Animal Models

Development of insulin resistance in Nischarin mutant female mice

Subjects

Abstract

Background/Objectives

NISCH–STAB1 is a newly identified locus correlated to human waist–hip ratio (WHR), which is a risk indicator of developing obesity-associated diabetes. Our previous studies have shown that Nisch mutant male mice increased glucose tolerance in chow-fed conditions. Thus we hypothesized that Nisch mutant mice will have changes in insulin resistance, adipocytes, hepatic steatosis when mice are fed with high-fat diet (HFD).

Methods

Insulin resistance was assessed in Nisch mutant mice and WT mice fed with high-fat diet (60% by kCal) or chow diet. Whole-body energy metabolism was examined using an indirect calorimeter. Adipose depots including inguinal white adipose tissue (WAT), perigonadal WAT, retroperitoneal WAT, and mesenteric WAT were extracted. Area and eqdiameter of each adipocyte were determined, and insulin signaling was examined as well. Paired samples of subcutaneous and omental visceral adipose tissue were obtained from 400 individuals (267 women, 133 men), and examined the expression of Nischarin.

Results

We found that insulin signaling was impaired in major insulin-sensitive tissues of Nisch mutant female mice. When mice were fed with HFD for 15 weeks, the Nisch mutant female mice not only developed severe insulin resistance and decreased glucose tolerance compared with wild-type control mice, but also accumulated more white fat, had larger adipocytes and developed severe hepatic steatosis than wild-type control mice. To link our animal studies to human diseases, we further analyzed Nischarin expression in the paired human samples of visceral and subcutaneous adipose tissue from Caucasians. In humans, we found that Nischarin expression is attenuated in adipose tissue with obesity. More importantly, we found that Nischarin mRNA inversely correlated with parameters of obesity, fat distribution, lipid and glucose metabolism.

Conclusions

Taken together, our data revealed sexual dimorphism of Nischarin in body fat distribution, insulin resistance, and glucose tolerance in mice.

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References

  1. 1.

    Reaven GM. Banting lecture 1988. Role Insul Resist Human Dis Diabetes. 1988;37:1595–607.

    CAS  Google Scholar 

  2. 2.

    DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14:173–94.

    Article  CAS  Google Scholar 

  3. 3.

    Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444:840–6.

    Article  CAS  Google Scholar 

  4. 4.

    Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell . 2013;152:673–84.

    Article  CAS  Google Scholar 

  5. 5.

    Agarwal AK, Garg A. Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genom Hum Genet. 2006;7:175–99.

    Article  CAS  Google Scholar 

  6. 6.

    Nelson TL, Vogler GP, Pedersen NL, Hong Y, Miles TP. Genetic and environmental influences on body fat distribution, fasting insulin levels and CVD: are the influences shared? Twin Res. 2000;3:43–50.

    Article  CAS  Google Scholar 

  7. 7.

    Gesta S, Bluher M, Yamamoto Y, Norris AW, Berndt J, Kralisch S, et al. Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci Usa. 2006;103:6676–81.

    Article  CAS  Google Scholar 

  8. 8.

    Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, Steinthorsdottir V, et al. Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010;42:949–U160.

    Article  CAS  Google Scholar 

  9. 9.

    Kuijl C, Pilli M, Alahari SK, Janssen H, Khoo PS, Ervin KE, et al. Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria. Embo J. 2013;32:713–27.

    Article  CAS  Google Scholar 

  10. 10.

    Reddig PJ, Alahari SK, Juliano RL. Nischarin, an integrin alpha 5 binding protein, forms complexes with Rac1 and PAK1 and inhibits PAK1 activation. Mol Biol Cell. 2002;13:348a–a.

    Article  CAS  Google Scholar 

  11. 11.

    Alahari SK, Lee JW, Juliano RL. Nischarin, a novel protein that interacts with the integrin alpha 5 subunit and inhibits cell migration. J Cell Biol. 2000;151:1141–54.

    Article  CAS  Google Scholar 

  12. 12.

