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

Intermedin/adrenomedullin 2 polypeptide promotes adipose tissue browning and reduces high-fat diet-induced obesity and insulin resistance in mice

International Journal of Obesity volume 40, pages 852–860 (2016)Cite this article

Subjects

Abstract

Objectives:

There is an urgent need to develop interventions and policies to mitigate the health effects of obesity by targeting its metabolic mediators. Adrenomedullin 2 (AM2)/intermedin (IMD) is a secreted peptide that has an important role in protecting the cardiovascular system. However, the role of AM2 in type 2 diabetes is unknown.

Methods:

Wild-type (WT) and aP2/AM2 transgenic (aAM2-tg) mice were fed a high-fat diet (HFD) for 8 weeks, and WT mice were treated with AM2 through mini-osmotic pumps. Indirect calorimetry, ambulatory activity and food intake, hyperinsulinemic-euglycemic clamp test, glucose and insulin tolerance tests were used for assessing insulin resistance. Rat primary adipocytes and pre-adipocyte-derived adipocytes were used for in vitro experiments. Real-time PCR and western blot were used for analyses of gene expression and protein level.

Results:

AM2 and receptor activity-modifying proteins expressions were significantly decreased in the adipose tissue of obese mice. AM2 treatment significantly reduced blood glucose, fasting serum insulin and free fatty acid levels, improved glucose tolerance and insulin sensitivity, and increased the glucose infusion rate during a hyperinsulinemic-euglycemic clamp test, indicating ameliorated HFD-induced insulin resistance. These effects were consistently observed in aAM2-tg mice under HFD conditions, whereas the aAM2-tg mice showed less weight gain and improved glucose tolerance and insulin sensitivity. More importantly, the aAM2-tg mice had increased oxygen consumption and CO2 production, reflecting more energy expenditure. These effects may be due to increased AMP-activated protein kinase phosphorylation and reduced peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) acetylation, which result in interactions between PGC1α and PR domain containing 16 and then promote uncoupling protein 1 (UCP1) expression in adipocytes.

Conclusions:

These results indicate that endogenous AM2 might be involved in energy metabolism in adipocytes through the upregulation of UCP1 expression.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Finucane MM, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek CJ et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377: 557–567.

    Article  Google Scholar 

  2. Prospective Studies C, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009; 373: 1083–1096.

    Article  Google Scholar 

  3. Roh J, Chang CL, Bhalla A, Klein C, Hsu SY . Intermedin is a calcitonin/calcitonin gene-related peptide family peptide acting through the calcitonin receptor-like receptor/receptor activity-modifying protein receptor complexes. J Biol Chem 2004; 279: 7264–7274.

    Article  CAS  Google Scholar 

  4. Takei Y, Hyodo S, Katafuchi T, Minamino N . Novel fish-derived adrenomedullin in mammals: structure and possible function. Peptides 2004; 25: 1643–1656.

    Article  CAS  Google Scholar 

  5. Hong Y, Hay DL, Quirion R, Poyner DR . The pharmacology of adrenomedullin 2/intermedin. Br J Pharmacol 2012; 166: 110–120.

    Article  CAS  Google Scholar 

  6. Bell D, McDermott BJ . Intermedin (adrenomedullin-2): a novel counter-regulatory peptide in the cardiovascular and renal systems. Br J Pharmacol 2008; 153: S247–S262.

    Article  CAS  Google Scholar 

  7. Hirose T, Totsune K, Mori N, Morimoto R, Hashimoto M, Nakashige Y et al. Increased expression of adrenomedullin 2/intermedin in rat hearts with congestive heart failure. Eur J Heart Fail 2008; 10: 840–849.

    Article  CAS  Google Scholar 

  8. Zhang HY, Jiang W, Liu JY, Li Y, Chen CL, Xin HB et al. Intermedin is upregulated and has protective roles in a mouse ischemia/reperfusion model. Hypertens Res 2009; 32: 861–868.

    Article  CAS  Google Scholar 

  9. Qin YW, Teng X, He JQ, Du J, Tang CS, Qi YF . Increased plasma levels of intermedin and brain natriuretic peptide associated with severity of coronary stenosis in acute coronary syndrome. Peptides 2013; 42: 84–88.

    Article  CAS  Google Scholar 

  10. Zeng Q, Yuan Y, Wang X, Wu HM, Fan L, Qi YF et al. Upregulated expression of intermedin and its receptor in the myocardium and aorta in spontaneously hypertensive rats. Peptides 2009; 30: 391–399.

    Article  CAS  Google Scholar 

  11. Hirose T, Totsune K, Mori N, Mori T, Morimoto R, Metoki H et al. Expression of adrenomedullin 2/intermedin, a possible reno-protective peptide, is decreased in the kidneys of rats with hypertension or renal failure. Am J Physiol Renal Physiol 2010; 299: F128–F134.

    Article  CAS  Google Scholar 

  12. Copple BL, Bustamante JJ, Welch TP, Kim ND, Moon JO . Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes. Liver Int 2009; 29: 1010–1021.

