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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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
Caseinolytic mitochondrial matrix proteolytic subunit
Mitochondrial large ribosomal subunit protein
DnaJ heat shock protein family (Hsp40) member A3
Epididymal white adipose tissue
Fibroblast growth factor 21
Growth differentiation factor 15
Heat shock 60 kDa protein 1
Lon peptidase 1
Normal chow diet
NADH:ubiquinone oxidoreductase subunit A9
NADH:ubiquinone oxidoreductase subunit B8
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
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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).
The authors declare that there is no duality of interest associated with this manuscript.
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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). https://doi.org/10.1007/s00125-019-05082-7
- Adipose tissue
- Energy metabolism
- Insulin resistance