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Cited by 208Metabolism, Diabetes, and CancerPeroxisome Proliferator-Activated ReceptorsAdipokines, Inflammation, and Metabolic Diseases

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METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice

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Jung, Tae Woo, Lee, Sung Hoon, Kim, Hyoung-Chun, Bang, Joon Seok, Abd El-Aty, A. M., Hacımüftüoğlu, Ahmet, Shin, Yong Kyoo, Jeong, Ji Hoon·2018·Experimental & Molecular Medicine
DOI 10.1038/s12276-018-0147-5PMC PMC6137187
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Abstract

Physical activity has many beneficial effects on metabolic disorders, such as obesity, insulin resistance, and diabetes. Meteorin-like protein (METRNL), a novel secreted protein homologous to the neurotrophin Metrn, is induced after exercise in the skeletal muscle. Herein, we investigated the effects of METRNL on lipid-mediated inflammation and insulin resistance in skeletal muscle via AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor δ (PPARδ). Treatment with METRNL suppressed inflammatory markers, such as nuclear factor κB (NFκB) nuclear translocation, inhibitory κBα (IκBα) phosphorylation, interleukin-6 (IL-6) expression, and pro-inflammatory cytokines (such as TNFα and MCP-1). METRNL treatment also attenuated the impaired insulin response both in palmitate-treated differentiated C2C12 cells and the skeletal muscle of high-fat diet (HFD)-fed mice. Furthermore, METRNL administration rescued glucose intolerance and reduced HFD-induced body weight gain in mice; however, METRNL did not affect calorie intake. METRNL treatment increased AMPK phosphorylation and PPARδ expression both in differentiated C2C12 cells and mouse skeletal muscle. siRNA-mediated suppression of AMPK and PPARδ abrogated the suppressive effects of METRNL on palmitate-induced inflammation and insulin resistance. Moreover, METRNL augmented the mRNA expression of fatty acid oxidation-associated genes, such as carnitine palmitoyltransferase 1 (CPT1), acyl-CoA oxidase (ACO), and fatty acid binding protein 3 (FABP3). siRNAs for AMPK and PPARδ reversed these changes. In the current study, we report for the first time that METRNL alleviates inflammation and insulin resistance and induces fatty acid oxidation through AMPK or PPARδ-dependent signaling in skeletal muscle.

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Fig. 1 METRNL attenuates insulin resistance in differentiated C2C12 myocytes and soleus skeletal muscle of mice. a Western blot analysis of phosphorylation of IRS-1 and Akt and b 2-deoxyglucose uptake in differentiated C2C12 cells treated with palmitate (200 μM) and METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) stimulates IRS-1 and Akt phosphorylation for 3 min. c Western blot analysis of IRS-1 and Akt phosphorylation in soleus skeletal muscle of HFD-fed mice treated with METRNL (5 animals/treatment group). Means ± SEM were calculated from three independent experiments. ***P < 0.001 and **P < 0.01 compared to levels in the control or insulin-injected ND-fed groups.!!!P < 0.001,!!P < 0.01, and !P < 0.05 compared to palmitate or insulin-injected HFD-fed groups
Fig. 1 METRNL attenuates insulin resistance in differentiated C2C12 myocytes and soleus skeletal muscle of mice. a Western blot analysis of phosphorylation of IRS-1 and Akt and b 2-deoxyglucose uptake in differentiated C2C12 cells treated with palmitate (200 μM) and METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) stimulates IRS-1 and Akt phosphorylation for 3 min. c Western blot analysis of IRS-1 and Akt phosphorylation in soleus skeletal muscle of HFD-fed mice treated with METRNL (5 animals/treatment group). Means ± SEM were calculated from three independent experiments. ***P < 0.001 and **P < 0.01 compared to levels in the control or insulin-injected ND-fed groups.!!!P < 0.001,!!P < 0.01, and !P < 0.05 compared to palmitate or insulin-injected HFD-fed groupsCC BY · PubMed Central
