Skeletal muscle insulin resistance in hamsters with diabetes developed from obesity is involved in abnormal skeletal muscle LXR, PPAR and SREBP expression

Li,Guo‑Sheng; Liu,Xu‑Han; Zhu,Hua; Huang,Lan; Liu,Ya‑Li; Ma,Chun‑Mei

doi:10.3892/etm.2016.3209

Skeletal muscle insulin resistance in hamsters with diabetes developed from obesity is involved in abnormal skeletal muscle LXR, PPAR and SREBP expression

Authors:
- Guo‑Sheng Li
- Xu‑Han Liu
- Hua Zhu
- Lan Huang
- Ya‑Li Liu
- Chun‑Mei Ma
View Affiliations

Affiliations: Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Endocrinology, Dalian Municipal Central Hospital, Dalian, Liaoning 116033, P.R. China, Department of Pathology, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P.R. China
Published online on: March 31, 2016 https://doi.org/10.3892/etm.2016.3209
Pages: 2259-2269
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetic ‘lipotoxicity’ theory suggests that fat‑induced skeletal muscle insulin resistance (FISMIR) in obesity induced by a high‑fat diet (HFD), which leads to ectopic lipid accumulation in insulin‑sensitive tissues, may play a pivotal role in the pathogenesis of type 2 diabetes. However, the changes in gene expression and the molecular mechanisms associated with the pathogenesis of FISMIR have not yet been fully elucidated. In the present study the changes in skeletal muscle gene expression were examined in FISMIR in obese insulin‑resistant and diabetic hamster models induced by HFD with or without low‑dose streptozotocin‑treatment. Microarray technology and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) were used to explore the potential underlying molecular mechanisms. The pathophysiological and metabolic features of obesity and type 2 diabetes in humans are closely resembled by these hamster models. The results of microarray analysis showed that the differentially expressed genes associated with metabolism were mostly related to the abnormal regulation and changes in the gene expression of liver X receptor (LXR), peroxisome proliferator‑activated receptor (PPAR) and sterol regulatory element‑binding protein (SREBP) transcriptional programs in the skeletal muscle from insulin‑resistant and diabetic hamsters. The microarray findings confirmed by RT‑qPCR indicated that the increased expression of SREBPs and LXRβ and the decreased expression of LXRα and PPARs were involved in the molecular mechanisms of FISMIR pathogenesis in insulin‑resistant and diabetic hamsters. A significant difference in the abnormal expression of skeletal muscle LXRs, PPARs and SREBPs was found between insulin‑resistant and diabetic hamsters. It may be concluded that the combined abnormal expression of LXR, PPAR and SREBP transcriptional programs may contribute to the development of FISMIR mediated by skeletal muscle lipid accumulation resulting from abnormal skeletal muscle glucose and lipid metabolism in these HFD‑ and streptozotocin injection‑induced insulin‑resistant and diabetic hamsters.

