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:

Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats

Abstract

Objective:

There is emerging evidence that angiotensin stimulates adipocyte differentiation and lipogenesis. This study tested the hypothesis that inhibition of angiotensin II by treatment with an angiotensin-converting enzyme inhibitor, perindopril, would reduce fat mass in rats.

Design:

After a 12-day baseline, rats were divided into two groups: one was untreated and the other received perindopril (1.2 mg kg−1 per day) in drinking water for 26 days.

Subjects:

In total, 16 male Sprague–Dawley rats aged 10 weeks at the start of the study.

Measurements:

Plasma leptin was measured in samples collected at baseline, half-way through and at the end of treatment. Body weight, food and water intake were measured daily throughout the experiment. Body fat mass, bone and lean mass were determined by dual energy X-ray absorptiometry (DEXA) at the end of the treatment period.

Results:

Daily food intake was the same in both groups throughout the study. By the end of treatment, animals receiving perindopril showed a modest reduction in weight gain relative to the untreated animals (62.4±5.0 g vs 73.0±4.0 g; P<0.05). DEXA analysis showed that body composition was greatly altered and the perindopril-treated group had 26% less body fat mass than the untreated group (61.0±5.2 g vs 44.4±4.2 g; P<0.01). The reduction in body fat mass was correlated with reductions in the weight of both the epididymal and retroperitoneal fat pads (P<0.001). Similarly, plasma leptin was reduced by perindopril treatment (4.64±0.56 ng ml−1) compared to the untreated group (8.27±1.03 ng ml−1; P<0.001). In contrast, there were no differences in lean or bone mass between the two groups.

Conclusion:

Oral treatment with perindopril selectively reduced body fat mass without influencing daily food intake. In contrast, there were no differences in lean or bone mass between the two groups.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Lafontan M, Viguerie N . Role of adipokines in the control of energy metabolism: focus on adiponectin. Curr Opin Pharmacol 2006; 6: 1–6.

    Article  Google Scholar 

  2. Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson LM . Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 1988; 83: 3925–3929.

    Google Scholar 

  3. Schling P, Mallow H, Trindl A, Loffler G . Evidence for a local renin angiotensin system in primary cultured human preadipocytes. Int J Obes Relat Metab Disord 1999; 23: 336–341.

    Article  CAS  Google Scholar 

  4. Engeli S, Negrel R, Sharma AM . Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000; 35: 1270–1277.

    Article  CAS  Google Scholar 

  5. Cooper R, Forrester T, Ogunbiyi O, Muffinda J . Angiotensinogen levels and obesity in four black populations. ICSHIB Investigators. J Hypertens 1988; 16: 571–575.

    Article  Google Scholar 

  6. Umemura S, Nyui N, Tamura K, Hibi K, Yamaguchi S, Nakamaru M et al. Plasma angiotensinogen concentrations in obese patients. Am J Hypertens 1997; 10: 629–633.

    Article  CAS  Google Scholar 

  7. Cooper R, McFarlane-Anderson N, Bennett FI, Wilks R, Puras A, Tewksbury D et al. ACE, angiotensinogen and obesity: a potential pathway leading to hypertension. J Hum Hypertens 1997; 11: 107–111.

    Article  CAS  Google Scholar 

  8. Licata G, Scaglione R, Ganguzza A, Corrao S, Donatelli M, Parrinello G et al. Central obesity and hypertension. Relationship between fasting serum insulin, plasma renin activity, and diastolic blood pressure in young obese subjects. Am J Hypertens 1994; 7: 314–320.

    Article  CAS  Google Scholar 

  9. van Harmelen V, Elizalde M, Ariapart P, Bergstedt-Lindqvist S, Reynisdottir S, Hoffstedt J et al. The association of human adipose angiotensinogen gene expression with abdominal fat distribution in obesity. Int J Obes Relat Metab Disord 2000; 24: 673–678.

    Article  CAS  Google Scholar 

  10. Strazzullo P, Iacone R, Iacovello L, Russo O, Barba G, Russo P et al. Genetic variation in the renin-angiotensin system and abdominal adiposity in men: the Olivetti Prospective Heart Study. Ann Intern Med 2003; 17: 17–23.

