Obesity and Type 2 diabetes (T2D) are complex and inter-related metabolic diseases associated with insulin resistance and pancreatic β-cell dysfunction. We recently identified a single gene, Regulator of calcineurin 1 (Rcan1), as a candidate gene linking hyperglycemia and functional changes in T2D β-cells (1). Rcan1 expression is also strongly correlated in both liver and adipose tissue with worsening metabolism. To determine whether such increasing levels of peripheral Rcan1 expression are causative in driving worsening metabolism, we placed Rcan1-/- mice under metabolic stress using a variety of different high fat diets. Rcan1-/- mice had an elevated resting metabolic rate and were resistant to diet-induced obesity. Furthermore, they maintained insulin sensitivity and showed no evidence of inflammation in visceral fat on a high fat diet. Cold-induced expression of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) and uncoupling protein 1 (Ucp1) was significantly higher in the subcutaneous fat of Rcan1 KO mice compared to in wild type, indicative of an increased capacity for thermogenic “beiging” of white adipose. The effect was cell-autonomous, as cultured adipocytes depleted of Rcan1 also showed enhanced expression of Pgc1α and Ucp1 in response to an adrenergic stimulus. On an evolutionary scale, in the context of limited food resources, Rcan1-mediated suppression of adaptive thermogenesis would be beneficial, however, in the face of current caloric abundance, Rcan1-mediated suppression of these adaptive avenues of energy expenditure may contribute to the growing epidemic in obesity.
(1) Peiris H, et al Keating DJ. A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes. PLoS Genetics. 2016 May 19;12(5):e1006033.