    Alahari SK, Reddig PJ, Juliano RL. The integrin-binding protein Nischarin regulates cell migration by inhibiting PAK. Embo J. 2004;23:2777–88.

    Article  CAS  Google Scholar 

  13. 13.

    Ding YM, Milosavljevic T, Alahari SK. Nischarin inhibits LIM kinase to regulate cofilin phosphorylation and cell invasion. Mol Cell Biol. 2008;28:3742–56.

    Article  CAS  Google Scholar 

  14. 14.

    Jain P, Baranawal S, Alahari SK. Tumor suppressor LKB1 cooperates with the integrin-binding protein Nischarin to inhibit breast cancer. Cancer Research. 288:15495–509

  15. 15.

    Jain P, Baranwal S, Dong SL, Struckhoff AP, Worthylake RA, Alahari SK. Integrin-binding protein Nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration of breast epithelial cells. J Biol Chem. 2013;288:15495–509.

    Article  CAS  Google Scholar 

  16. 16.

    Maziveyi M, Alahari SK. Breast cancer tumor suppressors: a special emphasis on novel protein Nischarin. Cancer Res. 2015;75:4252–9.

    Article  CAS  Google Scholar 

  17. 17.

    Dong SL, Baranwal S, Garcia A, Serrano-Gomez SJ, Eastlack S, Iwakuma T, et al. Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. J Biol Chem. 2017;292:16833–46.

    Article  CAS  Google Scholar 

  18. 18.

    Reddig PJ, Xu D, Juliano RL. Regulation of p21-activated kinase-independent Rac1 signal transduction by nischarin. J Biol Chem. 2005;280:30994–1002.

    Article  CAS  Google Scholar 

  19. 19.

    Sano H, Liu SCH, Lane WS, Piletz JE, Lienhard GE. Insulin receptor substrate 4 associates with the protein IRAS. J Biol Chem. 2002;277:19439–47.

    Article  CAS  Google Scholar 

  20. 20.

    Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994;372:182–6.

    Article  CAS  Google Scholar 

  21. 21.

    Araki E, Lipes MA, Patti ME, Bruning JC, Haag B 3rd, Johnson RS, et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature . 1994;372:186–90.

    Article  CAS  Google Scholar 

  22. 22.

    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998;391:900–4.

    Article  CAS  Google Scholar 

  23. 23.

    Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF, et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000;105:199–205.

    Article  CAS  Google Scholar 

  24. 24.

    Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;123:2764–72.

    Article  CAS  Google Scholar 

  25. 25.

    Zhang Y, Bone RN, Cui W, Peng JB, Siegal GP, Wang H, et al. Regeneration of pancreatic non-beta endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One 2012;7:e36675.

    Article  CAS  Google Scholar 

  26. 26.

    Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M, et al. Insulin-sensitive obesity. Am J Physiol Endocrinol Metab. 2010;299:E506–15.

    Article  CAS  Google Scholar 

  27. 27.

    Guiu-Jurado E, Unthan M, Bohler N, Kern M, Landgraf K, Dietrich A, et al. Bone morphogenetic protein 2 (BMP2) may contribute to partition of energy storage into visceral and subcutaneous fat depots. Obes (Silver Spring). 2016;24:2092–100.

    Article  CAS  Google Scholar 

  28. 28.

    Donahoo W, Wyatt HR, Kriehn J, Stuht J, Dong F, Hosokawa P, et al. Dietary fat increases energy intake across the range of typical consumption in the United States. Obes (Silver Spring). 2008;16:64–9.

    Article  CAS  Google Scholar 

  29. 29.

    Massiera F, Barbry P, Guesnet P, Joly A, Luquet S, Moreilhon-Brest C, et al. A western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations. J Lipid Res. 2010;51:2352–61.

    Article  CAS  Google Scholar 

  30. 30.

    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112:1821–30.

    Article  CAS  Google Scholar 

  31. 31.

    Berry DC, Stenesen D, Zeve D, Graff JM. The developmental origins of adipose tissue. Development. 2013;140:3939–49.

    Article  CAS  Google Scholar 

  32. 32.

    Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, et al. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996;15:6541–51.

