Nr4a1 β-細胞特異的欠損はメスマウスの糖耐性を損なう

The Nr4a family of transcription factors control 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 knock out 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-months of age. While 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.