Nr4a1 β-cell specific deletion impairs glucose tolerance in female mice

The Nr4a family of transcription factors controls the expression of genes essential for fuel metabolism and cellular proliferation. The loss of Nr4a1 in the 832/13 INS-1 β-cell line diminishes mitochondrial respiration, decreases ATP production, and impairs glucose-stimulated insulin secretion. Nr4a1 overexpression increases β-cell proliferation, and full-body Nr4a1 knockout mice have decreased β-cell area. Thus, we hypothesize that β-cell Nr4a1 expression plays a critical role in diabetes disease progression. Here we report the effects of β-cell specific Nr4a1 deletion in mice beginning at 3-mo of age. Although Nr4a1 β-cell specific deletion has no deleterious effect on male mice fed a standard or high-fat diet, or on female mice fed a standard chow diet, female mice fed a high-fat diet have decreased glucose tolerance, impaired insulin secretion, impaired expression of key glycolytic genes, and decreased pancreatic β-cell area. We demonstrate that estrogen is sufficient to induce β-cell Nr4a1 expression. Our data suggest that Nr4a1 is critical for maintaining functional β-cell mass in females as a response to the stress of increased adiposity.NEW & NOTEWORTHY We report the effects of β-cell specific Nr4a1 deletion in mice (Nr4a1β^-/-). We determined that Nr4a1β^-/- impairs glucose tolerance in female mice fed a high-fat diet. We found decreases in β-cell mass and glucose-stimulated insulin secretion. Nr4a1β^-/- decreased mRNA and protein levels of key genes involved in glucose utilization and cell cycle progression. Estrogen treatment induces mRNA and protein expression of Nr4a1 in cell lines as well as primary mouse islets.