View Figures

View References

1	Anandharajan R, Sayyed SG, Doshi LS, Dixit P, Chandak PG, Dixit AV, Brahma MK, Deshmukh NJ, Gupte R, Damre A, et al: 18F9 (4-(3,6-bis (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno (2,3-c)pyridin-2-ylamino)-4-oxobutanoic acid) enhances insulin-mediated glucose uptake in vitro and exhibits antidiabetic activity in vivo in db/db mice. Metabolism. 58:1503–1516. 2009. View Article : Google Scholar : PubMed/NCBI
2	Guri AJ, Hontecillas R and Bassaganya-Riera J: Dietary modulators of peroxisome proliferator-activated receptors: Implications for the prevention and treatment of metabolic syndrome. J Nutrigenet Nutrigenomics. 1:126–135. 2008. View Article : Google Scholar : PubMed/NCBI
3	Unger RH and Orci L: Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Relat Metab Disord. 24(Suppl 4): S28–S32. 2000. View Article : Google Scholar : PubMed/NCBI
4	Smith AG and Muscat GE: Skeletal muscle and nuclear hormone receptors: Implications for cardiovascular and metabolic disease. Int J Biochem Cell Biol. 37:2047–2063. 2005. View Article : Google Scholar : PubMed/NCBI
5	Guilherme A, Virbasius JV, Puri V and Czech MP: Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 9:367–377. 2008. View Article : Google Scholar : PubMed/NCBI
6	Li G, Liu X, Zhu H, Huang L, Liu Y, Ma C and Qin C: Insulin resistance in insulin-resistant and diabetic hamsters (Mesocricetus auratus) is associated with abnormal hepatic expression of genes involved in lipid and glucose metabolism. Comp Med. 59:449–458. 2009.PubMed/NCBI
7	Brown MS, Faust JR and Goldstein JL: Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts. J Clin Invest. 55:783–793. 1975. View Article : Google Scholar : PubMed/NCBI
8	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
9	Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, et al: Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA. 100:8466–8471. 2003. View Article : Google Scholar : PubMed/NCBI
10	Dumas JF, Simard G, Flamment M, Ducluzeau PH and Ritz P: Is skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of insulin resistance in humans? Diabetes Metab. 35:159–167. 2009. View Article : Google Scholar : PubMed/NCBI
11	Mullen KL, Pritchard J, Ritchie I, Snook LA, Chabowski A, Bonen A, Wright D and Dyck DJ: Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats. Am J Physiol Regul Integr Comp Physiol. 296:R243–R251. 2009. View Article : Google Scholar : PubMed/NCBI
12	Mauvais-Jarvis F, Clegg DJ and Hevener AL: The role of estrogens in control of energy balance and glucose homeostasis. Endocr Rev. 34:309–338. 2013. View Article : Google Scholar : PubMed/NCBI
13	Choi CS, Fillmore JJ, Kim JK, Liu ZX, Kim S, Collier EF, Kulkarni A, Distefano A, Hwang YJ, Kahn M, et al: Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest. 117:1995–2003. 2007. View Article : Google Scholar : PubMed/NCBI
14	Nieto-Vazquez I, Fernández-Veledo S, de Alvaro C and Lorenzo M: Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes. 57:3211–3221. 2008. View Article : Google Scholar : PubMed/NCBI
15	Tsou RC and Bence KK: The genetics of PTPN1 and obesity: Insights from mouse models of tissue-specific PTP1B deficiency. J Obes. 2012:9268572012. View Article : Google Scholar : PubMed/NCBI
16	Heikkinen S, Suppola S, Malkki M, Deeb SS, Jänne J and Laakso M: Mouse hexokinase II gene: Structure, cDNA, promoter analysis and expression pattern. Mamm Genome. 11:91–96. 2000. View Article : Google Scholar : PubMed/NCBI
17	Norris AW, Hirshman MF, Yao J, Jessen N, Musi N, Chen L, Sivitz WI, Goodyear LJ and Kahn CR: Endogenous peroxisome proliferator-activated receptor-gamma augments fatty acid uptake in oxidative muscle. Endocrinology. 149:5374–5383. 2008. View Article : Google Scholar : PubMed/NCBI
