A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells

Seo Woo Nam; Jin Wook Hwang; Youn Ho Han

doi:10.1016/j.biopha.2023.115433

A novel berberine derivative targeting adipocyte differentiation to alleviate TNF-α-induced inflammatory effects and insulin resistance in OP9 cells

Biomed Pharmacother. 2023 Nov:167:115433. doi: 10.1016/j.biopha.2023.115433. Epub 2023 Sep 9.

Authors

Seo Woo Nam¹, Jin Wook Hwang², Youn Ho Han³

Affiliations

¹ Department of Biomedical Science, College of Medicine, Wonkwang University, Iksan, the Republic of Korea.
² INSERM UA09, University Paris Saclay, 94800 Villejuif, France.
³ Department of Oral Pharmacology, College of Dentistry, Wonkwang University, Iksan, the Republic of Korea. Electronic address: daks262@wku.ac.kr.

PMID: 37696086
DOI: 10.1016/j.biopha.2023.115433

Abstract

Inflammation and insulin resistance play important roles in the development and progression of type 2 diabetes mellitus. The enhancement of adipocyte differentiation can improve insulin sensitivity by increasing glucose uptake, improving insulin signaling, and reducing inflammation. However, only a few adipogenic agents have shown clinical success in patients with type 2 diabetes mellitus. The therapeutic potential of berberine in type 2 diabetes mellitus was confirmed in terms of the target gene-disease relationship using a network pharmacology database prior to synthesizing the derivatives. Novel berberine derivatives were synthesized, and compound 3b promoted adipocyte differentiation and improvement of insulin resistance in OP9 cells. Compound 3b significantly increased the expression of key adipogenic markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein β (C/EBPβ) and promoted lipid accumulation without cytotoxicity. Furthermore, tumor necrosis factor α (TNF-α)-induced inhibition of adipocyte differentiation and the elevation of inflammatory responses were reversed by compound 3b. Subsequently glucose uptake level through insulin sensitivity improvement was enhanced by compound 3b. Mechanistically, TNF-α activated mitogen-activated protein kinases (MAPKs): ERK, JNK, and p38, whereas compound 3b attenuated phosphorylation of three MAPKs. Finally, in silico molecular docking suggested the possible binding sites of compound 3b on PPARγ. Collectively, the adipogenic and glucose uptake effects of compound 3b were associated with its anti-inflammatory effects and reduced phosphorylation of MAPKs. These findings suggest that the berberine derivative compound 3b may be a potent antidiabetic agent.

Keywords: Adipocyte differentiation; Berberine derivatives; Compound 3; Insulin resistance; Tumor necrosis factor alpha (TNF-α); Type 2 diabetes mellitus.