Abstract: It is widely accepted that body weight and adipose mass are tightly regulated by homeostatic mechanisms, in which leptin plays a critical role through hypothalamic pathways, and obesity is a result of homeostatic disorder. However, in C57BL/6J mice, we found that Rcan2 increases food intake and plays an important role in the development of age- and diet-induced obesity through a leptin-independent mechanism. RCAN2 was initially identified as a thyroid hormone (T3)-responsive gene in human fibroblasts. Expression of RCAN2 is regulated by T3 through the PI3K-Akt/PKB-mTOR-Rps6kb1 signaling pathway. Intriguingly, both Rcan2^−/− and Rps6kb1^−/− mutations were reported to result in lean phenotypes in mice. In this study we compared the effects of these two mutations on growth and body weight in C57BL/6J mice. We observed reduced body weight and lower fat mass in both Rcan2^−/− and Rps6kb1^−/− mice compared to the wild-type mice, and we reported other differences unique to either the Rcan2^−/− or Rps6kb1^−/− mice. Firstly, loss of Rcan2 does not directly alter body length; however, Rcan2^−/− mice exhibit reduced food intake. In contrast, Rps6kb1^−/− mice exhibit abnormal embryonic development, which leads to smaller body size and reduced food intake in adulthood. Secondly, when fed a normal chow diet, Rcan2^−/− mice weigh significantly more than Rps6kb1^−/− mice, but both Rcan2^−/− and Rps6kb1^−/− mice develop similar amounts of epididymal fat. On a high-fat diet, Rcan2^−/− mice gain body weight and fat mass at slower rates than Rps6kb1^−/− mice. Finally, using the double-knockout mice (Rcan2^−/− Rps6kb1^−/−), we demonstrate that concurrent loss of Rcan2 and Rps6kb1 has an additive effect on body weight reduction in C57BL/6J mice. Our data suggest that Rcan2 and Rps6kb1 mutations both affect growth and body weight of mice, though likely through different mechanisms.

Key words: Rcan2 gene, Rps6kb1 gene, Growth, Body weight regulation, Obesity

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