Abstract
Diabesity is a growing pandemic with substantial health and financial consequences. We are developing microRNA (miRNA)-based drug candidates that transform fat storing adipocytes into fat burning adipocytes (browning effect) to treat metabolic diseases characterized by lipotoxicity. Through phenotypic screening in primary cultures of human subcutaneous adipocytes, we discovered that inhibition of miRNA-22-3p by several complementary antagomirs resulted in increased lipid oxidation, mitochondrial activity, and energy expenditure (EE). These effects may be mediated through activation of target genes like KDM3A, KDM6B, PPARA, PPARGC1B, and SIRT1 involved in lipid catabolism, thermogenesis, and glucose homeostasis. In the model of Diet-Induced Obesity in mice of various ages, weekly subcutaneous injections of various miRNA-22-3p antagomirs produced a significant fat mass reduction, but no change of appetite or body temperature. Insulin sensitivity, as well as circulating glucose and cholesterol levels, was also improved. These original findings suggest that miRNA-22-3p inhibition could become a potent treatment of human obesity and type 2 diabetes mellitus, the so-called diabesity characterized by lipotoxicity and insulin resistance.
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