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Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075

Nature Metabolism volume 3, pages 1163–1174 (2021)Cite this article

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Abstract

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16–18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.

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Fig. 1: Hepatocyte-derived exosomes from early stage obese mice enhance insulin sensitivity.
Fig. 2: miRNAs are the key cargo causing the hepatocyte exos effects.
Fig. 3: Effects of hepatocyte-specific Rab27KO on exos secretion and miRNA content.
Fig. 4: miR-3075 is an insulin sensitizer within 4wk HFD Exos.
Fig. 5: Fa2h is a miR-3075 target gene that regulates cellular insulin responses.
Fig. 6: Chronic obesity induces hepatocytes to secrete pathogenic exosomal miRNAs that cause tissue inflammation and insulin resistance.
Fig. 7: Hepatocyte-derived exos from chronic obese mice stimulate the proinflammatory M1-like state in macrophages.

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Data availability

The datasets generated in current study are available from the corresponding authors upon reasonable request. There are no restrictions on data availability. All mouse lines in this study are available from the Jackson Laboratory. The miRNA-seq data have been deposited in the NCBI Gene Expression Omnibus under accession number GSE164310. Source data are provided with this paper.

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Acknowledgements

We thank the UCSD IGM Genomics Center for RNA-seq, the UCSD electron microscopy core for electron microscopic analysis, and the Vector Development Core Laboratory for lentivirus preparation. This study was funded by the US National Institute of Diabetes and Digestive and Kidney Diseases (grant nos. P30 DK063491, R00DK115998 and R01DK125560 to W.Y.) and the US National Institute of Diabetes and Digestive and Kidney Diseases (grant nos. P30 DK063491 and DK101395 to J.M.O.).

Author information

Author notes

  1. Yudong Ji

    Present address: Department of Anesthesiology, Institute of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

  2. Zhenlong Luo

    Present address: Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

  3. Meixiang Yang

    Present address: Zhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, the Biomedical Translational Research Institute, Jinan University, Guangzhou, China

  4. Wenxian Fu

    Present address: Department of Cancer Immunology, Genentech, San Francisco, CA, USA

  5. These authors contributed equally: Yudong Ji, Zhenlong Luo.

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, CA, USA

    Yudong Ji, Zhenlong Luo, Hong Gao, Felipe Castellani Gomes Dos Reis, Gautam Bandyopadhyay, Kameswari Ananthakrishnan Manda, Roi Isaac, Wei Ying & Jerrold M. Olefsky

  2. Division of Biological Sciences, University of California, San Diego, CA, USA

    Zhongmou Jin

  3. Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, CA, USA

    Meixiang Yang & Wenxian Fu

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Contributions

W.Y. designed the studies, and Y.J. and Z.L. performed most of the experiments. F.C.G.D.R., K.A.M. and H.G. assisted with in vivo insulin stimulation assays, cell culture, qPCR analysis and western blot analysis. Z.J. and H.G. assisted with bone marrow cell isolation and differentiation. R.I., M.Y., W.F. and Z.J. assisted with tissue collection. G.B. assisted with hepatocyte isolation and glucose output assays. W.Y. and J.M.O. supervised the project. W.Y. and J.M.O. analysed and interpreted the data and cowrote the paper.

Corresponding authors

Correspondence to Wei Ying or Jerrold M. Olefsky.

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Competing interests

W.Y. and J.M.O. are coinventors on a provisional patent covering the use of miR-3075 as an insulin sensitizer. Outside this, the other authors declare no competing interests.

Additional information

Peer review information Nature Metabolism thanks Jan-Wilhelm Kornfeld, Anja Zeigerer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary handling editor: Isabella Samuelson.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Hepatocyte exosomes from early stage obese mice improve cellular insulin sensitivity.

The marker characteristics (a) and production (b) of exosomes (Exos) derived from lean, 4wk or 16wk HFD WT hepatocytes. c, The appearance of red fluorescence in key metabolic tissues of 12wk HFD WT mice after tail vein injection with PKH26-labeled 4wk HFD hepatocyte Exos. 4wk HFD hepatocyte Exos without PKH26 labeling were injected to evaluate the level of autofluorescence. d, Effect of empty liposome treatment on metabolic phenotypes of 16wks HFD/obese WT mice. e, Effect of hepatocyte Exos treatment on body weight. f, the population and activation status of adipose tissue macrophages by flow cytometry analysis. Adipose tissue macrophages (ATM)=CD11b+F4/80+, M1 ATM=CD11c+CD206-, and M2 ATM=CD11c-CD206+. g, Effect of 4wk HFD Exos on proinflammatory cytokine abundance in epididymal fat of 18wk HFD mice by qPCR analysis. Effects of 4wk HFD Exos on glucose uptake of 3T3-L1 adipocytes (h), L6 myocytes (i), and glucose production of 12wk HFD/obese hepatocytes (j). k, The levels of insulin-stimulated AKT phosphorylation in 3T3-L1 adipocytes, L6 myocytes, and obese hepatocytes. e-k, empty liposomes were used in the control groups. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=7 (b), n=6 (d), n=5-10 (e), n=5 (f, h), n=3 (g), n=6 (i), n=8 (j) per group. Two-sided Student’s t-test.

