Acute Inhibition of Fatty Acid Import Inhibits GLUT4 Transcription in Adipose Tissue, but Not Skeletal or Cardiac Muscle Tissue, Partly Through Liver X Receptor (LXR) Signaling

Overview

Journal Diabetes

Specialty Endocrinology

Date 2010 Jan 28

PMID 20103707

Citations 23

Authors

Beth A Griesel

Juston Weems

Robert A Russell

E Dale Abel

Kenneth Humphries

Ann Louise Olson

Affiliations

Soon will be listed here.

Abstract

Objective: Insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative GLUT protein GLUT4. Transcription of the GLUT4 gene is repressed in states of insulin deficiency and insulin resistance and can be induced by states of enhanced energy output, such as exercise. The cellular signals that regulate GLUT4 transcription are not well understood. We hypothesized that changes in energy substrate flux regulate GLUT4 transcription.

Research Design And Methods: To test this hypothesis, we used transgenic mice in which expression of the chloramphenicol acetyltransferase (CAT) gene is driven by a functional 895-bp fragment of the human GLUT4 promoter, thereby acting as a reporter for transcriptional activity. Mice were treated with a single dose of etomoxir, which inhibits the transport of long-chain fatty acids into mitochondria and increases basal, but not insulin-mediated, glucose flux. GLUT4 and transgenic CAT mRNA were measured.

Results: Etomoxir treatment significantly reduced CAT and GLUT4 mRNA transcription in adipose tissue, but did not change transcription in heart and skeletal muscle. Downregulation of GLUT4 transcription was cell autonomous, since etomoxir treatment of 3T3-L1 adipocytes resulted in a similar downregulation of GLUT4 mRNA. GLUT4 transcriptional downregulation required the putative liver X receptor (LXR) binding site in the human GLUT4 gene promoter in adipose tissue and 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the LXR agonist, TO901317, partially restored GLUT4 expression in etomoxir-treated cells.

Conclusions: Our data suggest that long-chain fatty acid import into mitochondria in adipose tissue may produce ligands that regulate expression of metabolic genes.

Citing Articles

Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.

Mendez Garcia M, Matsuzaki S, Batushansky A, Newhardt R, Kinter C, Jin Y iScience. 2023; 26(7):107131.

PMID: 37534142 PMC: 10391959. DOI: 10.1016/j.isci.2023.107131.

Identification of a weight loss-associated causal eQTL in and the effects of deficiency on human adipocyte function.

Huang M, Coral D, Ardalani H, Spegel P, Saadat A, Claussnitzer M Elife. 2023; 12.

PMID: 36876906 PMC: 10023155. DOI: 10.7554/eLife.84168.

Quality More Than Quantity: The Use of Carbohydrates in High-Fat Diets to Tackle Obesity in Growing Rats.

Manzano M, Giron M, Salto R, Vilchez J, Reche-Perez F, Cabrera E Front Nutr. 2022; 9:809865.

PMID: 35425792 PMC: 9002105. DOI: 10.3389/fnut.2022.809865.

Emerging Role of Nuclear Receptors for the Treatment of NAFLD and NASH.

Welch R, Billon C, Losby M, Bedia-Diaz G, Fang Y, Avdagic A Metabolites. 2022; 12(3).

PMID: 35323681 PMC: 8953348. DOI: 10.3390/metabo12030238.

Dietary Complex and Slow Digestive Carbohydrates Prevent Fat Deposits During Catch-Up Growth in Rats.

Salto R, Giron M, Ortiz-Moral C, Manzano M, Vilchez J, Reche-Perez F Nutrients. 2020; 12(9).

PMID: 32854204 PMC: 7551611. DOI: 10.3390/nu12092568.