    Article  CAS  Google Scholar 

  33. 33.

    Ellis AC, Hyatt TC, Hunter GR, Gower BA. Respiratory quotient predicts fat mass gain in premenopausal women. Obes (Silver Spring). 2010;18:2255–9.

    Article  CAS  Google Scholar 

  34. 34.

    Weinsier RL, Hunter GR, Desmond RA, Byrne NM, Zuckerman PA, Darnell BE. Free-living activity energy expenditure in women successful and unsuccessful at maintaining a normal body weight. Am J Clin Nutr. 2002;75:499–504.

    Article  CAS  Google Scholar 

  35. 35.

    Weinsier RL, Hunter GR, Zuckerman PA, Darnell BE. Low resting and sleeping energy expenditure and fat use do not contribute to obesity in women. Obes Res. 2003;11:937–44.

    Article  Google Scholar 

  36. 36.

    Weinsier RL, Nelson KM, Hensrud DD, Darnell BE, Hunter GR, Schutz Y. Metabolic predictors of obesity. Contribution of resting energy expenditure, thermic effect of food, and fuel utilization to four-year weight gain of post-obese and never-obese women. J Clin Invest. 1995;95:980–5.

    Article  CAS  Google Scholar 

  37. 37.

    Chawla B, Hedman AC, Sayedyahossein S, Erdemir HH, Li Z, Sacks DB. Absence of IQGAP1 Protein Leads to Insulin Resistance. J Biol Chem. 2017;292:3273–89.

    Article  CAS  Google Scholar 

  38. 38.

    Wang Z, Oh E, Clapp DW, Chernoff J, Thurmond DC. Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. J Biol Chem. 2011;286:41359–67.

    Article  CAS  Google Scholar 

  39. 39.

    Sylow L, Jensen TE, Kleinert M, Hojlund K, Kiens B, Wojtaszewski J, et al. Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle. Diabetes. 2013;62:1865–75.

    Article  CAS  Google Scholar 

  40. 40.

    Reed SE, Hodgson LR, Song S, May MT, Kelly EE, McCaffrey MW, et al. A role for Rab14 in the endocytic trafficking of GLUT4 in 3T3-L1 adipocytes. J Cell Sci. 2013;126(Pt 9):1931–41.

    Article  CAS  Google Scholar 

  41. 41.

    Crompton M, Purnell T, Tyrer HE, Parker A, Ball G, Hardisty-Hughes RE, et al. A mutation in Nischarin causes otitis media via LIMK1 and NF-kappaB pathways. PLoS Genet. 2017;13:e1006969.

    Article  CAS  Google Scholar 

  42. 42.

    Zhang L, Zhao TY, Hou N, Teng Y, Cheng X, Wang B, et al. Generation and primary phenotypes of imidazoline receptor antisera-selected (IRAS) knockout mice. CNS Neurosci Ther. 2013;19:978–81.

    Article  CAS  Google Scholar 

  43. 43.

    Kuhl J, Hilding A, Ostenson CG, Grill V, Efendic S, Bavenholm P. Characterisation of subjects with early abnormalities of glucose tolerance in the Stockholm diabetes prevention programme: the impact of sex and type 2 diabetes heredity. Diabetologia. 2005;48:35–40.

    Article  CAS  Google Scholar 

  44. 44.

    Frias JP, Macaraeg GB, Ofrecio J, Yu JG, Olefsky JM, Kruszynska YT. Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes. 2001;50:1344–50.

    Article  CAS  Google Scholar 

  45. 45.

    Clark JB, Palmer CJ, Shaw WN. The diabetic Zucker fatty rat. Proc Soc Exp Biol Med. 1983;173:68–75.

    Article  CAS  Google Scholar 

  46. 46.

    Zierath JR, Houseknecht KL, Gnudi L, Kahn BB. High-fat feeding impairs insulin-stimulated GLUT4 recruitment via an early insulin-signaling defect. Diabetes. 1997;46:215–23.

    Article  CAS  Google Scholar 

  47. 47.

    Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000;106:523–31.

