BRD7 improves glucose homeostasis independent of IRS proteins

in Journal of Endocrinology
Authors:
Yoo Kim Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
Department of Nutritional Sciences, Oklahoma State University, Stillwater, Oklahoma, USA

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https://orcid.org/0000-0002-4525-1319
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Junsik M Lee Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA

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Youngah Han Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA

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Rongya Tao Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

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Morris F White Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

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Renyan Liu Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

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Sang Won Park Division of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts, USA
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA

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https://orcid.org/0000-0001-7764-3133

Correspondence should be addressed to S W Park: sangwon.park@childrens.harvard.edu

*(Y Kim and J M Lee contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-23-0119
Volume/Issue:
Volume 258: Issue 3
Article Type:
Research Article
Article ID:
e230119
Online Publication Date:
14 Aug 2023
Copyright:
© the author(s) 2023
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Bromodomain-containing protein 7 (BRD7) has emerged as a player in the regulation of glucose homeostasis. Hepatic BRD7 levels are decreased in obese mice, and the reinstatement of hepatic BRD7 in obese mice has been shown to establish euglycemia and improve glucose homeostasis. Of note, the upregulation of hepatic BRD7 levels activates the AKT cascade in response to insulin without enhancing the sensitivity of the insulin receptor (InsR)–insulin receptor substrate (IRS) axis. In this report, we provide evidence for the existence of an alternative insulin signaling pathway that operates independently of IRS proteins and demonstrate the involvement of BRD7 in this pathway. To investigate the involvement of BRD7 as a downstream component of InsR, we utilized liver-specific InsR knockout mice. Additionally, we employed liver-specific IRS1/2 knockout mice to examine the requirement of IRS1/2 for the action of BRD7. Our investigation of glucose metabolism parameters and insulin signaling unveiled the significance of InsR activation in mediating BRD7’s effect on glucose homeostasis in the liver. Moreover, we identified an interaction between BRD7 and InsR. Notably, our findings indicate that IRS1/2 is not necessary for BRD7's regulation of glucose metabolism, particularly in the context of obesity. The upregulation of hepatic BRD7 significantly reduces blood glucose levels and restores glucose homeostasis in high-fat diet-challenged liver-specific IRS1/2 knockout mice. These findings highlight the presence of an alternative insulin signaling pathway that operates independently of IRS1/2 and offer novel insights into the mechanisms of a previously unknown insulin signaling in obesity.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© the author(s) 2023
Article ID:
e230119
Article Type:
Research Article
Received Date:
13 Apr 2023
Accepted Date:
06 Jul 2023
Print Publication Date:
01 Sep 2023
Online Publication Date:
14 Aug 2023
Keywords:
BRD7; insulin receptor signaling; glucose metabolism; insulin receptor substrates

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