O-GlcNAc Transferase Inhibits Visceral Fat Lipolysis and Promotes Diet-induced Obesity

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jan 12

PMID 31924761

Citations 37

Authors

Yunfan Yang

Minnie Fu

Min-Dian Li

Kaisi Zhang

Bichen Zhang

Simeng Wang

Yuyang Liu

Weiming Ni

Qunxiang Ong

Jia Mi

Xiaoyong Yang

Affiliations

Soon will be listed here.

Abstract

Excessive visceral fat accumulation is a primary risk factor for metabolically unhealthy obesity and related diseases. The visceral fat is highly susceptible to the availability of external nutrients. Nutrient flux into the hexosamine biosynthetic pathway leads to protein posttranslational modification by O-linked β-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Here, we report that inducible deletion of adipose OGT causes a rapid visceral fat loss by specifically promoting lipolysis in visceral fat. Mechanistically, visceral fat maintains a high level of O-GlcNAcylation during fasting. Loss of OGT decreases O-GlcNAcylation of lipid droplet-associated perilipin 1 (PLIN1), which leads to elevated PLIN1 phosphorylation and enhanced lipolysis. Moreover, adipose OGT overexpression inhibits lipolysis and promotes diet-induced obesity. These findings establish an essential role for OGT in adipose tissue homeostasis and indicate a unique potential for targeting O-GlcNAc signaling in the treatment of obesity.

Citing Articles

Crosstalk between O-GlcNAcylation and phosphorylation in metabolism: regulation and mechanism.

Zhao Q, Zhou S, Lou W, Qian H, Xu Z Cell Death Differ. 2025; .

PMID: 40045035 DOI: 10.1038/s41418-025-01473-z.

Male Wistar Rats Chronically Fed with a High-Fat Diet Develop Inflammatory and Ionic Transport Angiotensin-(3-4)-Sensitive Myocardial Lesions but Preserve Echocardiographic Parameters.

Crisostomo T, Luzes R, Goncalves M, Pardal M, Muzi-Filho H, Costa-Sarmento G Int J Mol Sci. 2024; 25(22).

PMID: 39596537 PMC: 11594684. DOI: 10.3390/ijms252212474.

Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy.

Lei Y, Liu Q, Chen B, Wu F, Li Y, Dong X Nat Commun. 2024; 15(1):9334.

PMID: 39472558 PMC: 11522279. DOI: 10.1038/s41467-024-53601-x.

DeepO-GlcNAc: a web server for prediction of protein O-GlcNAcylation sites using deep learning combined with attention mechanism.

Zhang L, Deng T, Pan S, Zhang M, Zhang Y, Yang C Front Cell Dev Biol. 2024; 12:1456728.

PMID: 39450274 PMC: 11500328. DOI: 10.3389/fcell.2024.1456728.

-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice.

Ohgaku S, Ida S, Ohashi N, Morino K, Ishikado A, Yanagimachi T Heliyon. 2024; 10(14):e34490.

PMID: 39130439 PMC: 11315187. DOI: 10.1016/j.heliyon.2024.e34490.

References

Porter S, Massaro J, Hoffmann U, Vasan R, ODonnel C, Fox C . Abdominal subcutaneous adipose tissue: a protective fat depot?. Diabetes Care. 2009; 32(6):1068-75. PMC: 2681034. DOI: 10.2337/dc08-2280. View

Itabe H, Yamaguchi T, Nimura S, Sasabe N . Perilipins: a diversity of intracellular lipid droplet proteins. Lipids Health Dis. 2017; 16(1):83. PMC: 5410086. DOI: 10.1186/s12944-017-0473-y. View

Sztalryd C, Brasaemle D . The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis. Biochim Biophys Acta Mol Cell Biol Lipids. 2017; 1862(10 Pt B):1221-1232. PMC: 5595658. DOI: 10.1016/j.bbalip.2017.07.009. View

Kao H, Huang C, Bretana N, Lu C, Huang K, Weng S . A two-layered machine learning method to identify protein O-GlcNAcylation sites with O-GlcNAc transferase substrate motifs. BMC Bioinformatics. 2015; 16 Suppl 18:S10. PMC: 4682369. DOI: 10.1186/1471-2105-16-S18-S10. View

