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



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.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.



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

UPRmt :

Mitochondrial unfolded protein response


Ubiquinol–cytochrome c reductase core protein 2


White adipose tissue


  1. 1.

    Brand MD, Reynafarje B, Lehninger AL (1976) Stoichiometric relationship between energy-dependent proton ejection and electron transport in mitochondria. Proc Natl Acad Sci U S A 73(2):437–441.

  2. 2.

    Perks KL, Ferreira N, Richman TR et al (2017) Adult-onset obesity is triggered by impaired mitochondrial gene expression. Sci Adv 3(8):e1700677.

  3. 3.

    Silva JP, Kohler M, Graff C et al (2000) Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Nat Genet 26(3):336–340.

  4. 4.

    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350(7):664–671.

  5. 5.

    Dahlman I, Forsgren M, Sjogren A et al (2006) Downregulation of electron transport chain genes in visceral adipose tissue in type 2 diabetes independent of obesity and possibly involving tumor necrosis factor-alpha. Diabetes 55(6):1792–1799.

  6. 6.

    Vernochet C, Mourier A, Bezy O et al (2012) Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metab 16(6):765–776.

  7. 7.

    Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90(12):6650–6656.

  8. 8.

    Olswang Y, Cohen H, Papo O et al (2002) A mutation in the peroxisome proliferator-activated receptor gamma-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proc Natl Acad Sci U S A 99(2):625–630.

  9. 9.

    Fassina G, Dorigo P, Gaion RM (1974) Equilibrium between metabolic pathways producing energy: a key factor in regulating lipolysis. Pharmacol Res Commun 6(1):1–21.

  10. 10.

    Koh EH, Park JY, Park HS et al (2007) Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56(12):2973–2981.

  11. 11.

    Quiros PM, Mottis A, Auwerx J (2016) Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 17(4):213–226.

  12. 12.

    Yoneda T, Benedetti C, Urano F, Clark SG, Harding HP, Ron D (2004) Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J Cell Sci 117(Pt 18):4055–4066.

  13. 13.

    Moullan N, Mouchiroud L, Wang X et al (2015) Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep.

  14. 14.

    Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144(1):79–91.

  15. 15.

    Kim SJ, Kwon MC, Ryu MJ et al (2012) CRIF1 is essential for the synthesis and insertion of oxidative phosphorylation polypeptides in the mammalian mitochondrial membrane. Cell Metab 16(2):274–283.

  16. 16.

    Jung SB, Choi MJ, Ryu D et al (2018) Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat Commun 9(1):1551.

  17. 17.

    Ryu MJ, Kim SJ, Choi MJ et al (2013) Mitochondrial oxidative phosphorylation reserve is required for hormone- and PPARgamma agonist-induced adipogenesis. Molecules and Cells 35(2):134–141.

  18. 18.

    Chung HK, Ryu D, Kim KS et al (2017) Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol 216(1):149–165.

  19. 19.

    Bhaskaran S, Pharaoh G, Ranjit R et al (2018) Loss of mitochondrial protease ClpP protects mice from diet-induced obesity and insulin resistance. EMBO Rep 19(3).

  20. 20.

    Lee HJ, Chung K, Lee H, Lee K, Lim JH, Song J (2011) Downregulation of mitochondrial lon protease impairs mitochondrial function and causes hepatic insulin resistance in human liver SK-HEP-1 cells. Diabetologia 54(6):1437–1446.

  21. 21.

    Segal KR, Landt M, Klein S (1996) Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45(7):988–991.

  22. 22.

    Di Gregorio GB, Yao-Borengasser A, Rasouli N et al (2005) Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 54(8):2305–2313.

  23. 23.

    Quiros PM, Prado MA, Zamboni N et al (2017) Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol 216(7):2027–2045.

  24. 24.

    Smeitink JA, Zeviani M, Turnbull DM, Jacobs HT (2006) Mitochondrial medicine: a metabolic perspective on the pathology of oxidative phosphorylation disorders. Cell Metab 3(1):9–13.

  25. 25.

    Owusu-Ansah E, Song W, Perrimon N (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155(3):699–712.

  26. 26.

    Wu Y, Williams EG, Dubuis S et al (2014) Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158(6):1415–1430.

