Abstract
Objectives
Obesity is characterized by excessive fat accumulation due to an imbalance between energy intake and expenditure. Osmotin, a plant derived natural protein, is a known homolog of adiponectin. To analyze the role of Osmotin in controlling energy metabolism by suppressing abdominal fat accumulation.
Methods
We investigated the effects of osmotin in C57BL/6 mice on high-fat diet and in 3T3-L1 adipocytes by Biochemical tests, Immunofluorescence confocal Microscopy, RT-PCR, and Flow cytometry.
Results
In this study, we investigated the anti-obesity effects of osmotin on adipocyte differentiation and regulation of the related factors lipolysis and glucose uptake in 3T3-L1 cells in vitro. Moreover, we analyzed the role of osmotin in prevention of insulin resistance, excess fat accumulation and metabolic syndrome in high-fat diet mouse model via AMPK and MAPK pathways in vivo. In addition, osmotin caused cell cycle arrest in G0/G1 phase by regulating expression of p21, p27 and CDK2 and improved glucose control, as concluded from glucose and insulin tolerance tests.
Conclusion
These results reveal the role of osmotin in AMPK downstream signaling. These results provide the first indication that osmotin exerts therapeutic effects on obesity, which could promote development of therapeutic aspects for obesity and related diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766–81.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. J Am Med Assoc. 2003;289:76–9.
Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635–43.
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.
Haslam DW, James WP. Obesity. Lancet. 2005;366:1197–209.
Targher G, Byrne CD. Obesity: metabolically healthy obesity and NAFLD. Nat Rev. Gastroenterol Hepatol. 2016;13:442–4.
Curtis R, Geesaman BJ, DiStefano PS. Ageing and metabolism: drug discovery opportunities. Nat Rev Drug Discovery. 2005;4:569–80.
Nawrocki AR, Scherer PE. Keynote review: the adipocyte as a drug discovery target. Drug Discovery Today. 2005;10:1219–30.
Negrel R, Grimaldi P, Ailhaud G. Establishment of preadipocyte clonal line from epididymal fat pad of ob/ob mouse that responds to insulin and to lipolytic hormones. PNAS. 1978;75:6054–8.
Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol. 2013;92:229–36.
Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev. 1998;78:783–809.
Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7:885–96.
Rodgers RJ, Tschop MH, Wilding JP. Anti-obesity drugs: past, present and future. Dis Models Mech. 2012;5:621–6.
Adan RA. Mechanisms underlying current and future anti-obesity drugs. Trends Neurosci. 2013;36:133–40.
Narasimhan ML, Coca MA, Jin J, Yamauchi T, Ito Y, Kadowaki T, et al. Osmotin is a homolog of mammalian adiponectin and controls apoptosis in yeast through a homolog of mammalian adiponectin receptor. Mol Cell. 2005;17:171–80.
Miele M, Costantini S, Colonna G. Structural and functional similarities between osmotin from Nicotiana tabacum seeds and human adiponectin. PLoS ONE. 2011;6:e16690.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941–6.
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem. 2002;277:25863–6.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–53.
Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. PNAS. 2001;98:2005–10.
Mullen KL, Smith AC, Junkin KA, Dyck DJ. Globular adiponectin resistance develops independently of impaired insulin-stimulated glucose transport in soleus muscle from high-fat-fed rats. Am J Physiol Endocrinol Metab. 2007;293:E83–90.
Ghadge AA, Khaire AA, Kuvalekar AA. Adiponectin: a potential therapeutic target for metabolic syndrome. Cytokine Growth Factor Rev. 2018;39:151–8.
Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 2006;281:2654–60.
Shah SA, Yoon GH, Chung SS, Abid MN, Kim TH, Lee HY. et al. Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimeras disease neuropathological deficits. Mol Psychiatr. 2017;22:407–16.
Yoon G, Shah SA, Ali T, Kim MO. The adiponectin homolog osmotin enhances neurite outgrowth and synaptic complexity via AdipoR1/NgR1 signaling in Alzheimer’s disease. Mol Neurobiol. 2018;55:6673–86.
Abid NB, Yoon G, Kim MO. Molecular cloning and expression of osmotin in a baculovirus-insect system: purified osmotin mitigates amyloid-beta deposition in neuronal cells. Sci Rep. 2017;7:8147.
Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6:55–68.
Yamauchi T, Kadowaki T. Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases. Int J Obes (Lond). 2008;32(Suppl 7):S13–8.
Habinowski SA, Witters LA. The effects of AICAR on adipocyte differentiation of 3T3-L1 cells. Biochem Biophys Res Commun. 2001;286:852–6.
Daval M, Foufelle F, Ferre P. Functions of AMP-activated protein kinase in adipose tissue. J Physiol. 2006;574(Pt 1):55–62.
Jung Y, Park J, Kim HL, Sim JE, Youn DH, Kang J, et al. Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro. FASEB J. 2018;32:1388–402.
Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Investig. 2003;112:91–100.
Carling D, Zammit VA, Hardie DG. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 1987;223:217–22.
Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 2009;9:407–16.
Ahmad A, Ali T, Kim MW, Khan A, Jo MH, Rehman SU, et al. Adiponectin homolog novel osmotin protects obesity/diabetes-induced NAFLD by upregulating AdipoRs/PPARα signaling in ob/ob and db/db transgenic mouse models. Metab: Clin Exp. 2019;90:31–43.
