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An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models

  • Min Jeong Choi
  • Saet-Byel Jung
  • Seong Eun Lee
  • Seul Gi Kang
  • Ju Hee Lee
  • Min Jeong Ryu
  • Hyo Kyun Chung
  • Joon Young Chang
  • Yong Kyung Kim
  • Hyun Jung Hong
  • Hail Kim
  • Hyun Jin Kim
  • Chul-Ho Lee
  • Adil Mardinoglu
  • Hyon-Seung YiEmail author
  • Minho ShongEmail author



Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood.


We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO).


Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice.


The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.


Adipose tissue Energy metabolism Insulin resistance Mitochondria Mitokine 



AdKO mice with global Fgf21 knockout


AdKO mice with global Gdf15 knockout


Adipocyte-specific Crif1 knockout (mice)


Brown adipose tissue


Blue native-PAGE


Caseinolytic mitochondrial matrix proteolytic subunit


Mitochondrial large ribosomal subunit protein


DnaJ heat shock protein family (Hsp40) member A3


Energy expenditure


Epididymal white adipose tissue


Fibroblast growth factor 21


Growth differentiation factor 15


High-fat diet


Heat shock 60 kDa protein 1


Inguinal WAT


Lon peptidase 1


Normal chow diet


NADH:ubiquinone oxidoreductase subunit A9


NADH:ubiquinone oxidoreductase subunit B8


Oxidative phosphorylation


Succinate dehydrogenase complex flavoprotein subunit A


Stromal vascular fraction


Uncoupling protein 1


Mitochondrial unfolded protein response


Ubiquinol–cytochrome c reductase core protein 2


White adipose tissue



We are grateful to E. Rosen (Beth Israel Deaconess Medical Center, Boston) for providing the Adipoq-Cre transgenic mice, S-j Lee (Johns Hopkins University School of Medicine) for the Gdf15−/− mice, and N. Itoh (Kyoto University Graduate School of Pharmaceutical Sciences) for the Fgf21−/− mice.

Author contributions

MJC, S-BJ, SEL and SGK performed data acquisition, data analysis and revised the article’s intellectual content. MJC, H-SY and MS made substantial contribution to conception and design of the study and drafting the work for important intellectual content. JHL and MJR contributed to the analysis and interpretation of data and critically revised the article. HKC, JYC, YKK, HJH, HK, HJK, C-HL and AM helped with the interpretation of data and contributed to drafting the article. MJC, H-SY and MS wrote the manuscript. All authors approved the final version of the manuscript. MS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


This research was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (No. NRF-2017R1E1A1A01075126), and the Global Research Laboratory (GRL) Program, through the NRF (No. NRF-2017K1A1A2013124). H-SY and JHL were also supported by the NRF (NRF-2015R1C1A1A01052432, NRF-2018R1C1B6004439 and NRF-2017R1A1A1A05001474, respectively).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Research Center for Endocrine and Metabolic DiseasesChungnam National University School of MedicineDaejeonSouth Korea
  2. 2.Department of Medical ScienceChungnam National University School of MedicineDaejeonSouth Korea
  3. 3.Department of BiochemistryChungnam National University School of MedicineDaejeonSouth Korea
  4. 4.Graduate School of Medical Science and EngineeringKorea Advanced Institute of Science and TechnologyDaejeonSouth Korea
  5. 5.Animal Model CenterKorea Research Institute of Bioscience and BiotechnologyDaejeonSouth Korea
  6. 6.Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSweden
  7. 7.Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial SciencesKing’s College LondonLondonUK
  8. 8.Department of Internal MedicineChungnam National University HospitalDaejeonSouth Korea

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