Full body loss of the nuclear hormone receptor Nr4a3 results induces obesity and glucose intolerance.

Abstract

Type 2 diabetes (T2D) is increasing at an alarming rate worldwide. T2D is characterized by obesity, glucose intolerance, and elevated blood glucose level. The orphan nuclear receptor Nr4a3 has been shown to play critical roles in controlling expression of genes associated with proliferation, cell survival and fuel metabolism. However, Nr4a3’s role in glucose homeostasis has yet to be explored. Here we present data demonstrating that male and female Nr4a3 full‐body knock out (KO) mice have a ~22% increase in body mass when compared to control animals and fed a standard diet, and a ~30% increase when fed a high fat diet. In addition, these mice present with significantly elevated blood glucose and impaired glucose tolerance. Given Nr4a3’s role in mitochondrial function and fuel utilization, we measured respiration of liver, adipose and muscle. Nr4a3 KO mice fed a standard diet presented no difference in liver or muscle respiration, however adipose respiration was significantly impaired regardless of sex. Animals fed a high fat diet presented with impaired adipose, liver and muscle respiration. These data begin to demonstrate that Nr4a3 is necessary for whole‐body glucose homeostasis, that loss of Nr4a3 predisposes animals to obesity and glucose intolerance, and that high fat feeding worsens the observed phenotypes. These data serve as a step toward understanding the pathway of T2D progression and the role that Nr4a3 plays in this progression.