BRD7 deficiency leads to the development of obesity and hyperglycemia

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.

Intestinal ex vivo organoid culture reveals altered programmed crypt stem cells in patients with celiac disease

“…Most strikingly was the upregulation of bromodomain containing protein 7 (BRD7; 8,2 fold), and the inhibitor of growth 4 (ING4; 3,5 fold) in patients with CD. BRD7 is associated with tumor progression in prostate cancer 23 , but upregulation of BRD7 also protects from excessive weight gain and hyperglycemia at least in mice studies 24 . ING members are involved in cell proliferation, apoptosis, senescence, and DNA replication and repair.…”

Emerging Roles of BRD7 in Pathophysiology

“…Use of an adenovirus-mediated transfer system to overexpress BRD7 in the liver of genetically obese ob / ob and high-fat diet-induced obese mice induces the nuclear translocation of XBP1s, resulting in increased transcription of XBP1s target genes and a decrease in ER stress levels [ 35 ]. Upregulation of BRD7 in the liver of obese and type 2 diabetic mice reduces blood glucose levels and improves glucose homeostasis [ 35 , 42 ]. These findings suggest that BRD7 participates in UPR signaling and promotes euglycemia by restoring the activity of XBP1s [ 35 , 69 ].…”

“…BRD7 transgenic mice, in which hepatic BRD7 levels are elevated, do not gain as much body weight as wild-type control mice do when they are placed on a high-fat diet (45% kcal from fat) [ 42 ]. BRD7 transgenic mice that are fed on a high-fat diet also display reduced plasma triglyceride levels [ 42 ] and decreased mRNA expression of Pparγ , Fasn , Dgat2 , and Srebf1 in white adipose tissue, showing that upregulation of BRD7 in the liver affects the expression of lipogenic genes in other organs [ 42 ]. These findings suggest that BRD7 is an important regulator of the development of obesity and lipid metabolism.…”

“…Conversely, mice with a mixed 129/SvJ and C57BL/6J background that lack one allele of BRD7 display increased body weight when placed on a high-fat diet [ 42 ] and exhibit high levels of hepatic triglyceride [ 42 ]. Liver-specific BRD7 knockout mice (on the same background) that are fed on a high-fat diet also display increased body weight and elevated hepatic triglyceride levels [ 42 ]. These studies indicate that a lack of hepatic BRD7 leads to the development of obesity.…”

“…On the other hand, neither heterozygous whole-body BRD7 knockout mice nor liver-specific BRD7 knockout mice exhibit significant disruptions in glucose homeostasis, even when they are fed a high-fat diet [ 42 ]. This may be because of the difference in hepatic BRD7 levels between BRD7 knockouts and control mice that are fed on a high-fat diet is not enough to show strong phenotypic changes [ 13 ], given that the high-fat diet significantly reduces hepatic BRD7 levels [ 42 ]. However, knocking down BRD7 by BRD7-specific shRNA in mice after challenging them with a high-fat diet leads to hyperglycemia [ 13 ].…”