and DKO exhibited hyperphagia and increased body weight. All three mutants showed increased white adipose tissue mass and adipocyte size. Interestingly, although Mc3r KO did not show a significant elevation in lipids as seen in Mc4r KO, DKO displayed even higher lipid levels than Mc4r KO. DKO also showed more severe glucose intolerance and hyperglycaemia than Mc4r KO. These data demonstrated MC3R deficiency caused a reduction of food intake and body weight, whereas at the same time exhibited additive effects on top of MC4R deficiency on lipid and glucose metabolism. This is the first phenotypic analysis and systematic comparison of Mc3r KO, Mc4r KO and DKO rats on a homogenous genetic background. These mutant rats will be important in defining the complicated signalling pathways of MC3R and MC4R. Both Mc4r KO and DKO are good models for obesity and diabetes research.
Highlights
Mc4r and Mc3r knockout (KO) mouse models have provided some evidence for their respective role in energy homeostasis
In 2013 we published the generation of Mc4r KO, and Mc4r/Mc3r double knockout (DKO) rat by CRISPR-Cas[9] and observed a similar phenotype of the Mc4r KO rat in body weight, food intake, insulin and leptin level as compared to the N-ethyl-N-nitrosourea-induced Mc4r KO rat, these observations were only based on founders with biallelic mutants[26]
An investigation on Mc3r KO, Mc4r KO, and DKO rats was carried out and data were compared systematically regarding their metabolic phenotypes in a single genetic background, in order to provide an overall understanding of these two receptors in energy metabolism, and to evaluate the possibility of using these KO rats as suitable animal models for obesity or type 2 diabetes
Summary
Mc4r and Mc3r knockout (KO) mouse models have provided some evidence for their respective role in energy homeostasis. The first functional knockout rat (Wistar/ Crl background) for Mc4r (Mc4rK314X) was reported in 2011 as the result of an N-ethyl-N-nitrosourea-induced point mutation[24], and exhibited increased body weight, food intake and white adipose mass, and altered substrate preference[25]. An investigation on Mc3r KO, Mc4r KO, and DKO rats was carried out and data were compared systematically regarding their metabolic phenotypes in a single genetic background, in order to provide an overall understanding of these two receptors in energy metabolism, and to evaluate the possibility of using these KO rats as suitable animal models for obesity or type 2 diabetes. Results showed that MC4R deficiency led to a dramatic alteration in energy homeostasis including obesity and hyperglycaemia, whereas MC3R deficiency showed hypophagia and reduced body weight. Data from our extensive phenotypic comparison suggested that Mc4r KO and DKO might be good rat models for obesity or type 2 diabetes (T2D)
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