Angiopoietin-like protein 4 improves glucose tolerance and insulin resistance but induces liver steatosis in high-fat-diet mice

Wang,Yi; Liu,Li‑Ming; Wei,Li; Ye,Wei‑Wei; Meng,Xiang‑Ying; Chen,Feng; Xiao,Qian; Chen,Jian‑Yang; Zhou,Yong

doi:10.3892/mmr.2016.5637

Angiopoietin-like protein 4 improves glucose tolerance and insulin resistance but induces liver steatosis in high-fat-diet mice

Authors:
- Yi Wang
- Li‑Ming Liu
- Li Wei
- Wei‑Wei Ye
- Xiang‑Ying Meng
- Feng Chen
- Qian Xiao
- Jian‑Yang Chen
- Yong Zhou
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Affiliations: Department of Endocrinology, Dahua Hospital of Xuhui District, Shanghai 200237, P.R. China, Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China, Department of Endocrinology, Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200025, P.R. China
Published online on: August 18, 2016 https://doi.org/10.3892/mmr.2016.5637
Pages: 3293-3300

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Abstract

Angiopoietin-like protein 4 (Angptl4) is a secreted protein predominantly expressed in liver and adipose tissues, and has been identified as an adipokine. Angptl4 is the target gene of peroxisome proliferator‑activated receptors, which are widely used as lipid‑lowering and anti‑diabetic drugs, and previous studies have demonstrated that Angptl4 is able to directly stimulate adipocyte lipolysis. The current study focused on how Angptl4 was involved in regulating lipid and glucose metabolism in high‑fat‑diet (HFD) C57 mice. In the present study, mice were divided into three groups, with standard chow mice as a normal control, adenovirus (adv)‑injected HFD mice as a model control and adv‑Angptl4‑injected HFD mice as the Angptl4+ group. Firstly, compared with the normal control group, mice in the model control group gained more body weight with severe liver steatosis and increased serum levels of triglyceride, total cholesterol, free fatty acids, alanine aminotransferase and aspartate aminotransferase. In the Angptl4+ group, Angptl4 reduced the weight growth rate, aggravated hepatic steatosis and further increased all the aforementioned serum indexes. Secondly, compared with the normal control, the model control group had a reduced glucose tolerance and developed insulin resistance. Angptl4 expression and the phosphorylation levels of several insulin signaling pathway‑associated genes, insulin receptor substrate 1, protein kinase B, janus kinase 2, signal transducer and activator of transcription 3 were downregulated in the liver samples. Adv‑Angptl4 injection was observed to improve glucose tolerance and insulin resistance. The genes measured were identified to be upregulated close to normal levels. All the results suggested that Angptl4 served an important role in lipid and glucose metabolism in HFD‑induced obese mice, and this may have a great significance for treatment of hyperlipidemia, diabetes, metabolic syndrome and other diseases.

