Match!

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

Published on Jan 10, 2020in Diabetologia7.113
路 DOI :10.1007/s00125-019-05082-7
Min Jeong Choi8
Estimated H-index: 8
(CNU: Chungnam National University),
Saet-Byel Jung14
Estimated H-index: 14
(CNU: Chungnam National University)
+ 13 AuthorsMinho Shong38
Estimated H-index: 38
(CNU: Chungnam National University)
Abstract
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.
  • References (47)
  • Citations (0)
馃摉 Papers frequently viewed together
21 Authors (Min Jeong Ryu, ..., Minho Shong)
32 Citations
201243.07Nature
15 Authors (Johan W. Jonker, ..., Ronald M. Evans)
151 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References47
Newest
#1Thanhvien TranH-Index: 7
#2Jingping YangH-Index: 1
Last. Yumei XiongH-Index: 7
view all 4 authors...
Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockou...
7 CitationsSource
#1Garima Singhal (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 7
#2Gaurav Kumar (Emory University)H-Index: 1
Last. Eleftheria Maratos-Flier (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 59
view all 9 authors...
Abstract Objective Non-alcoholic fatty liver (NAFL) associated with obesity is a major cause of liver diseases which can progress to non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) plays an important role in liver metabolism and is also a potential marker for NAFL. Here we aimed to test the effect of FGF21 deficiency on liver pathology in mice consuming a conventional high fat, high sucrose (HFHS) obesogenic diet for up to 52 week...
10 CitationsSource
#1Saet Byel Jung (CNU: Chungnam National University)H-Index: 5
#2Min Jeong Choi (CNU: Chungnam National University)H-Index: 8
Last. Minho Shong (CNU: Chungnam National University)H-Index: 38
view all 19 authors...
Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and syste...
11 CitationsSource
#1Zachary I. Grunewald (MU: University of Missouri)H-Index: 4
#2Nathan C. Winn (MU: University of Missouri)H-Index: 7
Last. Jaume Padilla (MU: University of Missouri)H-Index: 34
view all 9 authors...
Brown adipose tissue (BAT) is considered protective against obesity and related cardiometabolic dysfunction. Indeed, activation of BAT improves glucose homeostasis and attenuates cardiovascular dis...
7 CitationsSource
#1Shylesh Bhaskaran (OMRF: Oklahoma Medical Research Foundation)H-Index: 10
#2Gavin Pharaoh (OMRF: Oklahoma Medical Research Foundation)H-Index: 6
Last. Sathyaseelan S. Deepa (OMRF: Oklahoma Medical Research Foundation)H-Index: 15
view all 13 authors...
Abstract Caseinolytic peptidase P (ClpP) is a mammalian quality control protease that is proposed to play an important role in the initiation of the mitochondrial unfolded protein response (UPR mt ), a retrograde signaling response that helps to maintain mitochondrial protein homeostasis. Mitochondrial dysfunction is associated with the development of metabolic disorders, and to understand the effect of a defective UPR mt on metabolism, ClpP knockout ( ClpP 鈭/鈭 ) mice were analyzed. ClpP 鈭/鈭 mic...
16 CitationsSource
#1Hyo Kyun Chung (CNU: Chungnam National University)H-Index: 21
#2Jung Tae Kim (CNU: Chungnam National University)H-Index: 4
Last. Hyon-Seung Yi (CNU: Chungnam National University)H-Index: 13
view all 8 authors...
Growth differentiation factor 15 (GDF15) has recently been shown to have an important role in the regulation of mitochondrial function and in the pathogenesis of complex human diseases. Nevertheless, the role of GDF15 in alcohol-induced or fibrotic liver diseases has yet to be determined. In this study, we demonstrate that alcohol- or carbon tetrachloride (CCl4)-mediated hepatic GDF15 production ameliorates liver inflammation and fibrosis. Alcohol directly enhanced GDF15 expression in primary he...
13 CitationsSource
#1Kara L. Perks (Harry Perkins Institute of Medical Research)H-Index: 7
#2Nicola Ferreira (Harry Perkins Institute of Medical Research)H-Index: 3
Last. Aleksandra Filipovska (UWA: University of Western Australia)H-Index: 31
view all 13 authors...
Mitochondrial gene expression is essential for energy production; however, an understanding of how it can influence physiology and metabolism is lacking. Several proteins from the pentatricopeptide repeat (PPR) family are essential for the regulation of mitochondrial gene expression, but the functions of the remaining members of this family are poorly understood. We created knockout mice to investigate the role of the PPR domain 1 (PTCD1) protein and show that loss of PTCD1 is embryonic lethal, ...
11 CitationsSource
#1Pedro M. Quir贸s (EPFL: 脡cole Polytechnique F茅d茅rale de Lausanne)H-Index: 18
#2Miguel A. Prado (Harvard University)H-Index: 6
Last. Johan Auwerx (EPFL: 脡cole Polytechnique F茅d茅rale de Lausanne)H-Index: 137
view all 8 authors...
Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprote...
113 CitationsSource
#1Takayuki Ohtomo (Tokyo University of Pharmacy and Life Sciences)H-Index: 8
#2Kanako Ino (Tokyo University of Pharmacy and Life Sciences)H-Index: 1
Last. Junji Yamada (Tokyo University of Pharmacy and Life Sciences)H-Index: 7
view all 10 authors...
Abstract Since brown adipose tissue (BAT) is involved in thermogenesis using fatty acids as a fuel, BAT activation is a potential strategy for treating obesity and diabetes. However, whether BAT fatty acid combusting capacity is preserved in these conditions has remained unclear. We therefore evaluated expression levels of fatty acid oxidation-associated enzymes and uncoupling protein 1 (Ucp1) in BAT by western blot using a diet-induced obesity C57BL/6J mouse model. In C57BL/6J mice fed a high-f...
3 CitationsSource
#1Hyo Kyun Chung (CNU: Chungnam National University)H-Index: 21
#2Dongryeol Ryu (EPFL: 脡cole Polytechnique F茅d茅rale de Lausanne)H-Index: 24
Last. Minho Shong (CNU: Chungnam National University)H-Index: 38
view all 22 authors...
Reduced mitochondrial electron transport chain activity promotes longevity and improves energy homeostasis via cell-autonomous and 鈥搉on-autonomous factors in multiple model systems. This mitohormetic effect is thought to involve the mitochondrial unfolded protein response (UPRmt), an adaptive stress-response pathway activated by mitochondrial proteotoxic stress. Using mice with skeletal muscle鈥搒pecific deficiency of Crif1 (muscle-specific knockout [MKO]), an integral protein of the large mitorib...
57 CitationsSource
Cited By0
Newest