Abstract
Obesity is a debilitating disease that has become a global epidemic. Although progress is being made, the underlying molecular mechanism by which obesity develops still remains elusive. Recently, we reported that the expression levels of bromodomain-containing protein 7 (BRD7) are significantly reduced in the liver of obese mice. However, it is not clear whether decreased levels of hepatic BRD7 are directly associated with the development of obesity and disturbance in glucose homeostasis. Here, using heterozygous BRD7 knockout and liver-specific BRD7 knockout mouse models, we report that reduced BRD7 levels lead to increased weight gain with little effect on glucose metabolism. On the other hand, upregulating BRD7 in the liver starting at an early age protects mice from gaining excessive weight and developing glucose intolerance and insulin resistance when challenged with a high-fat diet.
Highlights
Obesity is a global public health problem and a major risk factor behind several metabolic disorders such as type 2 diabetes and cardiovascular disease[1,2,3]
We have previously reported that homozygous knockout of bromodomain-containing protein 7 (BRD7) leads to embryonic lethality prior to embryonic day 16.513
BRD7+/− mice displayed an increase in body weight compared to BRD7+/+ mice, but this increase did not reach statistical significance when analyzed by twoway ANOVA (Fig. 1b)
Summary
Obesity is a global public health problem and a major risk factor behind several metabolic disorders such as type 2 diabetes and cardiovascular disease[1,2,3]. BRD7 interacts with the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85α and p85β, and shuttles p85 to the nucleus[10,11] This interaction between BRD7 and p85 leads to increased translocation of a transcription factor called the spliced form of X-box binding protein 1 (XBP1s) to the nucleus. BRD7 levels are decreased in the liver of obese and type 2 diabetic mouse models[11]. It was shown that BRD7 increases phosphorylation of glycogen synthase kinase 3β (GSK3β) and ribosomal protein S6 kinase (S6K)[12]. This phosphorylation is not observed in the absence of the mTORC1 signaling cascade. We utilized knockout and transgenic mouse models to investigate how BRD7 affects the development of obesity and glucose homeostasis
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