Authors: Jared Carter
Mentors: Jeff Tessem
Insitution: Brigham Young University
Type 2 diabetes mellitus (T2D) is a chronic condition affecting nearly half a billion people worldwide. Symptoms of T2D include impaired glucose tolerance, decreased insulin secretion and significant weight gain. While the symptoms of T2D are well-documented, the underlying pathology remains unclear. Recent research has indicated the critical role of the nuclear receptor Nr4a3 in the development of glucose intolerance and weight gain. In individuals with T2D, the Nr4a3 promoter is hypermethylated, leading to decreased Nr4a3 expression. Elucidating the role of Nr4a3 in mitochondrial respiration in adipose will help define the mechanism of T2D onset and treatment. I studied mice with full body knockout (KO) for Nr4a3. These mice exhibited T2D-like symptoms, including impaired glucose tolerance, reduced insulin secretion and increased adiposity. I measured mitochondrial respiration in muscle, liver, kidney, and adipose tissue, with impaired respiration only observed in adipose tissue. This impairment in adipose tissue respiration correlated with an increase in the size of all adipose deposits, larger adipocytes, and expanded lipid droplets. Intriguingly, the analysis of electron transport chain and tricarboxylic acid complex proteins revealed no significant differences compared to control samples. Instead, the change in respiration was attributed to a reduction in active DRP1 protein, responsible for mitochondrial fission and maintenance. These findings have important implications for our understanding of T2D and its potential treatment strategies, which will be discussed in more detail.