The G0/G1 Switch Gene 2 Regulates Adipose Lipolysis through Association with Adipose Triglyceride Lipase

Yang, Xingyuan; Lü, Xin; Lombès, Marc; Rha, Geun Bae; In, Young; Guerin, Theresa M.; Smart, Elizabeth; Liu, Jun

doi:10.1016/j.cmet.2010.02.003

Cited by 403 publications

(535 citation statements)

References 43 publications

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“…A limited number of studies have implied that G0s2 is involved in cell proliferation (33), differentiation (19), apoptosis (34), inflammation (35), and lipid metabolism (36) in various cellular settings. Moreover, G0s2 was reported to localize to the cytosol (33), endoplasmic reticulum (19), mitochondria (34), or the surface of lipid droplets (36). How G0s2 distinguishes these multiple functions is still not clear.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

Kioka¹,

Kato²,

Fujikawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The oxidative phosphorylation (OXPHOS) system generates most of the ATP in respiring cells. ATP-depleting conditions, such as hypoxia, trigger responses that promote ATP production. However, how OXPHOS is regulated during hypoxia has yet to be elucidated. In this study, selective measurement of intramitochondrial ATP levels identified the hypoxia-inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of OXPHOS. A mitochondria-targeted, FRET-based ATP biosensor enabled us to assess OXPHOS activity in living cells. Mitochondria-targeted, FRET-based ATP biosensor and ATP production assay in a semiintact cell system revealed that G0s2 increases mitochondrial ATP production. The expression of G0s2 was rapidly and transiently induced by hypoxic stimuli, and G0s2 interacts with OXPHOS complex V (F o F 1 -ATP synthase). Furthermore, physiological enhancement of G0s2 expression prevented cells from ATP depletion and induced a cellular tolerance for hypoxic stress. These results show that G0s2 positively regulates OXPHOS activity by interacting with F o F 1 -ATP synthase, which causes an increase in ATP production in response to hypoxic stress and protects cells from a critical energy crisis. These findings contribute to the understanding of a unique stress response to energy depletion. Additionally, this study shows the importance of assessing intramitochondrial ATP levels to evaluate OXPHOS activity in living cells.energy metabolism | live-cell imaging M aintaining cellular homeostasis and activities requires a stable energy supply. Most eukaryotic cells generate ATP as their energy currency mainly through the mitochondrial oxidative phosphorylation (OXPHOS) system. The OXPHOS system consists of five large protein complex units (i.e., complexes I-V), comprising more than 100 proteins. In this system, oxygen (O 2 ) is essential as the terminal electron acceptor for complex IV to finally produce the proton-motive force that drives the ATPgenerating molecular motor complex V (F o F 1 -ATP synthase).Hypoxia causes the depletion of intracellular ATP and triggers adaptive cellular responses to help maintain intracellular ATP levels and minimize any deleterious effects of energy depletion. Although the metabolic switch from mitochondrial respiration to anaerobic glycolysis is widely recognized (1-4), several recent reports have shown that hypoxic stimuli unexpectedly increase OXPHOS efficiency as well (5-7). In other words, cells have adaptive mechanisms to maintain intracellular ATP levels by enhancing OXPHOS, particularly in the early phase of hypoxia, in which the O 2 supply is limited but still remains. However, the mechanism by which OXPHOS is regulated during this early hypoxic phase is still not fully understood.Revealing the mechanism of this fine-tuned regulation of OXPHOS requires accurate and noninvasive measurements of OXPHOS activity. Although researchers have established methods to measure OXPHOS activity, precise measurement, especially in living cells, is still difficult. Measuring the intracellul...

