Min Jeong Choi1,2, Saet-Byel Jung1, Seong Eun Lee1, Seul Gi Kang1,2, Ju Hee Lee1,3, Min Jeong Ryu4, Hyo Kyun Chung1, Joon Young Chang1,2, Yong Kyung Kim1, Hyun Jung Hong1,2, Hail Kim5, Hyun Jin Kim1,3, Chul-Ho Lee6, Adil Mardinoglu7,8, Hyon-Seung Yi9, Minho Shong10,11. 1. Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, South Korea. 2. Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. 3. Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea. 4. Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, South Korea. 5. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea. 6. Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea. 7. Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden. 8. Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK. 9. Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea. jmpbooks@cnuh.co.kr. 10. Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon, 35015, South Korea. minhos@cnu.ac.kr. 11. Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, South Korea. minhos@cnu.ac.kr.
Abstract
AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/ INTERPRETATION: 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.
AIMS/HYPOTHESIS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS/ INTERPRETATION: 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.
Entities:
Keywords:
Adipose tissue; Energy metabolism; Insulin resistance; Mitochondria; Mitokine
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