Fig. 2 METRNL administration attenuates insulin resistance in mice. a The IPGTT of experimental mice and the glucose area under the curve (AUC) during the IPGTT. b The ITT and the glucose inverse AUC during the ITT. c Body weight measurement and d daily energy intake in mice (5 animals/treatment group). Closed circles, ND; opened circles, HFD; closed triangles, HFD + METRNL. Means ± SEM were calculated from five separate animals. ***P < 0.001 and **P < 0.01 compared to ND treatment.!!!P < 0.001,!!P < 0.01 and !P < 0.05 compared to HFD treatment
Fig. 2 METRNL administration attenuates insulin resistance in mice. a The IPGTT of experimental mice and the glucose area under the curve (AUC) during the IPGTT. b The ITT and the glucose inverse AUC during the ITT. c Body weight measurement and d daily energy intake in mice (5 animals/treatment group). Closed circles, ND; opened circles, HFD; closed triangles, HFD + METRNL. Means ± SEM were calculated from five separate animals. ***P < 0.001 and **P < 0.01 compared to ND treatment.!!!P < 0.001,!!P < 0.01 and !P < 0.05 compared to HFD treatmentCC BY · PubMed Central
Fig. 3 METRNL attenuates inflammation in myotubes. a Western blot analysis of palmitate-induced NFκB nuclear translocation and IκB phosphorylation in differentiated C2C12 cells treated with 200 μM palmitate and METRNL (0–200 ng/mL) for 24 h. b Western blot analysis of HFD-induced NFκB nuclear translocation and IκB phosphorylation in soleus skeletal muscle of mice treated with METRNL (1 μg/mouse/day) for 8 weeks. Serum analysis of c TNFα and d MCP-1 of mice treated with HFD and METRNL (5 animals/treatment group). Means ± SEM were calculated from five separate animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment.!!!P < 0.001,!!P < 0.01, and !P < 0.05 compared to palmitate or HFD treatment
Fig. 3 METRNL attenuates inflammation in myotubes. a Western blot analysis of palmitate-induced NFκB nuclear translocation and IκB phosphorylation in differentiated C2C12 cells treated with 200 μM palmitate and METRNL (0–200 ng/mL) for 24 h. b Western blot analysis of HFD-induced NFκB nuclear translocation and IκB phosphorylation in soleus skeletal muscle of mice treated with METRNL (1 μg/mouse/day) for 8 weeks. Serum analysis of c TNFα and d MCP-1 of mice treated with HFD and METRNL (5 animals/treatment group). Means ± SEM were calculated from five separate animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment.!!!P < 0.001,!!P < 0.01, and !P < 0.05 compared to palmitate or HFD treatmentCC BY · PubMed Central
Fig. 4 METRNL ameliorates inflammation and insulin resistance via an AMPK-mediated pathway. a Western blot analysis of LKB1, AMPK, and ACC phosphorylation in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. b Confirmation of AMPK siRNA efficiency in differentiated C2C12 cells. Western blot analysis of palmitate (200 μM)-induced inflammation markers in AMPK siRNA (20 nM)-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. c Western blot analysis of the palmitate-induced impairment of IRS-1 and Akt phosphorylation in AMPK siRNA-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) was used to stimulate insulin signaling for 3 min. d Western blot analysis of AMPK phosphorylation in soleus muscle of mice treated with HFD and METRNL (5 animals/treatment group). e Western blot analysis of PGC1α expression in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. f Western blot analysis of METRNL (200 ng/mL)-induced PGC1α expression in AMPK siRNA (20 nM)-transfected differentiated C2C12 cells for 24 h. Confirmation of AMPK siRNA efficiency in skeletal muscle of mice. Western blot analysis of IRS-1 and Akt phosphorylation (g), and inflammatory markers (h) in AMPK siRNA-transfected skeletal muscle of experimental mice. Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001, **P < 0.01, and *P < 0.05 compared to control or ND treatment.!!!P < 0.001 and !!P < 0.01 compared to palmitate or HFD treatment. ###P < 0.001, ##P < 0.01, and #P < 0.05 compared to palmitate plus METRNL treatment or HFD plus KA group
