Deletion of <i>Jazf1</i> gene causes early growth retardation and insulin resistance in mice.

Abstract

Single-nucleotide polymorphisms in the human juxtaposed with another zinc finger protein 1 (<i>JAZF1</i>) gene have repeatedly been associated with both type 2 diabetes (T2D) and height in multiple genome-wide association studies (GWAS); however, the mechanism by which JAZF1 causes these traits is not yet known. To investigate the possible functional role of JAZF1 in growth and glucose metabolism in vivo, we generated <i>Jazf1</i> knockout (KO) mice and examined body composition and insulin sensitivity both in young and adult mice by using ¹H-nuclear magnetic resonance and hyperinsulinemic-euglycemic clamp techniques. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were reduced in both young and adult <i>Jazf1</i> KO mice, and young <i>Jazf1</i> KO mice were shorter in stature than age-matched wild-type mice. Young <i>Jazf1</i> KO mice manifested reduced fat mass, whereas adult <i>Jazf1</i> KO mice manifested increased fat mass and reductions in lean body mass associated with increased plasma growth hormone (GH) concentrations. Adult <i>Jazf1</i> KO manifested muscle insulin resistance that was further exacerbated by high-fat diet feeding. Gene set enrichment analysis in <i>Jazf1</i> KO liver identified the hepatocyte hepatic nuclear factor 4 alpha (HNF4α), which was decreased in <i>Jazf1</i> KO liver and in <i>JAZF1</i> knockdown cells. Moreover, GH-induced IGF-1 expression was inhibited by <i>JAZF1</i> knockdown in human hepatocytes. Taken together these results demonstrate that reduction of JAZF1 leads to early growth retardation and late onset insulin resistance in vivo which may be mediated through alterations in the GH-IGF-1 axis and HNF4α.