Source data

Extended Data Fig. 2 Effect of hepatocyte-specific YBX1 knockout on the ability of hepatocyte Exos to regulate metabolic responses.

a, Hepatocyte YBX1 levels in the hepatocyte-specific Cas9 transgenic mice after 4 weeks of injection of lentivirus harbouring gRNA-YBX1 vectors. Control mice were treated with a lentiviral empty vector. b, Expression of TSG101 and CD63 in Exos derived from both 4wk HFD WT and YBX1KO hepatocytes. c, Body weight of both WT and YBX1KO mice after 4 weeks HFD feeding. d, Effect of hepatocyte Exos on body weight of 18wks HFD/obese recipient mice. Empty liposomes were used in the control HFD WT mice. e, Effect of 4wk HFD WT Exos or YBX1KO Exos on cellular phosphorylated AKT levels. Control cells were treated with empty liposomes. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=8 (c and d) per group.

Source data

Extended Data Fig. 3 Effect of hepatocyte-specific Rab27 knockout on metabolic phenotypes.

a, Hepatocyte Rab27 levels in the hepatocyte-specific Cas9 transgenic mice after 4 weeks of injection of lentivirus harboring gRNA Rab27 vectors. Control mice were treated with a lentiviral empty vector. b, Effect of 4wk HFD Rab27KO hepatocyte Exos on glucose production in 16wk HFD/obese primary hepatocytes. Empty liposomes were used in the control cells. c, Body weight of both WT and hepatocyte-specific Rab27KO mice after 4 weeks HFD feeding. d, Hepatic glucose production after Rab27 knockout. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=4 (b), n=6 (c), n=8 (d) per group. Two-sided Student’s t-test.

Source data

Extended Data Fig. 4 Effect of miR-3075 on insulin sensitivity.

miR-3075 abundance in liver (a), skeletal muscle (SKL, b), and eWAT (c) of 18wk HFD WT recipient mice after treatment with 4wk HFD Exos. qPCR analysis of miR-3075 abundance (d), hepatic glucose production (e), and insulin-stimulated AKT phosphorylation (f) in lean, 4wk or 16wk HFD WT hepatocytes. g, Effect of the miR-3075 antagomir on AKT phosphorylation level in 4wk HFD hepatocytes. h, miR-3075 abundance in key metabolic tissues of lean WT mice, 3T3-L1 adipocytes, and L6 myocytes. i, Effect of 4wk HFD Exos, 4wk HFD YBX1KO Exos, or combination treatment with 4wk HFD YBX1KO plus miR-3075 mimic on cellular insulin responses. j, Glucose tolerance of NCD, 4wk HFD, and 16wk HFD WT mice. k, qPCR analysis of miR-3075 abundance within Exos derived from lean hepatocytes transfected with the miR-3075 mimic. l, Effect of miR-3075-enriched hepatocyte (miR-3075oe) Exos on 3T3-L1 adipocyte glucose uptake. m, The levels of phosphorylated AKT in metabolic tissues of 4wks HFD WT mice after treatment with the miR-3075 antagomir. Effects of miR-3075 antagomir on glucose tolerance (n) and insulin sensitivity (o) of lean WT mice. n=4 (a-c, h, k), n=6-8 (d), n=8 (e), n=6 (i), n=8 (j, l), n=5-6 (n and o) per group. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. Two-sided Student’s t-test.

Source data

Extended Data Fig. 5 miR-3075 represses FA2H expression.

a, qPCR analysis of possible target genes of miR-3075. b, FA2H abundance after transfection with the miR-3075 mimic. c, The expression of miR-3075 in human HepG2 cells. d, Effect of miR-3075 overexpression on FA2H abundance in human HepG2 cells. e, Validation of FA2H knockdown in 3T3-L1 adipocytes, L6 myocytes, and obese hepatocytes. f, Effect of Fa2h knockdown on AKT phosphorylation in the cells without insulin stimulation. b and c, The control cells were transfected with a scramble miRNA mimic. e and f, non-targeting control siRNA was used in the control cells. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=5-6 (a, c) per group. Two-sided Student’s t-test.

Source data

Extended Data Fig. 6 16wk HFD Exos treatment did not affect cellular insulin sensitivity.

a-c, Effect of 16wk HFD Exos on cellular insulin responses. Empty liposomes were used in the control groups. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=5-6 (a), n=6 (b), n=4 (c) per group.

Extended Data Fig. 7 Effect of miR-434-3p on macrophage activation.

a, Gating strategy of flow cytometry analysis of adipose tissue macrophages. F4/80+CD11b+ ATMs were gated from viable CD45+ cells, and M1 (CD11c+CD206-) and M2 (CD11c-CD206+) cells were then gated from F4/80+CD11b+ ATMs. b, miR-434-3p abundance in epididymal fat of NCD recipient mice after treatment of 16wk HFD Exos for 5 weeks. c, qPCR analysis of miR-434-3p abundance in BMDMs after transfection with the miR-434-3p mimic. d, Effect of miR-434-3p overexpression on proinflammatory activation in naïve M0 BMDMs. e-g, Effect of miR-434-3p on glucose uptake in 3T3-L1 adipocytes and L6 myocytes and primary hepatocyte glucose production. c-g, A scramble miRNA mimic was used in control cells. All experiments were repeated at least twice with similar results. Data are presented as mean ± SEM. n=4 (a, e, g), n=5-6 (c), n=6-7 (d), n=12 (f) per group. Two-sided Student’s t-test.

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Ji, Y., Luo, Z., Gao, H. et al. Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075. Nat Metab 3, 1163–1174 (2021). https://doi.org/10.1038/s42255-021-00444-1

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