Antisense oligonucleotide‐mediated knockdown of Mpzl3 attenuates the negative metabolic effects of diet‐induced obesity in mice

Previously, we demonstrated that global knockout (KO) of the gene encoding myelin protein zero‐like 3 (Mpzl3) results in reduced body weight and adiposity, increased energy expenditure, and reduced hepatic lipid synthesis in mice. These mice also exhibit cyclic and progressive alopecia which may contribute to the observed hypermetabolic phenotype. The goal of the current study was to determine if acute and peripherally restricted knockdown of Mpzl3 could ameliorate the negative metabolic effects of exposure to a high‐fat and sucrose, energy‐dense (HED) diet similar to what was observed in global Mpzl3 KO mice in the absence of a skin phenotype. Mpzl3 antisense oligonucleotide (ASO) administration dose‐dependently decreased fat mass and circulating lipids in HED‐fed C57BL/6N mice. These changes were accompanied by a decrease in respiratory exchange ratio, a reduction in energy expenditure and food intake, a decrease in expression of genes regulating de novo lipogenesis in white adipose tissue, and an upregulation of genes associated with steroid hormone biosynthesis in liver, thermogenesis in brown adipose tissue and fatty acid transport in skeletal muscle. These data demonstrate that resistance to the negative metabolic effects of HED is a direct effect of Mpzl3 knockdown, rather than compensatory changes that could be associated with deletion of Mpzl3 during development in global KO mice. Inhibiting MPZL3 could be a potential therapeutic approach for the treatment of obesity and associated dyslipidemia.