    Article  CAS  Google Scholar 

  13. Cai Y, Xu MJ, Teng X, Zhou YB, Chen L, Zhu Y et al. Intermedin inhibits vascular calcification by increasing the level of matrix gamma-carboxyglutamic acid protein. Cardiovasc Res 2010; 85: 864–873.

    Article  CAS  Google Scholar 

  14. Dai XY, Cai Y, Mao DD, Qi YF, Tang C, Xu Q et al. Increased stability of phosphatase and tensin homolog by intermedin leading to scavenger receptor A inhibition of macrophages reduces atherosclerosis in apolipoprotein E-deficient mice. J Mol Cell Cardiol 2012; 53: 509–520.

    Article  CAS  Google Scholar 

  15. Dai XY, Cai Y, Sun W, Ding Y, Wang W, Kong W et al. Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA. Cardiovasc Res 2014; 101: 297–305.

    Article  CAS  Google Scholar 

  16. Taylor MM, Bagley SL, Samson WK . Intermedin/adrenomedullin-2 acts within central nervous system to elevate blood pressure and inhibit food and water intake. Am J Physiol 2005; 288: R919–R927.

    CAS  Google Scholar 

  17. Li H, Xu M, Lee J, He C, Xie Z . Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol 2012; 303: E1234–E1244.

    CAS  Google Scholar 

  18. Li Y, Jiang C, Xu G, Wang N, Zhu Y, Tang C et al. Homocysteine upregulates resistin production from adipocytes in vivo and in vitro. Diabetes 2008; 57: 817–827.

    Article  CAS  Google Scholar 

  19. Scarpulla RC . Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011; 1813: 1269–1278.

    Article  CAS  Google Scholar 

  20. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011; 121: 96–105.

    Article  CAS  Google Scholar 

  21. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007; 6: 38–54.

    Article  CAS  Google Scholar 

  22. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P . Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005; 434: 113–118.

    Article  CAS  Google Scholar 

  23. Larson-Meyer DE, Newcomer BR, Heilbronn LK, Volaufova J, Smith SR, Alfonso AJ et al. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity 2008; 16: 1355–1362.

    Article  CAS  Google Scholar 

  24. Civitarese AE, Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med 2007; 4: e76.

    Article  Google Scholar 

  25. Hashimoto H, Kitamura K, Kawasaki M, Saito T, Suzuki H, Otsubo H et al. Adrenomedullin 2/intermedin-like immunoreactivity in the hypothalamus and brainstem of rats. Auton Neurosci 2008; 139: 46–54.

    Article  CAS  Google Scholar 

  26. Morimoto R, Satoh F, Murakami O, Totsune K, Suzuki T, Sasano H et al. Expression of adrenomedullin2/intermedin in human brain, heart, and kidney. Peptides 2007; 28: 1095–1103.

    Article  CAS  Google Scholar 

  27. Takei Y, Inoue K, Ogoshi M, Kawahara T, Bannai H, Miyano S . Identification of novel adrenomedullin in mammals: a potent cardiovascular and renal regulator. FEBS Lett 2004; 556: 53–58.

    Article  CAS  Google Scholar 

  28. Chauhan M, Yallampalli U, Dong YL, Hankins GD, Yallampalli C . Expression of adrenomedullin 2 (ADM2)/intermedin (IMD) in human placenta: role in trophoblast invasion and migration. Biol Reprod 2009; 81: 777–783.

    Article  CAS  Google Scholar 

  29. Wong CW, O WS, Tang F . Intermedin in rat uterus: changes in gene expression and peptide levels across the estrous cycle and its effects on uterine contraction. Reprod Biol Endocrinol 2013; 11: 13.

    Article  CAS  Google Scholar 

  30. Fukai N, Yoshimoto T, Sugiyama T, Ozawa N, Sato R, Shichiri M et al. Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues. Am J Physiol 2005; 288: E56–E62.

    CAS  Google Scholar 

  31. Fernandez-Marcos PJ, Auwerx J . Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011; 93: 884S–890S.

    Article  CAS  Google Scholar 

  32. Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev 2008; 22: 1397–1409.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Basic Research Program of China (2012CB518002 and 2011CB503904), the National Natural Science Foundation of China (31230035, 91439206 and 81470557), and grant B07001 (111 project) from the Ministry of Education of PR China. We thank Dr Yuhui Wang and Professor George Liu from the Key Laboratory of Molecular Cardiovascular Science of Peking University for preparing the aAM2-tg mice.

Author contributions

HZ, SYZ designed and conducted mouse experiments and analyzed the results; CTJ, YL and GHX analyzed data and edited the manuscript; MJX and XW designed the experiments, wrote the manuscript and supervised the whole project.

Author information

Author notes

  1. H Zhang and S-Y Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China

    H Zhang, S-Y Zhang, C Jiang, Y Li, G Xu, M-J Xu & X Wang

Authors
  1. H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S-Y Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M-J Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M-J Xu or X Wang.

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

Zhang, H., Zhang, SY., Jiang, C. et al. Intermedin/adrenomedullin 2 polypeptide promotes adipose tissue browning and reduces high-fat diet-induced obesity and insulin resistance in mice. Int J Obes 40, 852–860 (2016). https://doi.org/10.1038/ijo.2016.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.2

This article is cited by

Search

Advanced search

Quick links