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. 2024 Sep 27;25(19):10447.
doi: 10.3390/ijms251910447.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Hepatic Steatosis and Insulin Resistance in Diet-Induced Obese Mice by Activating the FGF21-Adiponectin Axis

Bobae Kim  1 , Rwubuzizi Ronaldo  1 , Beet-Na Kweon  1 , Solhee Yoon  1 , Yein Park  1 , Jea-Hyun Baek  1 , Jung Min Lee  1 , Chang-Kee Hyun  1
Affiliations

Mesenchymal Stem Cell-Derived Exosomes Attenuate Hepatic Steatosis and Insulin Resistance in Diet-Induced Obese Mice by Activating the FGF21-Adiponectin Axis

Bobae Kim et al. Int J Mol Sci. .

Abstract

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21-adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders.

Keywords: FGF21; SIRT1; adiponectin; exosome; hepatic steatosis; insulin resistance.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
hWJMSC-derived exosomes reduce diet-induced adiposity and improve insulin sensitivity in HFD-fed mice. (A) Characterization of hWJMSC-derived exosomes by size analysis using nanoparticle tracking analysis (NTA) and Western blot analysis (Figure S1) of exosomal markers Calnexin, CD63, Syntenin, and CD81. (B) Body weight changes during 11 weeks of HFD feeding with exosome treatment (n = 9). (C) Tissue weights after 11 weeks of exosome treatment (n = 9). (D) Intraperitoneal glucose tolerance test in mice at 10 weeks of exosome treatment (n = 9). (E) Plasma concentration of insulin after 11 weeks of exosome treatment quantified by ELISA (n = 6). (F,G) Blood levels of glucose, TG, total cholesterol, and HDL and LDL cholesterol after 11 weeks of exosome treatment. (H) Akt phosphorylation levels in the liver, EAT, and SAT. (I) Representative images (×200) of H&E stained sections of the liver, EAT, and SAT. Data are presented as mean ± SD. # p < 0.05, ## p < 0.01, and ### p < 0.001 for ND vs. HFD, * p < 0.05, ** p < 0.01, and *** p < 0.001 for HFD vs. HFD+Exo. ND: normal chow diet-fed; HFD: high-fat diet-fed; HFD+Exo: exosome-treated HFD-fed group. EAT: epididymal adipose tissue; SAT: subcutaneous adipose tissue; MAT: mesenteric adipose tissue; BAT: brown adipose tissue; TG: triglyceride; T-chol: total cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein.
Figure 2
Figure 2
hWJMSC-derived exosomes restore immune homeostasis in the liver and adipose tissues of HFD-fed obese mice. Changes in mRNA expression of (A) pro-inflammatory cytokines and (B) immune cell markers in the liver, EAT, and SAT, and (C) tight junction proteins in the colon. The relative mRNA levels were analyzed by real-time PCR for the indicated genes and normalized to the expression of GAPDH or Arbp gene. (D) Plasma levels of LPS measured by the LAL assay. Data are presented as mean ± SD for 6~8 mice in each group. * p < 0.05, ** p < 0.01, and *** p < 0.001. ND: normal chow diet-fed; HFD: high-fat diet-fed; HFD+Exo: exosome-treated HFD-fed group; EAT: epididymal adipose tissue; SAT: subcutaneous adipose tissue.
Figure 3
Figure 3
hWJMSC-derived exosomes restore lipid metabolism, attenuate ER stress, and promote SAT browning and BAT thermogenesis in HFD-fed obese mice. Changes in mRNA expression of (A) genes involved in lipid oxidation, (B) de novo lipogenic genes, and (C) ER stress-related proteins in the liver, EAT, and SAT. Changes in mRNA expression of browning and thermogenesis in BAT (D) and SAT (E). The relative mRNA levels were analyzed by real-time PCR for the indicated genes and normalized to the expression of GAPDH or Arbp gene. Data are presented as mean ± SD for 6~8 mice in each group. * p < 0.05, ** p < 0.01, and *** p < 0.001. ND: normal chow diet-fed; HFD: high-fat diet-fed; HFD+Exo: exosome-treated HFD-fed group; EAT: epididymal adipose tissue; SAT: subcutaneous adipose tissue.
Figure 4
Figure 4
hWJMSC-derived exosomes activate the FGF21–adiponectin axis in the liver and adipose tissues of HFD-fed obese mice. Changes in (A) adiponectin mRNA expression in EAT and SAT and (B) plasma level of adiponectin. mRNA expression of (C) adiponectin receptors, (D) hepatic FGF21, and (E) FGF21 receptor (FGFR1) and co-receptor β-klotho in each tissue. The relative mRNA levels were analyzed by real-time PCR for the indicated genes and normalized to the expression of GAPDH or Arbp gene. (F) AMPK phosphorylation level in EAT, SAT, and BAT. Data are presented as mean ± SD for 6~8 mice in each group. * p < 0.05, ** p < 0.01, and *** p < 0.001. ND: normal chow diet-fed; HFD: high-fat diet-fed; HFD+Exo: exosome-treated HFD-fed group; EAT: epididymal adipose tissue; SAT: subcutaneous adipose tissue; BAT: brown adipose tissue.
Figure 5
Figure 5
A summary of possible mechanisms that explain how hWJMSC-derived exosomes protect against metabolic dysregulation in HFD-fed obese mice.
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