Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Animal Models

Central administration of vaspin inhibits glucose production and augments hepatic insulin signaling in high-fat-diet-fed rat

Abstract

Objective:

To investigate the effects of vaspin signaling conveyed by the brain on liver glucose fluxes in rats.

Methods:

To determine the effects and underlying mechanisms of central vaspin signaling, normal-chow-diet- and high-fat-diet (HFD)-fed rats with or without hepatic branch vagotomy (HBV) received acute infusion of vaspin to the third cerebral ventricle or MK801, a dorsal vagal complex (DVC) N-methyl-D-aspartate (NMDA) receptor inhibitor, to the DVC during the pancreatic euglycemic clamp.

Results:

Central administration of vaspin in HFD-fed rats significantly increased glucose infusion required to maintain euglycemia owing to an inhibition of glucose production during the clamps. These changes were accompanied by decreased hepatic phosphoenolpyruatecarboxykinase and G6Pase expression levels and increased hepatic insulin receptor, insulin receptor substrate-1, Akt kinase and the forkhead box-containing protein of the O subfamily-1 phosphorylation, suggesting improving hepatic insulin sensitivity in these animals. Conversely, selective HBV or DVC MK-801 infusion in HFD-fed rats blocked the effect of central vaspin on glucose production and hepatic insulin sensitivity.

Conclusions:

Our findings suggest that brain vaspin inhibited hepatic glucose production and improved insulin sensitivity via DVC to the hepatic branch of the vagus nerve in insulin resistance rats induced by HFD.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Obici S, Zhang BB, Karkanias G, Rossetti L . Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 2002; 8: 1376–1382.

    Article  CAS  Google Scholar 

  2. Pocai A, Morgan K, Buettner C, Gutierrez-Juarez R, Obici S, Rossetti L . Central leptin acutely reverses diet-induced hepatic insulin resistance. Diabetes 2005; 54: 3182–3189.

    Article  CAS  Google Scholar 

  3. Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG Jr, Rhodes CJ et al. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab 2006; 3: 67–73.

    Article  CAS  Google Scholar 

  4. Yang M, Zhang Z, Wang C, Li K, Li S, Boden G et al. Nesfatin-1 action in the brain increases insulin sensitivity through Akt/AMPK/TORC2 pathway in diet-induced insulin resistance. Diabetes 2012; 61: 1959–1968.

    Article  CAS  Google Scholar 

  5. Matsuhisa M, Yamasaki Y, Shiba Y, Nakahara I, Kuroda A, Tomita T et al. Important role of the hepatic vagus nerve in glucose uptake and production by the liver. Metabolism 2000; 49: 11–16.

    Article  CAS  Google Scholar 

  6. Pocai A, Obici S, Schwartz GJ, Rossetti L . A brain-liver circuit regulates glucose homeostasis. Cell Metab 2005; 1: 53–61.

    Article  CAS  Google Scholar 

  7. Lam TK, Gutierrez-Juarez R, Pocai A, Rossetti L . Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 2005; 309: 943–947.

    Article  CAS  Google Scholar 

  8. Lam TK, Schwartz GJ, Rossetti L . Hypothalamic sensing of fatty acids. Nat Neurosci 2005; 8: 579–584.

    Article  CAS  Google Scholar 

  9. Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest 2006; 116: 1081–1091.

    Article  CAS  Google Scholar 

  10. Bluher M . Vaspin in obesity and diabetes: pathophysiological and clinical significance. Endocrine 2012; 41: 176–182.

    Article  Google Scholar 

  11. Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci USA 2005; 102: 10610–10615.

    Article  CAS  Google Scholar 

  12. Kloting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schon MR et al. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochem Biophys Res Commun 2006; 339: 430–436.

    Article  Google Scholar 

  13. Korner A, Neef M, Friebe D, Erbs S, Kratzsch J, Dittrich K et al. Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children. Int J Obes (Lond) 2011; 35: 578–586.

    Article  CAS  Google Scholar 

  14. Brunetti L, Di Nisio C, Recinella L, Chiavaroli A, Leone S, Ferrante C et al. Effects of vaspin, chemerin and omentin-1 on feeding behavior and hypothalamic peptide gene expression in the rat. Peptides 2011; 32: 1866–1871.