Jo MG, Ikram M, Jo MH, Yoo L, Chung KC, Nah SY. et al. Gintonin mitigates MPTP-induced loss of nigrostriatal dopaminergic neurons and accumulation of alpha-synuclein via the Nrf2/HO-1 pathway. Mol Neurobiol. 2019;56:39–55.
Perfield JW 2nd, Lee Y, Shulman GI, Samuel VT, Jurczak MJ, Chang E, et al. Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance. Diabetes. 2011;60:1168–76.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002;420:333–6.
Carlson CJ, Koterski S, Sciotti RJ, Poccard GB, Rondinone CM. Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes. 2003;52:634–41.
Tang QQ, Otto TC, Lane MD. Mitotic clonal expansion: a synchronous process required for adipogenesis. PNAS. 2003;100:44–9.
Reichert M, Eick D. Analysis of cell cycle arrest in adipocyte differentiation. Oncogene. 1999;18:459–66.
Kotani K, Peroni OD, Minokoshi Y, Boss O, Kahn BB. GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J Clin Investig. 2004;114:1666–75.
Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A, Sweeney G, Wheeler MB. Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion. J Biol Chem. 2010;285:33623–31.
Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C, et al. New insight into adiponectin role in obesity and obesity-related diseases. Biomed Res Int. 2014;2014:658913.
Chouchani ET, Kajimura S. Metabolic adaptation and maladaptation in adipose tissue. Nat Metab. 2019;1:189–200.
Liu Y, Palanivel R, Rai E, Park M, Gabor TV, Scheid MP, et al. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice. Diabetes. 2015;64:36–48.
Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. International J Mol Sci. 2017;18.
Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y. Leptin stimulates fatty acid oxidation and peroxisome proliferator-activated receptor alpha gene expression in mouse C2C12 myoblasts by changing the subcellular localization of the alpha2 form of AMP-activated protein kinase. Mol Cell Biol. 2007;27:4317–27.
Luo Z, Saha AK, Xiang X, Ruderman NB. AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci. 2005;26:69–76.
Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int J Mol Sci. 2014;15:6184–223.
Anil Kumar S, Hima Kumari P, Shravan Kumar G, Mohanalatha C, Kavi Kishor PB. Osmotin: a plant sentinel and a possible agonist of mammalian adiponectin. Front Plant Sci. 2015;6:163.
Hui X, Gu P, Zhang J, Nie T, Pan Y, Wu D, et al. Adiponectin enhances cold-induced browning of subcutaneous adipose tissue via promoting M2 macrophage proliferation. Cell Metab. 2015;22:279–90.
Wei Q, Lee JH, Wang H, Bongmba OYN, Wu CS, Pradhan G, et al. Adiponectin is required for maintaining normal body temperature in a cold environment. BMC Physiol. 2017;17:8.
Evans M, Lin X, Odle J, McIntosh M. Trans-10, cis-12 conjugated linoleic acid increases fatty acid oxidation in 3T3-L1 preadipocytes. J Nutr. 2002;132:450–5.
Patel YM, Lane MD. Mitotic clonal expansion during preadipocyte differentiation: calpain-mediated turnover of p27. J Biol Chem. 2000;275:17653–60.
Tang QQ, Lane MD. Activation and centromeric localization of CCAAT/enhancer-binding proteins during the mitotic clonal expansion of adipocyte differentiation. Genes Dev. 1999;13:2231–41.
Rattan R, Giri S, Singh AK, Singh I. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem. 2005;280:39582–93.
Kim S, Jung J, Kim H, Heo RW, Yi CO, Lee JE, et al. Exendin-4 improves nonalcoholic fatty liver disease by regulating glucose transporter 4 expression in ob/ob mice. Korean J Physiol Pharmacol. 2014;18:333–9.
Fu Q, Olson P, Rasmussen D, Keith B, Williamson M, Zhang KK, et al. A short-term transition from a high-fat diet to a normal-fat diet before pregnancy exacerbates female mouse offspring obesity. Int J Obes (Lond). 2016;40:564–72.
Acknowledgements
This research was supported by the Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (NRF-2016M3C7A1904391).
Author information
Authors and Affiliations
Contributions
MGJ conceived the hypothesis, designed the research, performed overall experiments, wrote manuscript, and performed data analysis. MWK and MHJ designed the research and performed the in vivo experiments, calculations, and data analysis. NBA contributed to the discussion and edited the manuscript. All authors approved the results and the final version of this manuscript. MOK revised the manuscript and holds all responsibilities related to this manuscript as the corresponding author.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The experimental procedures of animal care and treatment minimized the number of mice and their suffering and were approved by the Animal Ethics Committee (IACUC) of the Division of Applied Life Sciences, Department of Biology at Gyeongsang National University, Republic of Korea (Approval ID: 125).
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Jo, M.G., Kim, M.W., Jo, M.H. et al. Adiponectin homolog osmotin, a potential anti-obesity compound, suppresses abdominal fat accumulation in C57BL/6 mice on high-fat diet and in 3T3-L1 adipocytes. Int J Obes 43, 2422–2433 (2019). https://doi.org/10.1038/s41366-019-0383-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41366-019-0383-3
This article is cited by
-
Key homeobox transcription factors regulate the development of the firefly’s adult light organ and bioluminescence
Nature Communications (2024)
-
Neuroprotective effects of osmotin in Parkinson’s disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways
Journal of Biomedical Science (2023)