Tang H, Tang C, Man X, Tan S, Guo Y, Tang J . Plasticity of adipose tissue in response to fasting and refeeding in male mice. Nutr Metab (Lond). 2017; 14:3. PMC: 5217231. DOI: 10.1186/s12986-016-0159-x. View

Li M, Vera N, Yang Y, Zhang B, Ni W, Ziso-Qejvanaj E . Adipocyte OGT governs diet-induced hyperphagia and obesity. Nat Commun. 2018; 9(1):5103. PMC: 6269424. DOI: 10.1038/s41467-018-07461-x. View

Hart G, Slawson C, Ramirez-Correa G, Lagerlof O . Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem. 2011; 80:825-58. PMC: 3294376. DOI: 10.1146/annurev-biochem-060608-102511. View

Granneman J, Moore H, Granneman R, Greenberg A, Obin M, Zhu Z . Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem. 2006; 282(8):5726-35. DOI: 10.1074/jbc.M610580200. View

Zhang H, Souza S, Muliro K, Kraemer F, Obin M, Greenberg A . Lipase-selective functional domains of perilipin A differentially regulate constitutive and protein kinase A-stimulated lipolysis. J Biol Chem. 2003; 278(51):51535-42. DOI: 10.1074/jbc.M309591200. View

10.

Ruan H, Singh J, Li M, Wu J, Yang X . Cracking the O-GlcNAc code in metabolism. Trends Endocrinol Metab. 2013; 24(6):301-9. PMC: 3783028. DOI: 10.1016/j.tem.2013.02.002. View

11.

Oh Y, Moon J, Kim H, Kong M . Visceral-to-subcutaneous fat ratio as a predictor of the multiple metabolic risk factors for subjects with normal waist circumference in Korea. Diabetes Metab Syndr Obes. 2017; 10:505-511. PMC: 5729827. DOI: 10.2147/DMSO.S150914. View

12.

Fukuda T, Bouchi R, Takeuchi T, Nakano Y, Murakami M, Minami I . Ratio of visceral-to-subcutaneous fat area predicts cardiovascular events in patients with type 2 diabetes. J Diabetes Investig. 2017; 9(2):396-402. PMC: 5835471. DOI: 10.1111/jdi.12713. View

13.

Zhang K, Yin R, Yang X . O-GlcNAc: A Bittersweet Switch in Liver. Front Endocrinol (Lausanne). 2015; 5:221. PMC: 4269194. DOI: 10.3389/fendo.2014.00221. View

14.

McDonough P, Maciejewski-Lenoir D, Hartig S, Hanna R, Whittaker R, Heisel A . Differential phosphorylation of perilipin 1A at the initiation of lipolysis revealed by novel monoclonal antibodies and high content analysis. PLoS One. 2013; 8(2):e55511. PMC: 3566132. DOI: 10.1371/journal.pone.0055511. View

15.

Greenberg A, Egan J, Wek S, Moos Jr M, Londos C, Kimmel A . Isolation of cDNAs for perilipins A and B: sequence and expression of lipid droplet-associated proteins of adipocytes. Proc Natl Acad Sci U S A. 1993; 90(24):12035-9. PMC: 48120. DOI: 10.1073/pnas.90.24.12035. View

16.

Jochmann R, Holz P, Sticht H, Sturzl M . Validation of the reliability of computational O-GlcNAc prediction. Biochim Biophys Acta. 2013; 1844(2):416-21. DOI: 10.1016/j.bbapap.2013.12.002. View

17.

Aune U, Ruiz L, Kajimura S . Isolation and differentiation of stromal vascular cells to beige/brite cells. J Vis Exp. 2013; (73). PMC: 3641667. DOI: 10.3791/50191. View

18.

Ida S, Morino K, Sekine O, Ohashi N, Kume S, Chano T . Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice. Diabetologia. 2017; 60(9):1761-1769. DOI: 10.1007/s00125-017-4327-y. View

19.

Sahakyan K, Somers V, Rodriguez-Escudero J, Hodge D, Carter R, Sochor O . Normal-Weight Central Obesity: Implications for Total and Cardiovascular Mortality. Ann Intern Med. 2015; 163(11):827-35. PMC: 4995595. DOI: 10.7326/M14-2525. View

20.

Booth A, Magnuson A, Foster M . Detrimental and protective fat: body fat distribution and its relation to metabolic disease. Horm Mol Biol Clin Investig. 2014; 17(1):13-27. DOI: 10.1515/hmbci-2014-0009. View