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. 2022 Sep 29:13:1012904.
doi: 10.3389/fendo.2022.1012904. eCollection 2022.

Exenatide improves hepatocyte insulin resistance induced by different regional adipose tissue

Chuanmin Bai  1 , Yujun Wang  1 , Zhi Niu  1 , Yaxin Guan  1 , Jingshan Huang  2 , Xin Nian  1 , Fan Zuo  1 , Juan Zhao  1 , Tsutomu Kazumi  3   4   5 , Bin Wu  1
Affiliations

Exenatide improves hepatocyte insulin resistance induced by different regional adipose tissue

Chuanmin Bai et al. Front Endocrinol (Lausanne). .

Abstract

Obesity is resulted from energy surplus and is characterized by abnormal adipose tissue accumulation and/or distribution. Adipokines secreted by different regional adipose tissue can induce changes in key proteins of the insulin signaling pathway in hepatocytes and result in impaired hepatic glucose metabolism. This study aimed to investigate whether exenatide affects key proteins of IRS2/PI3K/Akt2 signaling pathway in hepatocytes altered by the different regional fat depots. Six non-obese patients without endocrine diseases were selected as the research subjects. Their subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)were co-cultured with HepG2 cells in the transwell chamber. In the presence or absence of exenatide, adipokines content in the supernatant of each experimental group was detected by ELISA. In addition, HepG2 cells in each co-culture group with and without insulin were collected, and the expression of key proteins IRS2, p-IRS2(S731), PI3K-p85, Akt2, and p-Akt2(S473) was detected by western blotting (WB). The results showed that the adipokines IL-8, MCP-1, VEGF, and sTNFR2 in the supernatant of HepG2 cells induced by different regional adipose tissue were significantly higher than those in the HepG2 group, and VAT released more adipokines than SAT. Furthermore, these adipokines were significantly inhibited by exenatide. Importantly, the different regional fat depot affects the IRS2/PI3K/Akt2 insulin signaling pathway of hepatocytes. Exenatide can up-regulate the expression of hepatocyte proteins IRS2, PI3K-p85, p-Akt2(S731) inhibited by adipose tissue, and down-regulate the expression of hepatocyte proteins p-IRS2(S731) promoted by adipose tissue. The effect of VAT on the expression of these key proteins in hepatocytes is more significant than that of SAT. But there was no statistical difference in the expression of Akt2 protein among each experimental group, suggesting that exenatide has no influence on the expression of Akt2 protein in hepatocytes. In conclusion, exenatide may improve hepatic insulin resistance (IR) by inhibiting adipokines and regulating the expression of key proteins in the IRS2/PI3K/Akt2 pathway.

Keywords: GLP-1; adipose tissue; exenatide; incretin; insulin resistance; obesity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The content of LDH in supernatant of each group. Data are means ± SEM, n = 3/group, *P < 0.05 vs. HepG2 group; #P < 0.05 vs. HepG2 + VAT group; $$P < 0.01 vs. HepG2+SAT group.
Figure 2
Figure 2
HepG2 cells in each group after 48 hours of culture (magnification, ×100). ①A photo of cell growth in the HepG2 group; ②A photo of cell growth in the HepG2+VAT group; ③A photo of cell growth in the HepG2+SAT group; ④A photo of cell growth in the HepG2+VAT+EXE group; ⑤A photo of cell growth in the HepG2+SAT+EXE group; ⑥A photo of cell growth in the HepG2+TritonX-100 group.
Figure 3
Figure 3
Exenatide inhibits adipokines secreted by adipose tissue at different sites. (A)The content of IL-8 in the supernatant of each group. (B) The content of MCP-1 in the supernatant of each group. (C) The content of VEGF in the supernatant of each group. (D) The content of sTNFR2 in the supernatant of each group. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2 group; ##P < 0.01 vs. HepG2+VAT group; $$P < 0.01 vs. HepG2+SAT group.
Figure 4
Figure 4
Key protein bands of insulin signaling pathway detected by western blot in each group. (1) Key protein bands in the HepG2 group. (2) Key protein bands in the HepG2+VAT group. (3) Key protein bands in the HepG2+SAT group. (4) Key protein bands in the HepG2+VAT+EXE group. (5) Key protein bands in the HepG2+SAT+EXE group. (6) Key protein bands in the HepG2+insulin group. (7) Key protein bands in the HepG2+VAT +insulin group. (8) Key protein bands in the HepG2+SAT +insulin group. (9) Key protein bands in the HepG2+VAT+EXE +insulin group. (10) Key protein bands in the HepG2+SAT+EXE +insulin group.
Figure 5
Figure 5
The influence of exenatide on the expression of IRS2 protein in hepatocytes conducted by different regional adipose tissue. (A) Expression of IRS2 protein in HepG2 cells of each group. Data are means ± SEM, n = 3/group, *P < 0.05, **P < 0.01 vs. HepG2 group; ##P < 0.01 vs. HepG2+VAT group; $P< 0.05 vs. HepG2+SAT group. (B) Expression of IRS2 protein in HepG2 cells of each group under the action of insulin. Data are means ± SEM, n = 3/group, *P < 0.05, **P < 0.01 vs. HepG2+INS group; $$P < 0.01 vs. HepG2+SAT+INS group.
Figure 6
Figure 6
The influence of exenatide on the expression of p-IRS2(S731) protein in hepatocytes conducted by different regional adipose tissue. (A) Expression of p-IRS2(S731) protein in HepG2 cells of each group. Data are means ± SEM, n = 3/group, *P < 0.05, **P < 0.01 vs. HepG2 group. (B) Expression of p-IRS2(S731) protein in HepG2 cells of each group under the action of insulin. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2+INS group; #P < 0.05 vs. HepG2+VAT+INS group; $$P < 0.01 vs. HepG2+SAT+INS group.
Figure 7
Figure 7
The influence of exenatide on the expression of PI3K-p85 protein in hepatocytes conducted by different regional adipose tissue. (A) Expression of PI3K-p85 protein in HepG2 cells of each group. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2 group; #P < 0.05, ##P < 0.01 vs. HepG2+VAT group; $P < 0.05 vs. HepG2+SAT group. (B) Expression of PI3K-p85protein in HepG2 cells of each group under the action of insulin. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2+INS group; #P < 0.05 vs. HepG2+VAT+INS group.
Figure 8
Figure 8
The influence of exenatide on the expression of Akt2 protein in hepatocytes conducted by different regional adipose tissue. (A) Expression of Akt2 protein in HepG2 cells of each group. Data are means ± SEM, n = 3/group. (B) Expression of Akt2 protein in HepG2 cells of each group under the action of insulin. Data are means ± SEM, n = 3/group.
Figure 9
Figure 9
The influence of exenatide on the expression of p-AKt2(S473) protein in hepatocytes conducted by different regional adipose tissue. (A) Expression of p-AKt2(S473) protein in HepG2 cells of each group. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2 group; ##P < 0.01 vs. HepG2+VAT group; $$P < 0.01 vs. HepG2+SAT group. (B) Expression of p-AKt2(S473) protein in HepG2 cells of each group under the action of insulin. Data are means ± SEM, n = 3/group, **P < 0.01 vs. HepG2+INS group; #P < 0.05, ##P < 0.01 vs. HepG2+VAT+INS group.
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