    Article  CAS  Google Scholar 

  15. Kloting N, Kovacs P, Kern M, Heiker JT, Fasshauer M, Schon MR et al. Central vaspin administration acutely reduces food intake and has sustained blood glucose-lowering effects. Diabetologia 2011; 54: 1819–1823.

    Article  CAS  Google Scholar 

  16. Tan BK, Heutling D, Chen J, Farhatullah S, Adya R, Keay SD et al. Metformin decreases the adipokine vaspin in overweight women with polycystic ovary syndrome concomitant with improvement in insulin sensitivity and a decrease in insulin resistance. Diabetes 2008; 57: 1501–1507.

    Article  CAS  Google Scholar 

  17. Li K, Li L, Yang M, Liu H, Liu D, Yang H et al. Short-term continuous subcutaneous insulin infusion decreases the plasma vaspin levels in patients with type 2 diabetes mellitus concomitant with improvement in insulin sensitivity. Eur J Endocrinol 2011; 164: 905–910.

    Article  CAS  Google Scholar 

  18. Youn BS, Kloting N, Kratzsch J, Lee N, Park JW, Song ES et al. Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 2008; 57: 372–377.

    Article  CAS  Google Scholar 

  19. Lam CK, Chari M, Rutter GA, Lam TK . Hypothalamic nutrient sensing activates a forebrain-hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes 2011; 60: 107–113.

    Article  CAS  Google Scholar 

  20. Wu D, Yang M, Chen Y, Jia Y, Ma ZA, Boden G et al. Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats. Diabetes 2014; 63: 1234–1247.

    Article  CAS  Google Scholar 

  21. la Fleur SE, Ji H, Manalo SL, Friedman MI, Dallman MF . The hepatic vagus mediates fat-induced inhibition of diabetic hyperphagia. Diabetes 2003; 52: 2321–2330.

    Article  CAS  Google Scholar 

  22. Wang C, Dai J, Yang M, Deng G, Xu S, Jia Y et al. Silencing of FGF-21 expression promotes hepatic gluconeogenesis and glycogenolysis by regulation of the STAT3-SOCS3 signal. FEBS J 2014; 281: 2136–2147.

    Article  CAS  Google Scholar 

  23. Yang CS, Lam CK, Chari M, Cheung GW, Kokorovic A, Gao S et al. Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes 2010; 59: 2435–2443.

    Article  CAS  Google Scholar 

  24. Kim JJ, Fan W, Olefsky JM . Putting the brakes on FOXO1 in fat. Embo j 2012; 31: 2240–2241.

    Article  CAS  Google Scholar 

  25. Coll AP, Farooqi IS, O'Rahilly S . The hormonal control of food intake. Cell 2007; 129: 251–262.

    Article  CAS  Google Scholar 

  26. Cummings DE, Overduin J . Gastrointestinal regulation of food intake. J Clin Invest 2007; 117: 13–23.

    Article  CAS  Google Scholar 

  27. Bourque CW . Central mechanisms of osmosensation and systemic osmoregulation. Nat Rev Neurosci 2008; 9: 519–531.

    Article  CAS  Google Scholar 

  28. Christie JM, Wenthold RJ, Monaghan DT . Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. J Neurochem 1999; 72: 1523–1528.

    Article  CAS  Google Scholar 

  29. Lam CK, Chari M, Su BB, Cheung GW, Kokorovic A, Yang CS et al. Activation of N-methyl-D-aspartate (NMDA) receptors in the dorsal vagal complex lowers glucose production. J Biol Chem 2010; 285: 21913–21921.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (81100567, 81300702 and 81300670). Doctoral Fund of Ministry of Education of China (20125503110003) and the grant of CQ cstc (cstc2011jjA10077).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L Li.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Luo, X., Li, K., Zhang, C. et al. Central administration of vaspin inhibits glucose production and augments hepatic insulin signaling in high-fat-diet-fed rat. Int J Obes 40, 947–954 (2016). https://doi.org/10.1038/ijo.2016.24

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.24

This article is cited by

Search

Quick links