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Section: Discussionmentioning

confidence: 99%

Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

Kioka¹,

Kato²,

Fujikawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous reports indicate that G0s2 specifically interacts with ATGL, and G0s2 functions to attenuate ATGL activity. 18 To examine whether the function of G0s2 in the terminal differentiation program is dependent on ATGL, we performed knockdown of ATGL expression in 3T3-L1 cells.…”

Section: Role Of G0s2 In Adipogenesis H Choi Et Almentioning

confidence: 99%

“…16 It was shown that murine G0s2 is predominantly expressed in adipose tissue, and the gene is upregulated by PPARg in 3T3-L1 cells. 17 More recently, it has been suggested that G0s2 is involved in lipid metabolism as an inhibitor of adipose triglyceride lipase (ATGL)-mediated lipolysis; 18 however, a G0s2-related activity in adipogenesis has not been investigated so far. In this report, we present data supporting G0s2 as a novel regulator of the adipogenic process.…”

mentioning

confidence: 99%

G0/G1 switch gene 2 has a critical role in adipocyte differentiation

Choi

Kim

et al. 2014

Cell Death Differ

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Mouse 3T3-L1 preadipocytes differentiate into adipocytes when treated with 3-isobutyl-1-methylxanthine, dexamethasone, and insulin. Although mechanisms of adipogenesis, including transcriptional cascades, are understood, it is still unclear how clonally expanded cells eventually enter the terminal differentiation program. From gene expression profile studies, we identified G0/G1 switch gene 2 (G0s2) as a novel regulator of adipogenesis. The gene was found to be expressed at a higher level in white and brown adipose tissues, and it was induced in 3T3-L1 cells by hormonal treatment. Importantly, G0s2 expression was closely associated with the transition from mitotic clonal expansion to terminal differentiation. Knockdown of G0s2 expression with siRNA inhibited adipocyte differentiation, whereas constitutive overexpression of G0s2 accelerated differentiation of preadipocytes to mature adipocytes. Expression of G0s2 was found to be regulated by peroxisome proliferator-activated receptor c (PPARc), which is a well-known regulator of adipocyte differentiation. Absence of either PPARc or G0s2 expression resulted in apoptotic pathway activation before terminal differentiation. To determine whether G0s2 has a role in vivo, G0s2-knockout mice were generated. The knockout mice were normal in appearance, but they had less adipose mass than wild-type littermates. Mouse embryonic fibroblast cells from G0s2-deficient mice exhibited impaired adipogenesis and contained unusually small intracellular lipid droplets, suggesting that G0s2 has a role in lipid droplet formation. Our studies demonstrate that G0s2 has an important role in adipogenesis and accumulation of triacylglycerol.

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“…Real-time electrical impedance was monitored every hour in each well for several h. Data from two replicates were averaged. The EC 50 was calculated using GraphPad Prism5 software.…”

Section: Methodsmentioning

confidence: 99%

“…(error bars) per concentration. The data were normalized and analyzed using GraphPad Prism software version 5 with an equation for binding, competitive with one site, fit log IC 50 . The estimated IC 50 Next, we investigated the role of PEDF-R PLA 2 activity in mediating the effects of PEDF.…”

Section: Expression Of Pedf-r Fragments Fused To N-end-his 6 /Xpressmentioning

confidence: 99%

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

Subramanian

Locatelli-Hoops

Kenealey

et al. 2013

Journal of Biological Chemistry

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Background: PEDF has neurotrophic activity and interacts with PEDF-R, a membrane-linked lipase. Results: A PEDF-binding region of PEDF-R is required for PEDF-R enzymatic stimulation, and peptides derived from this region block PEDF⅐PEDF-R-mediated retinal survival activities. Conclusion: A ligand binding domain is identified in PEDF-R, a critical receptor for the survival activity of PEDF. Significance: The findings provide mechanistic insight into the survival activity of PEDF.

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The G0/G1 Switch Gene 2 Regulates Adipose Lipolysis through Association with Adipose Triglyceride Lipase

Cited by 403 publications

References 43 publications

Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

Evaluation of intramitochondrial ATP levels identifies G0/G1 switch gene 2 as a positive regulator of oxidative phosphorylation

G0/G1 switch gene 2 has a critical role in adipocyte differentiation

Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R)

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