    Article  CAS  Google Scholar 

  48. 48.

    Macotela Y, Boucher J, Tran TT, Kahn CR. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes. 2009;58:803–12.

    Article  CAS  Google Scholar 

  49. 49.

    Sun Z, Chang CH, Ernsberger P. Identification of IRAS/Nischarin as an I1-imidazoline receptor in PC12 rat pheochromocytoma cells. J Neurochem. 2007;101:99–108.

    Article  CAS  Google Scholar 

  50. 50.

    Velliquette RA, Kossover R, Previs SF, Ernsberger P. Lipid-lowering actions of imidazoline antihypertensive agents in metabolic syndrome X. Naunyn Schmiede Arch Pharmacol. 2006;372:300–12.

    Article  CAS  Google Scholar 

  51. 51.

    Velliquette RA, Ernsberger P. The role of I(1)-imidazoline and alpha(2)-adrenergic receptors in the modulation of glucose metabolism in the spontaneously hypertensive obese rat model of metabolic syndrome X. J Pharmacol Exp Ther. 2003;306:646–57.

    Article  CAS  Google Scholar 

  52. 52.

    Koletsky RJ, Velliquette RA, Ernsberger P. The role of I(1)-imidazoline receptors and alpha(2)-adrenergic receptors in the modulation of glucose and lipid metabolism in the SHROB model of metabolic syndrome X. Ann N Y Acad Sci. 2003;1009:251–61.

    Article  CAS  Google Scholar 

  53. 53.

    Ernsberger P, Ishizuka T, Liu S, Farrell CJ, Bedol D, Koletsky RJ, et al. Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB). J Pharmacol Exp Ther. 1999;288:139–47.

    PubMed  CAS  Google Scholar 

  54. 54.

    Ebinc H, Ozkurt ZN, Ebinc FA, Ucardag D, Caglayan O, Yilmaz M. Effects of sympatholytic therapy with moxonidine on serum adiponectin levels in hypertensive women. J Int Med Res. 2008;36:80–7.

    Article  CAS  Google Scholar 

  55. 55.

    Derosa G, Cicero AF, D’Angelo A, Fogari E, Salvadeo S, Gravina A, et al. Metabolic and antihypertensive effects of moxonidine and moxonidine plus irbesartan in patients with type 2 diabetes mellitus and mild hypertension: a sequential, randomized, double-blind clinical trial. Clin Ther. 2007;29:602–10.

    Article  CAS  Google Scholar 

  56. 56.

    Chazova I, Schlaich MP. Improved hypertension control with the imidazoline agonist moxonidine in a multinational metabolic syndrome population: principal results of the MERSY Study. Int J Hypertens. 2013;2013:541689.

    Article  CAS  Google Scholar 

  57. 57.

    Lambert EA, Sari CI, Eikelis N, Phillips SE, Grima M, Straznicky NE, et al. Effects of moxonidine and low-calorie diet: cardiometabolic benefits from combination of both therapies. Obes (Silver Spring). 2017;25:1894–902.

    Article  CAS  Google Scholar 

  58. 58.

    Head GA, Mayorov DN. Imidazoline receptors, novel agents and therapeutic potential. Cardiovasc Hematol Agents Med Chem. 2006;4:17–32.

    Article  CAS  Google Scholar 

  59. 59.

    Weiss M, Bouchoucha S, Aiad F, Ayme-Dietrich E, Dali-Youcef N, Bousquet P, et al. Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance. Am J Physiol Endocrinol Metab. 2015;309:E95–104.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by funds from LSUSHC School of Medicine and Fred G, Brazda Foundation. Also patient related work was supported by grants of the Deutsche Forschungsgemeinschaft, Obesity Mechanisms (SFB 1052, B01 to MB). We would like to thank Steven Eastlack for critical reading of the paper.

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Correspondence to Suresh K. Alahari.

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Dong, S., Blüher, M., Zhang, Y. et al. Development of insulin resistance in Nischarin mutant female mice. Int J Obes 43, 1046–1057 (2019). https://doi.org/10.1038/s41366-018-0241-8

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