Fig. 4 METRNL ameliorates inflammation and insulin resistance via an AMPK-mediated pathway. a Western blot analysis of LKB1, AMPK, and ACC phosphorylation in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. b Confirmation of AMPK siRNA efficiency in differentiated C2C12 cells. Western blot analysis of palmitate (200 μM)-induced inflammation markers in AMPK siRNA (20 nM)-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. c Western blot analysis of the palmitate-induced impairment of IRS-1 and Akt phosphorylation in AMPK siRNA-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) was used to stimulate insulin signaling for 3 min. d Western blot analysis of AMPK phosphorylation in soleus muscle of mice treated with HFD and METRNL (5 animals/treatment group). e Western blot analysis of PGC1α expression in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. f Western blot analysis of METRNL (200 ng/mL)-induced PGC1α expression in AMPK siRNA (20 nM)-transfected differentiated C2C12 cells for 24 h. Confirmation of AMPK siRNA efficiency in skeletal muscle of mice. Western blot analysis of IRS-1 and Akt phosphorylation (g), and inflammatory markers (h) in AMPK siRNA-transfected skeletal muscle of experimental mice. Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001, **P < 0.01, and *P < 0.05 compared to control or ND treatment.!!!P < 0.001 and !!P < 0.01 compared to palmitate or HFD treatment. ###P < 0.001, ##P < 0.01, and #P < 0.05 compared to palmitate plus METRNL treatment or HFD plus KA groupCC BY · PubMed Central
Fig. 5 METRNL alleviates inflammation and insulin resistance through a PPARδ-mediated pathway. a Western blot analysis of PPARδ expression in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. b Confirmation of PPARδ siRNA efficiency in differentiated C2C12 cells. Western blot analysis of palmitate (200 μM)-induced inflammation markers in PPARα siRNA (20 nM)-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. c Western blot analysis of the palmitate-induced impairment of IRS-1 and Akt phosphorylation in PPARδ siRNA-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) was used to stimulate insulin signaling for 3 min. d Western blot analysis of PPARδ expression in soleus muscle of mice treated with HFD and METRNL (5 animals/treatment group). e Western blot analysis of METRNL (200 ng/mL)-induced PGC1α expression in PPARδ siRNA (20 nM)-transfected differentiated C2C12 cells for 24 h. Western blot analysis of f AMPK phosphorylation in PPARδ siRNA or g PPARδ expression in AMPK siRNA-transfected differentiated C2C12 cells treated with METRNL (200 ng/mL) for 24 h. Confirmation of PPARδ siRNA efficiency in skeletal muscle of mice. Western blot analysis of IRS-1 and Akt phosphorylation (h), and inflammatory markers (i) in PPARδ siRNA-transfected skeletal muscle of experimental mice. j Western blot analysis of PPARδ expression in AMPK siRNA-transfected skeletal muscle of experimental mice. k Western blot analysis of AMPK phosphorylation in PPARδ siRNA-transfected skeletal muscle of experimental mice. Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment. !!!P < 0.001, !!P < 0.01, and !P < 0.05 compared to palmitate, HFD or METRNL treatment. ###P < 0.001, ##P < 0.01, and #P < 0.05 compared to palmitate plus METRNL treatment
Fig. 5 METRNL alleviates inflammation and insulin resistance through a PPARδ-mediated pathway. a Western blot analysis of PPARδ expression in differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. b Confirmation of PPARδ siRNA efficiency in differentiated C2C12 cells. Western blot analysis of palmitate (200 μM)-induced inflammation markers in PPARα siRNA (20 nM)-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. c Western blot analysis of the palmitate-induced impairment of IRS-1 and Akt phosphorylation in PPARδ siRNA-transfected differentiated C2C12 cells treated with METRNL (0–200 ng/mL) for 24 h. Human insulin (10 nM) was used to stimulate insulin signaling for 3 min. d Western blot analysis of PPARδ expression in soleus muscle of mice treated with HFD and METRNL (5 animals/treatment group). e Western blot analysis of METRNL (200 ng/mL)-induced PGC1α expression in PPARδ siRNA (20 nM)-transfected differentiated C2C12 cells for 24 h. Western blot analysis of f AMPK phosphorylation in PPARδ siRNA or g PPARδ expression in AMPK siRNA-transfected differentiated C2C12 cells treated with METRNL (200 ng/mL) for 24 h. Confirmation of PPARδ siRNA efficiency in skeletal muscle of mice. Western blot analysis of IRS-1 and Akt phosphorylation (h), and inflammatory markers (i) in PPARδ siRNA-transfected skeletal muscle of experimental mice. j Western blot analysis of PPARδ expression in AMPK siRNA-transfected skeletal muscle of experimental mice. k Western blot analysis of AMPK phosphorylation in PPARδ siRNA-transfected skeletal muscle of experimental mice. Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment. !!!P < 0.001, !!P < 0.01, and !P < 0.05 compared to palmitate, HFD or METRNL treatment. ###P < 0.001, ##P < 0.01, and #P < 0.05 compared to palmitate plus METRNL treatmentCC BY · PubMed Central
