305-LB: BRD7 Deficiency Leads to the Development of Obesity

Elevated endoplasmic reticulum (ER) stress is tightly associated with the development of obesity and insulin resistance. Previous reports showed that haploinsufficiency of X-box binding protein 1 (XBP1), one of the master regulators of ER protein folding function, results in obesity and type 2 diabetes. In our previous work, we showed that bromodomain-containing protein 7 (BRD7) regulates the nuclear translocation of XBP1 through its interaction with the regulatory subunits of phosphatidylinositol 3 kinase (PI3K), p85s. We reported that the expression levels of BRD7 are significantly reduced in the liver of obese mice and acute upregulation of hepatic BRD7 in obese and type 2 diabetic mice improves glucose homeostasis. In our current unpublished work, we show that nuclear translocation of BRD7 is independent of PI3K activity and p110, the catalytic subunit of PI3K, is not involved in the degradation of BRD7. We show that both whole-body reduction and liver-specific deletion of BRD7 lead to increased weight gain. We also show that sustained restoration of BRD7 in the liver starting at an early age protects mice from developing obesity, glucose intolerance, and insulin resistance even when challenged with a high-fat diet.