TNIK is a conserved regulator of glucose and lipid metabolism in obesity.

Abstract

Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in <i>Drosophila</i> and mice. Loss of the <i>Drosophila</i> ortholog of <i>TNIK</i>, <i>misshapen</i>, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. <i>Tnik</i> knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of <i>Tnik</i> knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of <i>TNIK</i> variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.