Nuclear Receptors Reverse McGarry's Vicious Cycle to Insulin Resistance

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2012 May 8

PMID 22560214

Citations 22

Authors

David D Moore

Affiliations

Soon will be listed here.

Abstract

Several pathways and pathologies have been suggested as connections between obesity and diabetes, including inflammation of adipose and other tissues, toxic lipids, endoplasmic reticulum stress, and fatty liver. One specific proposal is that insulin resistance induces a vicious cycle in which hyperinsulinemia increases hepatic lipogenesis and exacerbates fatty liver, in turn further increasing insulin resistance. Here I suggest that reversing this cycle via suppression of the lipogenic transcription factor SREBP-1c is a common thread that connects the antidiabetic effects of a surprising number of nuclear hormone receptors, including CAR, LRH-1, TRβ, ERα, and FXR/SHP.

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References

Shimano H, Shimomura I, Hammer R, Herz J, Goldstein J, Brown M . Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest. 1997; 100(8):2115-24. PMC: 508404. DOI: 10.1172/JCI119746. View

Hashimoto K, Yamada M, Matsumoto S, Monden T, Satoh T, Mori M . Mouse sterol response element binding protein-1c gene expression is negatively regulated by thyroid hormone. Endocrinology. 2006; 147(9):4292-302. DOI: 10.1210/en.2006-0116. View

Mauvais-Jarvis F . Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab. 2010; 22(1):24-33. PMC: 3011051. DOI: 10.1016/j.tem.2010.10.002. View

Bryzgalova G, Effendic S, Khan A, Rehnmark S, Barbounis P, Boulet J . Anti-obesity, anti-diabetic, and lipid lowering effects of the thyroid receptor beta subtype selective agonist KB-141. J Steroid Biochem Mol Biol. 2008; 111(3-5):262-7. DOI: 10.1016/j.jsbmb.2008.06.010. View

Ferre P, Foufelle F . Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010; 12 Suppl 2:83-92. DOI: 10.1111/j.1463-1326.2010.01275.x. View

Dimitriadis G, Baker B, Marsh H, Mandarino L, Rizza R, Bergman R . Effect of thyroid hormone excess on action, secretion, and metabolism of insulin in humans. Am J Physiol. 1985; 248(5 Pt 1):E593-601. DOI: 10.1152/ajpendo.1985.248.5.E593. View

Holland W, Summers S . Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev. 2008; 29(4):381-402. PMC: 2528849. DOI: 10.1210/er.2007-0025. View

Yang Z, Shen W, Sun H . Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2011; 4(4):741-8. PMC: 2994619. DOI: 10.1007/s12072-010-9202-6. View

Kelley D, McKolanis T, Hegazi R, Kuller L, Kalhan S . Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003; 285(4):E906-16. DOI: 10.1152/ajpendo.00117.2003. View

10.

Lalloyer F, Staels B . Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2010; 30(5):894-9. PMC: 2997800. DOI: 10.1161/ATVBAHA.108.179689. View

11.

Hotamisligil G . Inflammation and metabolic disorders. Nature. 2006; 444(7121):860-7. DOI: 10.1038/nature05485. View

12.

Houde V, Brule S, Festuccia W, Blanchard P, Bellmann K, Deshaies Y . Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 2010; 59(6):1338-48. PMC: 2874694. DOI: 10.2337/db09-1324. View

13.

Cai D, Yuan M, Frantz D, Melendez P, Hansen L, Lee J . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11(2):183-90. PMC: 1440292. DOI: 10.1038/nm1166. View

14.

Karvonen I, Stengard J, Huupponen R, Stenback F, Sotaniemi E . Effects of enzyme induction therapy on glucose and drug metabolism in obese mice model of non-insulin dependent diabetes mellitus. Diabetes Res. 1989; 10(2):85-92. View

15.

Yahagi N, Shimano H, Hasty A, Matsuzaka T, Ide T, Yoshikawa T . Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem. 2002; 277(22):19353-7. DOI: 10.1074/jbc.M201584200. View

16.

Paquette A, Wang D, Jankowski M, Gutkowska J, Lavoie J . Effects of ovariectomy on PPAR alpha, SREBP-1c, and SCD-1 gene expression in the rat liver. Menopause. 2008; 15(6):1169-75. DOI: 10.1097/gme.0b013e31817b8159. View

17.

Amorim B, Ueta C, Freitas B, Nassif R, Gouveia C, Christoffolete M . A TRbeta-selective agonist confers resistance to diet-induced obesity. J Endocrinol. 2009; 203(2):291-9. PMC: 3133532. DOI: 10.1677/JOE-08-0539. View

18.

Takiishi T, Gysemans C, Bouillon R, Mathieu C . Vitamin D and diabetes. Endocrinol Metab Clin North Am. 2010; 39(2):419-46, table of contents. DOI: 10.1016/j.ecl.2010.02.013. View

19.

Manolescu D, Sima A, Bhat P . All-trans retinoic acid lowers serum retinol-binding protein 4 concentrations and increases insulin sensitivity in diabetic mice. J Nutr. 2009; 140(2):311-6. DOI: 10.3945/jn.109.115147. View

20.

Briggs M, Yokoyama C, Wang X, Brown M, Goldstein J . Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem. 1993; 268(19):14490-6. View