Study Of The Relationship Between Rcan2 And Rps6Kb1 On Body Weight Regulation In Mice

With the improvement of living standards of people, the incidence of obesity has increased dramatically in the past several decades. Obesity is becoming a global problem endangering human health. Obese individuals and over weight in dividuals are always accompanied with diabetes, lipid metabolic disorders and the developments of cardiovascular diseases, so studying on the mechanism of obesity will be the urgent issue that need to be resolved. It had been reported that the bodyweight is affected by the interaction of multiple factors, such as genetics, gender, age, diet composition, physical activity, psychological stress, health conditions, financial situation and the education levels, it is difficult to distinguish the roles of each factor in the body weight regulation. At present, laboratory animals especially the C57BL/6J mice are used to studying the regulatory mechanism of the bodyweight, which could offer valuable information forhuman obesity.Recently, with the widespread use of the gene targeting technology, the researchers have found that the deletion of various genes has impacts on body weight in mice. But it remains unclear that through which mechanism these genes affect body weight, what relationships exist among them, and whether the mechanisms on weight regulation of these genes are necessarily relevant to the prevalence of obesity.In our past study, we found that the inactivation of the Rcan2 gene in mice ameliorates the age- and diet-induced obeity by causing a reduction in food intake, and Rcan2 gene regulates food intake and promotes weight gain through a leptin-independent pathway. RCAN2 was initially identified as a T3-responsive gene in human fibroblast. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway. Intriguingly, Rps6kbp1-/- mice was reported to have lean phenotypes. In this study we compared the effects of these two mutations on growth and bodyweight in C57BL/6J mice, and speculate the relationship of these two genes on the body weight.We observed reduced body weight and lower fat mass in both Rcan2-/- and Rps6kb1-/- mice compared to the wildtype (WT) mice, and we report other differences unique to either the Rcan2-/- or Rps6kbpl-/- mice. Firstly, loss of Rcan2 does not alter body length, however Rcan2-/- mice exhibit reduced food intake. Incontrast, Rps6kbp1-/- mice exhibit abnormal embryonic development, which leads to smaller bodysize and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2-/- mice weigh significantly more than Rps6kbpl-/- mice, but both Rcan2-/- and Rps6kbp1-/- mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2-/- mice gain body weight and fat mass at slower rates than Rps6kbp1-/- mice. Finally, using the double-knock out mice (Rcan2-/- Rps6kbpl-/-), we demonstrate that concurrent loss of Rcan2-/- and Rps6kbpl-/- has an additive effect on body weight reduction in C57BL/6J mice. In addition, we performed pair-feeding experiments for a period of 16 weeks on HFD. Our results showed that if WT mice consumed the same amount of food as Rcan2-/- mice, their body weight trajectories were nearly identical, and they gained similar amount of weight during the 16-week monitoring period.Our data suggest that Rcan2 and Rps6kbl both regulate growth and body weight, though through different mechanisms. The absence of Rps6kbl affect the embryonic development of mice firstly, and then leading to the decrease of the body length and the reduction of the food intake and bodyweight, and thus Rps6kbl may be the key gene in the development of the mice, while the mutation of Rcan2 possibly only affect the ingestion of mice, the changes of body length and the body weight are the indirect results of the reduced food-intake, so Rcan2 was identified as an important gene in the process of obesity. Thus, we compared the effects of these two genes on the growth and body weight, and then elucidate their function in obesity.