18	Hessvik NP, Boekschoten MV, Baltzersen MA, Kersten S, Xu X, Andersén H, Rustan AC and Thoresen GH: LXR{beta} is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux. Am J Physiol Endocrinol Metab. 298:E602–E613. 2010. View Article : Google Scholar : PubMed/NCBI
19	Zhu R, Ou Z, Ruan X and Gong J: Role of liver X receptors in cholesterol efflux and inflammatory signaling. Mol Med Rep. 5:895–900. 2012.PubMed/NCBI
20	Guillet-Deniau I, Pichard AL, Koné A, Esnous C, Nieruchalski M, Girard J and Prip-Buus C: Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-bnding-protein-1c-dependent pathway. J Cell Sci. 117:1937–1944. 2004. View Article : Google Scholar : PubMed/NCBI
21	Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Okazaki H, Tamura Y, et al: 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. 277:19353–19357. 2002. View Article : Google Scholar : PubMed/NCBI
22	Thompson AL and Cooney GJ: Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes. 49:1761–1765. 2000. View Article : Google Scholar : PubMed/NCBI
23	Yen CF, Jiang YN, Shen TF, Wong IM, Chen CC, Chen KC, Chang WC, Tsao YK and Ding ST: Cloning and expression of the genes associated with lipid metabolism in Tsaiya ducks. Poult Sci. 84:67–74. 2005. View Article : Google Scholar : PubMed/NCBI
24	Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL and Brown MS: Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem. 277:9520–9528. 2002. View Article : Google Scholar : PubMed/NCBI
25	Kruszynska YT, Mulford MI, Baloga J, Yu JG and Olefsky JM: Regulation of skeletal muscle hexokinase II by insulin in nondiabetic and NIDDM subjects. Diabetes. 47:1107–1113. 1998. View Article : Google Scholar : PubMed/NCBI
26	Gosmain Y, Lefai E, Ryser S, Roques M and Vidal H: Sterol regulatory element-binding protein-1 mediates the effect of insulin on hexokinase II gene expression in human muscle cells. Diabetes. 53:321–329. 2004. View Article : Google Scholar : PubMed/NCBI
27	Whitehead JP, Richards AA, Hickman IJ, Macdonald GA and Prins JB: Adiponectin - a key adipokine in the metabolic syndrome. Diabetes Obes Metab. 8:264–280. 2006. View Article : Google Scholar : PubMed/NCBI
28	Almabouada F, Diaz-Ruiz A, Rabanal-Ruiz Y, Peinado JR, Vazquez-Martinez R and Malagon MM: Adiponectin receptors form homomers and heteromers exhibiting distinct ligand binding and intracellular signaling properties. J Biol Chem. 288:3112–3125. 2013. View Article : Google Scholar : PubMed/NCBI
29	Yamauchi T and Kadowaki T: Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond). 32(Suppl 7): S13–S18. 2008. View Article : Google Scholar : PubMed/NCBI
30	Muscat GE and Dressel U: Cardiovascular disease and PPARdelta: Targeting the risk factors. Curr Opin Investig Drugs. 6:887–894. 2005.PubMed/NCBI
31	Chung SS, Kim M, Youn BS, Lee NS, Park JW, Lee IK, Lee YS, Kim JB, Cho YM, Lee HK and Park KS: Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells. Mol Cell Biol. 29:20–30. 2009. View Article : Google Scholar : PubMed/NCBI
32	Wang H, Knaub LA, Jensen DR, Young Jung D, Hong EG, Ko HJ, Coates AM, Goldberg IJ, de la Houssaye BA, Janssen RC, et al: Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues. Diabetes. 58:116–124. 2009. View Article : Google Scholar : PubMed/NCBI
33	Choi CS, Befroy DE, Codella R, Kim S, Reznick RM, Hwang YJ, Liu ZX, Lee HY, Distefano A, Samuel VT, et al: Paradoxical effects of increased expression of PGC-1alpha on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. Proc Natl Acad Sci USA. 105:19926–19931. 2008. View Article : Google Scholar : PubMed/NCBI
34	Kadowaki T and Yamauchi T: Adiponectin and adiponectin receptors. Endocr Rev. 26:439–451. 2005. View Article : Google Scholar : PubMed/NCBI
35	Awazawa M, Ueki K, Inabe K, Yamauchi T, Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S, Nagai R and Kadowaki T: Adiponectin suppresses hepatic SREBP1c expression in an AdipoR1/LKB1/AMPK dependent pathway. Biochem Biophys Res Commun. 382:51–56. 2009. View Article : Google Scholar : PubMed/NCBI