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1	Kershaw EE and Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 89:2548–2556. 2004. View Article : Google Scholar : PubMed/NCBI
2	Friedman JM and Halaas JL: Leptin and the regulation of body weight in mammals. Nature. 395:763–770. 1998. View Article : Google Scholar : PubMed/NCBI
3	Matsuzawa Y, Funahashi T, Kihara S and Shimomura I: Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol. 24:29–33. 2004. View Article : Google Scholar
4	Yoon JC, Chickering TW, Rosen ED, Dussault B, Qin Y, Soukas A, Friedman JM, Holmes WE and Spiegelman BM: Peroxisome proliferator-activated receptor gamma target genen encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol Cell Biol. 20:5343–5349. 2000. View Article : Google Scholar : PubMed/NCBI
5	Kersten S, Mandard S, Tan NS, Escher P, Metzger D, Chambon P, Gonzalez FJ, Desvergne B and Wahli W: Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator activated receptor target gene. J Biol Chem. 275:28488–28493. 2000. View Article : Google Scholar : PubMed/NCBI
6	Koster A, Chao YB, Mosior M, Ford A, Gonzalez-DeWhitt PA, Hale JE, Li D, Qiu Y, Fraser CC, Yang DD, et al: Transgenic angiopoietin-like (angptl)4 overexpression and targeted disrupt ion of angptl4 and angptl3: Regulation of triglyceride metabolism. Endocrinology. 146:4943–4950. 2005. View Article : Google Scholar
7	Ge H, Cha JY, Gopal H, Harp C, Yu X, Repa JJ and Li C: Differential regulation and properties of angiopoietin-like proteins 3 and 4. J Lipid Res. 46:1484–1490. 2005. View Article : Google Scholar : PubMed/NCBI
8	Sanderson LM, Degenhardt T, Koppen A, Kalkhoven E, Desvergne B, Müller M and Kersten S: Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver. Mol Cell Biol. 29:6257–6267. 2009. View Article : Google Scholar : PubMed/NCBI
9	Mattijssen F and Kersten S: Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta. 1821:782–789. 2012. View Article : Google Scholar
10	Merkel M, Eckel RH and Goldberg IJ: Lipoprotein lipase: Genetics, lipid uptake, and regulation. J Lipid Res. 43:1997–2006. 2002. View Article : Google Scholar : PubMed/NCBI
11	Le Jan S, Amy C, Cazes A, Monnot C, Lamandé N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P and Germain S: Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol. 162:1521–1528. 2003. View Article : Google Scholar : PubMed/NCBI
12	Xu A, Lam MC, Chan KW, Wang Y, Zhang J, Hoo RL, Xu JY, Chen B, Chow WS, Tso AW and Lam KS: Angiopoietin-like protein4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci USA. 102:6086–6091. 2005. View Article : Google Scholar
13	Mandard S, Zandbergen F, van Straten E, Wahli W, Kuipers F, Müller M and Kersten S: The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. J Biol Chem. 281:934–944. 2006. View Article : Google Scholar
14	Reitman S and Frankel S: A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 28:56–63. 1957. View Article : Google Scholar : PubMed/NCBI
15	Cusi K, Maezono K, Oaman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR and Mandarino LJ: Insulin resistance differentially affects the pi3-kinase- and MAP kinase-mediated signaling in human muscle. J Clin Invest. 105:311–320. 2000. View Article : Google Scholar : PubMed/NCBI
16	Wang WZ, Zhao SM and Gao SZ: Research progress on leptin-mediated JAK/STAT signaling pathway in lipid metabolism. Chin J Cell Biol. 33:584–589. 2011.
17	Kim HK, Youn BS, Shin MS, Namkoong C, Park KH, Baik JH, Kim JB, Park JY, Lee KU, Kim YB and Kim MS: Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes. 59:2772–2780. 2010. View Article : Google Scholar : PubMed/NCBI
18	Yoshida K, Shimizugawa T, Ono M and Furukawa H: Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res. 43:1770–1772. 2002. View Article : Google Scholar : PubMed/NCBI
19	Oike Y, Akao M, Kubota Y and Suda T: Angiopoietin-like proteins: Potential new targets for metabolic syndrome therapy. Trends Mol Med. 11:473–479. 2005. View Article : Google Scholar : PubMed/NCBI
20	Lee CH, Olson P and Evans RM: Minireview: Lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology. 144:2201–2207. 2003. View Article : Google Scholar : PubMed/NCBI
21	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
22	Samuel VT, Petersen KF and Shulman GI: Lipid-induced insulin resistance: Unravelling the mechanism. Lancet. 375:2267–2277. 2010. View Article : Google Scholar : PubMed/NCBI
23	Gray NE, Lam LN, Yang K, Zhou AY, Koliwad S and Wang JC: Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J Biol Chem. 287:8444–8456. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ono H, Shimano H, Katagiri H, Yahagi N, Sakoda H, Onishi Y, Anai M, Ogihara T, Fujishiro M, Viana AY, et al: Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. Diabetes. 52:2905–2913. 2003. View Article : Google Scholar : PubMed/NCBI
25	Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim YJ, Sherwin R, Devaskar S, Lesche R, Magnuson MA and Wu H: Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proc Natl Acad Sci USA. 101:2082–2087. 2004. View Article : Google Scholar :
26	Mizutani N, Ozaki N, Seino Y, Fukami A, Sakamoto E, Fukuyama T, Sugimura Y, Nagasaki H, Arima H and Oiso Y: Reduction of insulin signaling upregulates angiopoietin-like protein 4 through elevated free fatty acids in diabetic mice. Exp Clin Endocrinol Diabetes. 120:139–144. 2012. View Article : Google Scholar
27	Yamada T, Ozaki N, Kato Y, Miura Y and Oiso Y: Insulin downregulates angiopoietin-like protein 4 mRNA in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 347:1138–1144. 2006. View Article : Google Scholar : PubMed/NCBI
28	Prudente S, Morini E and Trischitta V: Insulin signaling regulating genes: Effect on T2DM and cardiovascular risk. Nat Rev Endocrinol. 5:682–693. 2009. View Article : Google Scholar : PubMed/NCBI
29	Karlsson HK and Zierath JR: Insulin signaling and glucose transport in insulin resistant human skeletal muscle. Cell Biochem Biophys. 48:103–113. 2007. View Article : Google Scholar : PubMed/NCBI
30	Hou M, Cui J, Liu J, Liu F, Jiang R, Liu K, Wang Y, Yin L, Liu W and Yu B: Angiopoietin-like 4 confers resistance to hypoxia/serum deprivation-induced apoptosis through PI3K/Akt and ERK1/2 signaling pathways in mesenchymal stem cells. PLoS One. 9:e858082014. View Article : Google Scholar : PubMed/NCBI
31	Chong HC, Chan JS, Goh CQ, Gounko NV, Luo B, Wang X, Foo S, Wong MT, Choong C, Kersten S and Tan NS: Angiopoietin-like 4 stimulates STAT3-mediated iNOS expression and enhances angiogenesis to accelerate wound healing in diabetic mice. Mol Ther. 22:1593–1604. 2014. View Article : Google Scholar : PubMed/NCBI
32	Yan ZK, Yang ZJ and Chen F: Effect of electroacupuncture stimulation of 'Housanli' (ST 36) and 'Zhongwan' (CV 12) on serum leptin and hepatocellular JAK 2-STAT 3 signaling in obese rats. Zhen Ci Yan Jiu. 40:1–5. 2015.In Chinese. PubMed/NCBI