IGF2BP3 Down-Regulating DMRT2 Protein Level Enhances Adipocyte Insulin Resistance and the Related Mechanism

ZHENG Hongjian^1,2,3, WANG Yongtao^2,3, WANG Zijie^3,4, ZENG Lu^2,3, YANG Yining^2,3, TAO Jing^2,3*

(¹Medical College of Shihezi University, Shihezi 832003, China; ²Cardiac and Panvascular Medicine Clinic, Xinjiang Uygur Autonomous Region People’s Hospital, Urumqi 830001, China; ³Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regenerative Medicine Research, Urumqi 830001, China; ⁴College of Life Science and Technology, Xinjiang University, Urumqi 830001, China)

Abstract:

The aim of this work is to explore if m6A methylation modification of DMRT2 is a regulator in IR (insulin resistance) in adipocytes. Firstly, key regulatory proteins that are significantly associated with the m6A modification level of DMRT2 mRNA in the adipose tissue of IR patients were identified using multiple databases (RM2Target, GEO, RNA-seq datasets) and Pearson correlation analysis. Subsequently, an in vitro IR model was established using the 3T3-L1 preadipocyte cell line. Following interventions, including DMRT2 overexpression or knockdown, and treatment with an m6A inhibitor, several parameters were assessed: DMRT2 protein levels, the m6A modification level on DMRT2 mRNA, and key IR-related indicators such as glucose uptake, expression of inflammatory cytokines, and triglyceride content. The bioinformatic analysis determined that IGF2BP3 was significantly associated with DMRT2 m6A in IR. In IR cell models, knockdown of IGF2BP3 promoted the expression of DMRT2, GLUT4, p-Akt/Akt, and down-regulated m6A levels on DMRT2 mRNA, as well as promoted glucose uptake, inhibited the expression of adipocyte inflammatory factors, and reduced triglyceride levels compared with the CONTROL group, overexpression of IGF2BP3 showed the opposite trend; whereas m6A inhibitor intervention counteracted the effects of IGF2BP3 overexpression on regulating DMRT2 mRNA m6A modification and IR progression. While m6A inhibitor intervention counteracted the effects of IGF2BP3 on regulating DMRT2 mRNA m6A modification and the progression of IR. Furthermore, overexpression DMRT2 partially abrogated the promotional effect of IGF2BP3 on IR progression. This study concluded that IGF2BP3-mediated DMRT2 m6A methylation modification accelerated the progression of insulin resistance and inflammation in adipocytes. This research determined that IGF2BP3 was significantly associated with DMRT2 m6A methylation modification and had a role in IR formation, which provided some clue for seeking new targets for insulin resistance.

CSTR: 32200.14.cjcb.2025.08.0006