References

Bruning J, Michael M, Winnay J, Hayashi T, Horsch D, Accili D . A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998; 2(5):559-69. DOI: 10.1016/s1097-2765(00)80155-0. View

Sponarova J, Mustard K, Horakova O, Flachs P, Rossmeisl M, Brauner P . Involvement of AMP-activated protein kinase in fat depot-specific metabolic changes during starvation. FEBS Lett. 2005; 579(27):6105-10. DOI: 10.1016/j.febslet.2005.09.078. View

McGee S, van Denderen B, Howlett K, Mollica J, Schertzer J, Kemp B . AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes. 2008; 57(4):860-7. DOI: 10.2337/db07-0843. View

Richardson J, Balon T, TREADWAY J, Pessin J . Differential regulation of glucose transporter activity and expression in red and white skeletal muscle. J Biol Chem. 1991; 266(19):12690-4. View

Dobbins R, Szczepaniak L, Bentley B, ESSER V, Myhill J, McGarry J . Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes. 2001; 50(1):123-30. DOI: 10.2337/diabetes.50.1.123. View

Olson A, Knight J . Regulation of GLUT4 expression in vivo and in vitro. Front Biosci. 2003; 8:s401-9. DOI: 10.2741/1072. View

TREADWAY J, Hargrove D, Nardone N, McPherson R, Russo J, Milici A . Enhanced peripheral glucose utilization in transgenic mice expressing the human GLUT4 gene. J Biol Chem. 1994; 269(47):29956-61. View

Ranalletta M, Jiang H, Li J, Tsao T, Stenbit A, Yokoyama M . Altered hepatic and muscle substrate utilization provoked by GLUT4 ablation. Diabetes. 2005; 54(4):935-43. DOI: 10.2337/diabetes.54.4.935. View

Rafaeloff R, Patel R, Yip C, Goldfine I, Hawley D . Mutation of the high cysteine region of the human insulin receptor alpha-subunit increases insulin receptor binding affinity and transmembrane signaling. J Biol Chem. 1989; 264(27):15900-4. View

10.

Morillas M, Clotet J, Rubi B, Serra D, Arino J, Hegardt F . Inhibition by etomoxir of rat liver carnitine octanoyltransferase is produced through the co-ordinate interaction with two histidine residues. Biochem J. 2000; 351 Pt 2:495-502. PMC: 1221386. View

11.

Liu M, GIBBS E, McCoid S, Milici A, Stukenbrok H, McPherson R . Transgenic mice expressing the human GLUT4/muscle-fat facilitative glucose transporter protein exhibit efficient glycemic control. Proc Natl Acad Sci U S A. 1993; 90(23):11346-50. PMC: 47979. DOI: 10.1073/pnas.90.23.11346. View

12.

Stenbit A, Tsao T, Li J, Burcelin R, Geenen D, Factor S . GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med. 1997; 3(10):1096-101. DOI: 10.1038/nm1097-1096. View

13.

Eyster C, Duggins Q, Olson A . Expression of constitutively active Akt/protein kinase B signals GLUT4 translocation in the absence of an intact actin cytoskeleton. J Biol Chem. 2005; 280(18):17978-85. DOI: 10.1074/jbc.M409806200. View

14.

Yang J, Craddock L, Hong S, Liu Z . AMP-activated protein kinase suppresses LXR-dependent sterol regulatory element-binding protein-1c transcription in rat hepatoma McA-RH7777 cells. J Cell Biochem. 2009; 106(3):414-26. DOI: 10.1002/jcb.22024. View

15.

Kalaany N, Gauthier K, Zavacki A, Mammen P, Kitazume T, Peterson J . LXRs regulate the balance between fat storage and oxidation. Cell Metab. 2005; 1(4):231-44. DOI: 10.1016/j.cmet.2005.03.001. View

16.

Kelley D, Mandarino L . Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000; 49(5):677-83. DOI: 10.2337/diabetes.49.5.677. View

17.

Garvey W, Maianu L, Huecksteadt T, Birnbaum M, Molina J, Ciaraldi T . Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity. J Clin Invest. 1991; 87(3):1072-81. PMC: 329903. DOI: 10.1172/JCI115068. View

18.

Mitro N, Mak P, Vargas L, Godio C, Hampton E, Molteni V . The nuclear receptor LXR is a glucose sensor. Nature. 2006; 445(7124):219-23. DOI: 10.1038/nature05449. View

19.

Yagyu H, Chen G, Yokoyama M, Hirata K, Augustus A, Kako Y . Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest. 2003; 111(3):419-26. PMC: 151861. DOI: 10.1172/JCI16751. View

20.

Neufer P, Carey J, Dohm G . Transcriptional regulation of the gene for glucose transporter GLUT4 in skeletal muscle. Effects of diabetes and fasting. J Biol Chem. 1993; 268(19):13824-9. View