Increased Accumulation of Long‐chain Fatty Acids in Skeletal Muscle May Contribute Insulin Resistance in Znt7 Knockout Mice

Abstract

The Slc30a7 (Znt7) gene encodes a ubiquitously expressed zinc transporter involved in transporting cytoplasmic zinc into the Golgi apparatus and vesicles. The Znt7 knockout (KO) mouse is mildly zinc deficient. Our previous studies have demonstrated that insulin resistance may underlie severe glucose intolerance in Znt7 KO mice fed a high fat diet (45% Kcal). In humans, insulin resistance in peripheral tissues is a precursor to Type 2 diabetes (T2D). Abnormal lipid metabolism in peripheral tissues is implicated in the development of insulin resistance in humans and in mouse models of T2D. To understand the mechanisms underlying insulin resistance in Znt7 KO mice, we used a metabolomics approach to detect changes in major metabolites related to fatty acid metabolism in peripheral tissues including skeletal muscle, liver and fat between Znt7 KO and age-matched control mice. We found that Znt7 KO mice had elevated triglycerides in skeletal muscle. Fatty acid levels including palmitic acid, stearic acid, oleic acid, linoleic acid, and arachidonic acid in skeletal muscle and subcutaneous fat tissues of Znt7 KO mice were 2-fold higher than the control. As a result, metabolic products from these free fatty acids, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 12,13-dihydroxyo (12,13-DiHOME) were also elevated in the skeletal muscle and subcutaneous fat of Znt7 KO mice. These data suggest that abnormal free fatty acid metabolism may contribute to muscle and fat insulin resistance in Znt7 KO mice.