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

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An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. / Choi, Min Jeong; Jung, Saet Byel; Lee, Seong Eun; Kang, Seul Gi; Lee, Ju Hee; Ryu, Min Jeong; Chung, Hyo Kyun; Chang, Joon Young; Kim, Yong Kyung; Hong, Hyun Jung; Kim, Hail; Kim, Hyun Jin; Lee, Chul Ho; Mardinoglu, Adil; Yi, Hyon Seung; Shong, Minho.

In: Diabetologia, Vol. 63, No. 4, 01.04.2020, p. 837-852.

Research output: Contribution to journalArticle

Harvard

Choi, MJ, Jung, SB, Lee, SE, Kang, SG, Lee, JH, Ryu, MJ, Chung, HK, Chang, JY, Kim, YK, Hong, HJ, Kim, H, Kim, HJ, Lee, CH, Mardinoglu, A, Yi, HS & Shong, M 2020, 'An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models', Diabetologia, vol. 63, no. 4, pp. 837-852. https://doi.org/10.1007/s00125-019-05082-7

APA

Choi, M. J., Jung, S. B., Lee, S. E., Kang, S. G., Lee, J. H., Ryu, M. J., ... Shong, M. (2020). An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia, 63(4), 837-852. https://doi.org/10.1007/s00125-019-05082-7

Vancouver

Choi MJ, Jung SB, Lee SE, Kang SG, Lee JH, Ryu MJ et al. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia. 2020 Apr 1;63(4):837-852. https://doi.org/10.1007/s00125-019-05082-7

Author

Choi, Min Jeong ; Jung, Saet Byel ; Lee, Seong Eun ; Kang, Seul Gi ; Lee, Ju Hee ; Ryu, Min Jeong ; Chung, Hyo Kyun ; Chang, Joon Young ; Kim, Yong Kyung ; Hong, Hyun Jung ; Kim, Hail ; Kim, Hyun Jin ; Lee, Chul Ho ; Mardinoglu, Adil ; Yi, Hyon Seung ; Shong, Minho. / An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. In: Diabetologia. 2020 ; Vol. 63, No. 4. pp. 837-852.

Bibtex Download

@article{f51711d57fbd440f8707070f03b70601,
title = "An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models",
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.",
keywords = "Adipose tissue, Energy metabolism, Insulin resistance, Mitochondria, Mitokine",
author = "Choi, {Min Jeong} and Jung, {Saet Byel} and Lee, {Seong Eun} and Kang, {Seul Gi} and Lee, {Ju Hee} and Ryu, {Min Jeong} and Chung, {Hyo Kyun} and Chang, {Joon Young} and Kim, {Yong Kyung} and Hong, {Hyun Jung} and Hail Kim and Kim, {Hyun Jin} and Lee, {Chul Ho} and Adil Mardinoglu and Yi, {Hyon Seung} and Minho Shong",
year = "2020",
month = "4",
day = "1",
doi = "10.1007/s00125-019-05082-7",
language = "English",
volume = "63",
pages = "837--852",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "4",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models

AU - Choi, Min Jeong

AU - Jung, Saet Byel

AU - Lee, Seong Eun

AU - Kang, Seul Gi

AU - Lee, Ju Hee

AU - Ryu, Min Jeong

AU - Chung, Hyo Kyun

AU - Chang, Joon Young

AU - Kim, Yong Kyung

AU - Hong, Hyun Jung

AU - Kim, Hail

AU - Kim, Hyun Jin

AU - Lee, Chul Ho

AU - Mardinoglu, Adil

AU - Yi, Hyon Seung

AU - Shong, Minho

PY - 2020/4/1

Y1 - 2020/4/1

N2 - 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.

AB - 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.

KW - Adipose tissue

KW - Energy metabolism

KW - Insulin resistance

KW - Mitochondria

KW - Mitokine

UR - http://www.scopus.com/inward/record.url?scp=85077689777&partnerID=8YFLogxK

U2 - 10.1007/s00125-019-05082-7

DO - 10.1007/s00125-019-05082-7

M3 - Article

AN - SCOPUS:85077689777

VL - 63

SP - 837

EP - 852

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 4

ER -

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