Dysregulation of Mitochondrial Function and Biogenesis Modulators in Adipose Tissue of Obese Children

Overview

Journal Int J Obes (Lond)

Specialty Endocrinology

Date 2017 Nov 22

PMID 29158541

Citations 31

Authors

R Zamora-Mendoza

H Rosas-Vargas

M T Ramos-Cervantes

P Garcia-Zuniga

H Perez-Lorenzana

P Mendoza-Lorenzo

A C Perez-Ortiz

F J Estrada-Mena

A Miliar-Garcia

E Lara-Padilla

G Ceballos

A Rodriguez

F Villarreal

I Ramirez-Sanchez

Affiliations

Soon will be listed here.

Abstract

Background/objectives: We aimed to evaluate mitochondrial biogenesis (MB), structure, metabolism and dysfunction in abdominal adipose tissue from male pediatric patients with obesity.

Subjects/methods: Samples were collected from five children with obesity (percentile ⩾95) and five eutrophic boys (percentile ⩾5/⩽85) (8-12 years old) following parental informed consent. We analyzed the expression of key genes involved in MB (sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ coactivator-1α (PGC1α), nuclear respiratory factors 1 and 2 (NRF1, NRF2) and mitochondrial transcription factor A (TFAM) and surrogates for mitochondrial function/structure/metabolism (porin, TOMM20, complex I and V, UCP1, UCP2, SIRT3, SOD2) by western blot. Citrate synthase (CS), complex I (CI) activity, adenosine triphosphate (ATP) levels, mitochondrial DNA (mtDNA) content and oxidative stress end points were also determined.

Results: Most MB proteins were significantly decreased in samples from children with obesity except complex I, V and superoxide dismutase-2 (SOD2). Similarly, CS and CI activity showed a significant reduction, as well as ATP levels and mtDNA content. PPARγ, PGC1α, complex I and V and SOD2 were hyperacetylated compared with lean samples. Concurrently, in samples from children with obesity, we found decreased SOD2 activity and redox state imbalance highlighted by decreased reduced glutathione/oxidized glutathione (GSH/GSSG) ratio and significant increases in protein carbonylation.

Conclusions: Adipose tissue from children with obesity demonstrates a dysregulation of key modulators of MB and organelle structure, and displays hyperacetylation of key proteins and altered expression of upstream regulators of cell metabolism.

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References

Vieira V, Valentine R . Mitochondrial biogenesis in adipose tissue: can exercise make fat cells 'fit'?. J Physiol. 2009; 587(Pt 14):3427-8. PMC: 2742270. DOI: 10.1113/jphysiol.2009.175307. View

Shimazu T, Hirschey M, Hua L, Dittenhafer-Reed K, Schwer B, Lombard D . SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010; 12(6):654-61. PMC: 3310379. DOI: 10.1016/j.cmet.2010.11.003. View

Yoshizaki T, Milne J, Imamura T, Schenk S, Sonoda N, Babendure J . SIRT1 exerts anti-inflammatory effects and improves insulin sensitivity in adipocytes. Mol Cell Biol. 2008; 29(5):1363-74. PMC: 2643824. DOI: 10.1128/MCB.00705-08. View

Canto C, Auwerx J . PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009; 20(2):98-105. PMC: 3627054. DOI: 10.1097/MOL.0b013e328328d0a4. View

Hansen M, Lund M, Gregers E, Kraunsoe R, van Hall G, Helge J . Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB. Obesity (Silver Spring). 2015; 23(10):2022-9. DOI: 10.1002/oby.21223. View

Norvell A, McMahon S . Cell biology. Rise of the rival. Science. 2010; 327(5968):964-5. DOI: 10.1126/science.1187159. View

Frohnert B, Sinaiko A, Serrot F, Foncea R, Moran A, Ikramuddin S . Increased adipose protein carbonylation in human obesity. Obesity (Silver Spring). 2011; 19(9):1735-41. PMC: 4644541. DOI: 10.1038/oby.2011.115. View

Thompson M, Kim D . Links between fatty acids and expression of UCP2 and UCP3 mRNAs. FEBS Lett. 2004; 568(1-3):4-9. DOI: 10.1016/j.febslet.2004.05.011. View

Fernandez-Marcos P, Auwerx J . Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011; 93(4):884S-90. PMC: 3057551. DOI: 10.3945/ajcn.110.001917. View

10.

Muoio D, Neufer P . Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab. 2012; 15(5):595-605. PMC: 3348508. DOI: 10.1016/j.cmet.2012.04.010. View

11.

Hirschey M, Shimazu T, Huang J, Schwer B, Verdin E . SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harb Symp Quant Biol. 2011; 76:267-77. DOI: 10.1101/sqb.2011.76.010850. View

12.

Mahadik S, Lele R, Saranath D, Seth A, Parikh V . Uncoupling protein-2 (UCP2) gene expression in subcutaneous and omental adipose tissue of Asian Indians: Relationship to adiponectin and parameters of metabolic syndrome. Adipocyte. 2013; 1(2):101-107. PMC: 3609085. DOI: 10.4161/adip.19671. View

13.

Hirschey M, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard D . SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010; 464(7285):121-5. PMC: 2841477. DOI: 10.1038/nature08778. View

14.

Kaaman M, Sparks L, van Harmelen V, Smith S, Sjolin E, Dahlman I . Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue. Diabetologia. 2007; 50(12):2526-33. DOI: 10.1007/s00125-007-0818-6. View

15.

Kraunsoe R, Boushel R, Hansen C, Schjerling P, Qvortrup K, Stockel M . Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. J Physiol. 2010; 588(Pt 12):2023-32. PMC: 2911209. DOI: 10.1113/jphysiol.2009.184754. View

16.

Brownlee M . Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):813-20. DOI: 10.1038/414813a. View

17.

Scarpulla R . Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2010; 1813(7):1269-78. PMC: 3035754. DOI: 10.1016/j.bbamcr.2010.09.019. View

18.

Civitarese A, Ukropcova B, Carling S, Hulver M, DeFronzo R, Mandarino L . Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab. 2006; 4(1):75-87. PMC: 2671025. DOI: 10.1016/j.cmet.2006.05.002. View

19.

Zhang D, Liu Z, Choi C, Tian L, Kibbey R, Dong J . Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A. 2007; 104(43):17075-80. PMC: 2040460. DOI: 10.1073/pnas.0707060104. View

20.

Xu H, Barnes G, Yang Q, Tan G, Yang D, Chou C . Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112(12):1821-30. PMC: 296998. DOI: 10.1172/JCI19451. View