Impact of Sex on the Therapeutic Efficacy of Rosiglitazone in Modulating White Adipose Tissue Function and Insulin Sensitivity

Overview

Journal Nutrients

Date 2024 Sep 28

PMID 39339665

Authors

Marco Bauza-Thorbrugge

Emilia Amengual-Cladera

Bel Maria Galmes-Pascual

Andrea Moran-Costoya

Magdalena Gianotti

Adamo Valle

Ana Maria Proenza

Isabel Llado

Affiliations

Soon will be listed here.

Abstract

Obesity and type 2 diabetes mellitus are global public health issues. Although males show higher obesity and insulin resistance prevalence, current treatments often neglect sex-specific differences. White adipose tissue (WAT) is crucial in preventing lipotoxicity and inflammation and has become a key therapeutic target. Rosiglitazone (RSG), a potent PPARγ agonist, promotes healthy WAT growth and mitochondrial function through MitoNEET modulation. Recent RSG-based strategies specifically target white adipocytes, avoiding side effects. Our aim was to investigate whether sex-specific differences in the insulin-sensitizing effects of RSG exist on WAT during obesity and inflammation. We used Wistar rats of both sexes fed a high-fat diet (HFD, 22.5% fat content) for 16 weeks. Two weeks before sacrifice, a group of HFD-fed rats received RSG treatment (4 mg/kg of body weight per day) within the diet. HFD male rats showed greater insulin resistance, inflammation, mitochondrial dysfunction, and dyslipidemia than females. RSG had more pronounced effects in males, significantly improving insulin sensitivity, fat storage, mitochondrial function, and lipid handling in WAT while reducing ectopic fat deposition and enhancing adiponectin signaling in the liver. Our study suggests a significant sexual dimorphism in the anti-diabetic effects of RSG on WAT, correlating with the severity of metabolic dysfunction.

References

Ye J, DOYLE P, Iglesias M, Watson D, Cooney G, Kraegen E . Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes. 2001; 50(2):411-7. DOI: 10.2337/diabetes.50.2.411. View

Duan S, Usher M, Foley 4th E, Milstone D, Brosius 3rd F, Mortensen R . Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient mice. Diabetologia. 2010; 53(7):1493-505. PMC: 2896206. DOI: 10.1007/s00125-010-1748-2. View

Amengual-Cladera E, Llado I, Proenza A, Gianotti M . High-fat diet feeding induces a depot-dependent response on the pro-inflammatory state and mitochondrial function of gonadal white adipose tissue. Br J Nutr. 2012; 109(3):413-24. DOI: 10.1017/S0007114512001171. View

Hiradate R, Khalil I, Matsuda A, Sasaki M, Hida K, Harashima H . A novel dual-targeted rosiglitazone-loaded nanoparticle for the prevention of diet-induced obesity via the browning of white adipose tissue. J Control Release. 2020; 329:665-675. DOI: 10.1016/j.jconrel.2020.10.002. View

Kusminski C, Holland W, Sun K, Park J, Spurgin S, Lin Y . MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012; 18(10):1539-49. PMC: 3745511. DOI: 10.1038/nm.2899. View

Nadal-Casellas A, Amengual-Cladera E, Proenza A, Llado I, Gianotti M . Long-term high-fat-diet feeding impairs mitochondrial biogenesis in liver of male and female rats. Cell Physiol Biochem. 2010; 26(3):291-302. DOI: 10.1159/000320552. View

Carobbio S, Pellegrinelli V, Vidal-Puig A . Adipose Tissue Function and Expandability as Determinants of Lipotoxicity and the Metabolic Syndrome. Adv Exp Med Biol. 2017; 960:161-196. DOI: 10.1007/978-3-319-48382-5_7. View

Brasaemle D, Rubin B, Harten I, Kimmel A, Londos C . Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem. 2000; 275(49):38486-93. DOI: 10.1074/jbc.M007322200. View

Chen Y, Kim M, Paye S, Benayoun B . Sex as a Biological Variable in Nutrition Research: From Human Studies to Animal Models. Annu Rev Nutr. 2022; 42:227-250. PMC: 9398923. DOI: 10.1146/annurev-nutr-062220-105852. View

10.

Tramunt B, Smati S, Grandgeorge N, Lenfant F, Arnal J, Montagner A . Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia. 2019; 63(3):453-461. PMC: 6997275. DOI: 10.1007/s00125-019-05040-3. View

11.

Crewe C, Funcke J, Li S, Joffin N, Gliniak C, Ghaben A . Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 2021; 33(9):1853-1868.e11. PMC: 8429176. DOI: 10.1016/j.cmet.2021.08.002. View

12.

Galmes-Pascual B, Nadal-Casellas A, Bauza-Thorbrugge M, Sbert-Roig M, J Garcia-Palmer F, Proenza A . 17β-estradiol improves hepatic mitochondrial biogenesis and function through PGC1B. J Endocrinol. 2016; 232(2):297-308. DOI: 10.1530/JOE-16-0350. View

13.

Shabalala S, Dludla P, Mabasa L, Kappo A, Basson A, Pheiffer C . The effect of adiponectin in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the potential role of polyphenols in the modulation of adiponectin signaling. Biomed Pharmacother. 2020; 131:110785. DOI: 10.1016/j.biopha.2020.110785. View

14.

Twig G, Elorza A, Molina A, Mohamed H, Wikstrom J, Walzer G . Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008; 27(2):433-46. PMC: 2234339. DOI: 10.1038/sj.emboj.7601963. View

15.

Arimura N, Horiba T, Imagawa M, Shimizu M, Sato R . The peroxisome proliferator-activated receptor gamma regulates expression of the perilipin gene in adipocytes. J Biol Chem. 2004; 279(11):10070-6. DOI: 10.1074/jbc.M308522200. View

16.

Otero M, Lago R, Lago F, Casanueva F, Dieguez C, Gomez-Reino J . Leptin, from fat to inflammation: old questions and new insights. FEBS Lett. 2005; 579(2):295-301. DOI: 10.1016/j.febslet.2004.11.024. View

17.

Parlee S, Lentz S, Mori H, MacDougald O . Quantifying size and number of adipocytes in adipose tissue. Methods Enzymol. 2014; 537:93-122. PMC: 4069255. DOI: 10.1016/B978-0-12-411619-1.00006-9. View

18.

Rodbell M . METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. J Biol Chem. 1964; 239:375-80. View

19.

Opie L, Newsholme E . The activities of fructose 1,6-diphosphatase, phosphofructokinase and phosphoenolpyruvate carboxykinase in white muscle and red muscle. Biochem J. 1967; 103(2):391-9. PMC: 1270420. DOI: 10.1042/bj1030391. View

20.

He H, Tao H, Xiong H, Duan S, McGowan Jr F, Mortensen R . Rosiglitazone causes cardiotoxicity via peroxisome proliferator-activated receptor γ-independent mitochondrial oxidative stress in mouse hearts. Toxicol Sci. 2014; 138(2):468-81. PMC: 4243497. DOI: 10.1093/toxsci/kfu015. View