  27. 27.

    Chen HS, Wu TE, Juan CC, Lin HD (2009) Myocardial heat shock protein 60 expression in insulin-resistant and diabetic rats. J Endocrinol 200(2):151–157.

  28. 28.

    Ryu MJ, Kim SJ, Kim YK et al (2013) Crif1 deficiency reduces adipose OXPHOS capacity and triggers inflammation and insulin resistance in mice. PLoS Genet 9(3):e1003356.

  29. 29.

    Fu Y, Luo N, Lopes-Virella MF (2000) Oxidized LDL induces the expression of ALBP/aP2 mRNA and protein in human THP-1 macrophages. J Lipid Res 41(12):2017–2023

  30. 30.

    Ferrell RE, Kimak MA, Lawrence EC, Finegold DN (2008) Candidate gene analysis in primary lymphedema. Lymphat Res Biol 6(2):69–76.

  31. 31.

    Urs S, Harrington A, Liaw L, Small D (2006) Selective expression of an aP2/fatty acid binding protein 4-Cre transgene in non-adipogenic tissues during embryonic development. Transgenic Res 15(5):647–653.

  32. 32.

    Enguix N, Pardo R, Gonzalez A et al (2013) Mice lacking PGC-1beta in adipose tissues reveal a dissociation between mitochondrial dysfunction and insulin resistance. Mol Metab 2(3):215–226.

  33. 33.

    Schottl T, Kappler L, Fromme T, Klingenspor M (2015) Limited OXPHOS capacity in white adipocytes is a hallmark of obesity in laboratory mice irrespective of the glucose tolerance status. Mol Metab 4(9):631–642.

  34. 34.

    Vernochet C, Damilano F, Mourier A et al (2014) Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J 28(10):4408–4419.

  35. 35.

    Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M (2015) GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion 20:34–42.

  36. 36.

    Suomalainen A, Elo JM, Pietilainen KH et al (2011) FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 10(9):806–818.

  37. 37.

    Houtkooper RH, Mouchiroud L, Ryu D et al (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497(7450):451–457.

  38. 38.

    Chung HK, Kim JT, Kim HW et al (2017) GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep 7(1):17238.

  39. 39.

    Kim KH, Jeong YT, Oh H et al (2013) Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 19(1):83–92.

  40. 40.

    Tran T, Yang J, Gardner J, Xiong Y (2018) GDF15 deficiency promotes high fat diet-induced obesity in mice. PLoS One 13(8):e0201584.

  41. 41.

    Singhal G, Kumar G, Chan S et al (2018) Deficiency of fibroblast growth factor 21 (FGF21) promotes hepatocellular carcinoma (HCC) in mice on a long term obesogenic diet. Mol Metab 13:56–66.

  42. 42.

    Yoneshiro T, Aita S, Matsushita M et al (2013) Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 123(8):3404–3408.

  43. 43.

    Chondronikola M, Volpi E, Borsheim E et al (2014) Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63(12):4089–4099.

  44. 44.

    Ohtomo T, Ino K, Miyashita R et al (2017) Chronic high-fat feeding impairs adaptive induction of mitochondrial fatty acid combustion-associated proteins in brown adipose tissue of mice. Biochem Biophys Rep 10:32–38.

  45. 45.

    Grunewald ZI, Winn NC, Gastecki ML et al (2018) Removal of interscapular brown adipose tissue increases aortic stiffness despite normal systemic glucose metabolism in mice. Am J Physiol Regul Integr Comp Phys 314(4):R584–R597.

  46. 46.

    Poher AL, Veyrat-Durebex C, Altirriba J et al (2015) Ectopic UCP1 overexpression in white adipose tissue improves insulin sensitivity in Lou/C rats, a model of obesity resistance. Diabetes 64(11):3700–3712.

  47. 47.

    Seale P, Conroe HM, Estall J et al (2011) Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 121(1):96–105.

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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.


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).

Author information

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.

Correspondence to Hyon-Seung Yi or Minho Shong.

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Choi, M.J., Jung, S., Lee, S.E. et al. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia (2020).

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  • Adipose tissue
  • Energy metabolism
  • Insulin resistance
  • Mitochondria
  • Mitokine