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Pharmacological research

Pharmacological research

IF: 9.1
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Glia maturation factor-β deficiency improves insulin resistance by promoting CARM1-mediated lipid turnover

Published:30 August 2025 DOI: 10.1016/j.phrs.2025.107937
Jinyuan Xu , Lilin Zhu , Jiao Li , Jie Xu , Tingting Cui , Song Jia , Tong Zhu , Si Shi , Furong Gao , Caixia Jin , Haibin Tian , Juan Wang , Qingjian Ou , Jing-Ying Xu , Yan-long Bi , Guo-Tong Xu , Xiaoqing Zhang , Lixia Lu

Abstract

Insulin resistance (IR) is a major factor for obesity-associated type 2 diabetes. The molecular mechanisms of IR and its systemic control remain poorly understood, and pharmacological drugs to ameliorate IR are an unmet need. So finding new therapeutic targets and drugs is important. Here, we report that glia maturation factor-β (GMFB), a growth and differentiation factor for glia and neurons, is a systemic regulator of IR, and we developed its inhibitor. We found that GMFB expression in adipose tissue is related to IR in rats, mice and humans. Systemic or adipocyte-specific Gmfb depletion improved IR and the lipotoxicity of plasma long chain fatty acids. Gmfb KO promotes lipid turnover (adipogenesis and lipid removal (lipolysis and fatty acid β-oxidation)) in adipocytes. Mechanistically, GMFB was degraded via chaperone-mediated autophagy under insulin stimulation in adipocytes. Gmfb KO boosted its interacting protein coactivator-associated arginine methyltransferase 1 (CARM1) nuclear translocation to coactivate peroxisome proliferator-activated receptor gamma (PPARγ), thereby promoting lipid turnover in adipocytes to improve IR. DS19, a potential GMFB inhibitor, showed strong insulin sensitizing effect by attenuating GMFB-CARM1 interaction. In conclusion, our results uncover GMFB, regulating adipocyte lipid turnover, as a novel therapeutic target in obesity-induced IR. The GMFB inhibitor DS19 will merit further clinical investigation.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Atglistatin 1469924-27-3 C17H21N3O 174 suppliers $26.00-$1900.00
Atglistatin 1469924-27-3 C17H21N3O 174 suppliers $26.00-$1900.00
Atglistatin 1469924-27-3 C17H21N3O 174 suppliers $26.00-$1900.00
Atglistatin 1469924-27-3 C17H21N3O 174 suppliers $26.00-$1900.00
R-(+)-Etomoxir 124083-20-1 C17H23ClO4 128 suppliers $19.00-$2240.00
R-(+)-Etomoxir 124083-20-1 C17H23ClO4 128 suppliers $19.00-$2240.00
R-(+)-Etomoxir 124083-20-1 C17H23ClO4 128 suppliers $19.00-$2240.00
R-(+)-Etomoxir 124083-20-1 C17H23ClO4 128 suppliers $19.00-$2240.00

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