Metabolism Phenotype Research Of Melanocorin Receptor 3 And Melanocorin Receptor 4 Knockout Rats

Obesity, a pathologic state defined by excess adipose tissue, that caused by long-term excess energy intake which induces energy balance disorders. Obesity is a global public health issue as it affects a large population and is linked with increased risk for numerous chronic diseases. Recently, the number of persons categorized as obese (body mass index, BMI>30kg/m2) has risen dramatically in developed countries and is now also increasing in developing countries. Obesity can affect multiple organs of the body, increase risk of developing chronic conditions associated with metabolism disorders such as type 2 diabetes and cardiovascular disease. So far, the World Health Organization (WHO) reported that obesity has become one of leading public health problem in the world. Strategies for preventing as well as attenuating obesity and its comorbidities are urgently needed. In this case, we need suitable animal models for basic research and therapeutic development.The hypothalamic melanocortin system plays an important role in maintenance of body weight and energy homeostasis. It is a crucial part of convergence connecting signals of metabolic status with the neural circuitry that regulate appetite and the autonomic and neuroendocrine system controlling metabolism. The melanocortin receptors are members of the G protein coupled receptor (GPCR) family. There are five melanocortin receptors (MC1R to MC5R) named in order of their cloning. Two melanocortin receptors, melanocortin 3 receptor and melanocortin 4 receptors (MC3R and MC4R), play critical roles in the regulation of energy balance. MC3R have a certain regulate functions in energy homeostasis, while there are a lot of literature indicating that Mc4r play an essential role in regulating both energy intake through the control of satiety and energy expenditure, and mutations in the MC4R gene are the most common cause of monogenic obesity in human beings.Compared with mouse, rat models are more suitable for mimicking many human diseases and for investigation in toxicology, behavior and nutriology. By injection of Cas9/guide RNA against MC3R and MC4R into rat zygotes, rat with single mutant gene and double mutant genes were obtained. By study these mutant gene rats, we hope to identify suitable models for obesity or diabetes diseases investigations.By comparing their phenotype, we found MC3R konckout rats showed a certain extent of lipid metabolism disorder,such as higher total abdominal fat percentage, enlarged perirenal adipose cell volume, but there seems little change in glucose metabolism. In addition, MC4R single gene mutation and MC3R?MC4R double genes mutation rats developed metabolism disorder-related phenotype such as weight gain, hyperlipidemia, hyperglycemia impaired glucose tolerance etc. And metabolism disorder in MC3R?MC4R double gene mutation rat start more early than MC4R single gene mutation rats. Our study demonstrate that MC3R especially MC4R regulate lipid and glucose metabolism, and MC4R mutant rats or MC3R/MC4R double mutant rats maybe useful for obesity or type 2 diabetes related research.