Fig. 6 METRNL stimulates fatty acid oxidation-associated gene expression. a Quantitative real-time PCR analysis of CPT1, ACO, and FABP3 mRNA expression in AMPK (20 nM) or PPARδ siRNA (20 nM)-transfected C2C12 cells treated with METRNL (200 ng/mL) for 24 h. b Quantitative real-time PCR analysis of CPT1, ACO, and FABP3 mRNA expression in HFD-fed mice treated with METRNL. c Intracellular acetyl-CoA and d ATP levels in soleus skeletal muscle of HFD-fed mice treated with METRNL (1 μg/mouse/day) for 8 weeks (5 animals/treatment group). Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment. !!!P < 0.001 compared to METRNL or HFD treatment
Fig. 6 METRNL stimulates fatty acid oxidation-associated gene expression. a Quantitative real-time PCR analysis of CPT1, ACO, and FABP3 mRNA expression in AMPK (20 nM) or PPARδ siRNA (20 nM)-transfected C2C12 cells treated with METRNL (200 ng/mL) for 24 h. b Quantitative real-time PCR analysis of CPT1, ACO, and FABP3 mRNA expression in HFD-fed mice treated with METRNL. c Intracellular acetyl-CoA and d ATP levels in soleus skeletal muscle of HFD-fed mice treated with METRNL (1 μg/mouse/day) for 8 weeks (5 animals/treatment group). Means ± SEM were obtained from three separate experiments or five animals. ***P < 0.001 and **P < 0.01 compared to control or ND treatment. !!!P < 0.001 compared to METRNL or HFD treatmentCC BY · PubMed Central
Fig. 7 METRNL did not affect palmitate-induced ER stress. Quantitative real-time PCR analysis of spliced XBP-1 mRNA expression in C2C12 cells treated with METRNL (0–200 ng/ml) for 24 h. Means ± SEM were obtained from three separate experiments. ***P < 0.001 compared to control
Fig. 7 METRNL did not affect palmitate-induced ER stress. Quantitative real-time PCR analysis of spliced XBP-1 mRNA expression in C2C12 cells treated with METRNL (0–200 ng/ml) for 24 h. Means ± SEM were obtained from three separate experiments. ***P < 0.001 compared to controlCC BY · PubMed Central
Fig. 8 Schematic diagram showing the effects of METRNL on skeletal muscle insulin resistance
Fig. 8 Schematic diagram showing the effects of METRNL on skeletal muscle insulin resistanceCC BY · PubMed Central

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Authors
Jung, T. W., Lee, S. H., Kim, H.-C., Bang, J. S., Abd El-Aty, A. M., Hacımüftüoğlu, A., Shin, Y. K., & Jeong, J. H.
Affiliations
  • Seoul National University Bundang Hospital (KR)
  • Chung-Ang University (KR)
  • Kangwon National University (KR)
  • Sookmyung Women's University (KR)
  • Atatürk University (TR)
Corresponding author
  • Shin, Yong Kyoo
  • Jeong, Ji Hoon
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-09
Volume
50
Issue
9
Pages
1-11
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-018-0147-5
PMC
PMC6137187
OpenAlex
W2890380917
Cited by
203
References
49
Citations by year
2026: 25 · 2025: 47 · 2024: 29 · 2023: 37 · 2022: 19 · 2021: 19 · 2020: 15 · 2019: 12
FWCI
4.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
National Research Foundation of Korea (2016R1C1B2012674)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
Metrnl, meteorin-like protein, skeletal muscle, insulin resistance, AMPK, PPARδ, fatty acid oxidation, high-fat diet, impaired glucose tolerance, NF-κB signaling, interleukin-6, obesity
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Cell Differentiation, Cell Line, Hyperlipidemias, Inflammation, Insulin Resistance, Lipids, Male, Mice, Inbred C57BL, Nerve Growth Factors, Signal Transduction, Muscle, Skeletal, Palmitic Acid, Muscle Cells, PPAR delta, AMP-Activated Protein Kinases, Diet, High-Fat, Endoplasmic Reticulum Stress

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