    Article  Google Scholar 

  11. Giacchetti G, Faloia E, Sardu C, Camilloni MA, Mariniello B, Gatti C et al. Gene expression of angiotensinogen in adipose tissue of obese patients. Int J Obes Relat Metab Disord 2000; 24 (Suppl 2): S142–S143.

    Article  CAS  Google Scholar 

  12. Matsushita K, Wu Y, Okamoto Y, Pratt RE, Dzau VJ . Local renin-angiotensin system regulates human mesenchymal differentiation to adipocytes. Hypertension 2006; 48: 1095–1102.

    Article  CAS  Google Scholar 

  13. Goossens GH, Blaak EE, Baak MA . Possible involvement of the adipose tissue renin-angiotensin system in the pathophysiology of obesity and obesity-related disorders. Obes Rev 2003; 4: 43–55.

    Article  CAS  Google Scholar 

  14. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM . Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes 2002; 51: 1699–1707.

    Article  CAS  Google Scholar 

  15. Jones BH, Standridge MK, Moustaid N . Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells. Endocrinology 1997; 138: 1512–1519.

    Article  CAS  Google Scholar 

  16. Blaak EE, van Baak MA, Kemerink GJ, Pakbiers MT, Heidendal GA, Saris WH . Beta-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects. Metabolism 1995; 44: 183–187.

    Article  CAS  Google Scholar 

  17. Boschmann M, Ringel J, Klaus S, Sharma AM . Metabolic and hemodynamic response of adipose tissue to angiotensin II. Obes Res 2001; 9: 486–491.

    Article  CAS  Google Scholar 

  18. Boschmann M, Engeli M, Adams F, Franke G, Luft FC, Sharma AM et al. Influence of AT-1 receptor blockade on tissue metabolism in obese men. Am J Physiol 2006; 290: R219–R223.

    CAS  Google Scholar 

  19. Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J et al. Long term angiotensin AT1 receptor inhibition induced adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPAR gamma. Eur J Pharmacol 2006; 552: 112–122.

    Article  CAS  Google Scholar 

  20. Zanchi A, Dulloo AG, Perregaux C, Montani JP, Burnier M . Telmisartan prevents the glitazone-induced weight gain without interfering with its insulin-sensitising properties. Am J Physiol Endocrinol Metab 2007; 293: E91–E95.

    Article  CAS  Google Scholar 

  21. Sugimoto K, Qi NR, Kazdova L, Pravenec M, Ogihara T, Kurtz TW . Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension 2006; 47: 1003–1009.

    Article  CAS  Google Scholar 

  22. Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M et al. PPAR-gamma activating angiotensin receptor type-1 blockers induce adiponectin. Hypertension 2005; 46: 137–143.

    Article  CAS  Google Scholar 

  23. Shimabukuro M, Tanaka H, Shimabukuro T . Effects of telmisartan on fat distribution in individuals with the metabolic syndrome. J Hyperten 2007; 25: 841–848.

    Article  CAS  Google Scholar 

  24. Massiera F, Seydoux J, Geloen A, Quignard-Boulange A, Turban S, Saint-Marc P et al. Angiotensinogen-deficient mice exhibit impairment of diet-induced weight gain with alteration in adipose tissue development and increased locomotor activity. Endocrinology 2001; 142: 5220–5225.

    Article  CAS  Google Scholar 

  25. Kasper SO, Ferrario CM, Ganten D, Diz DI . Rats with low brain angiotensionogen do not exhibit insulin resistance during early aging. Endocr J 2006; 30: 167–174.

    Article  CAS  Google Scholar 

  26. Brink M, Wellen J, Delafontaine P . Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest 1996; 97: 2509–2516.

    Article  CAS  Google Scholar 

  27. Cassis LA, Marshall DE, Fettinger MJ, Rosenbluth B, Lodder RA . Mechanisms contributing to angiotensin II regulation of body weight. Am J Physiol 1998; 274: E867–E876.

    CAS  PubMed  Google Scholar 

  28. Heimann AS, Favarato MH, Gozzo FC, Rioli V, Carreno FR, Eberlin MN et al. ACE gene titration in mice uncovers a new mechanism on the control of body weight. Physiol Genomics 2005; 20: 173–182.

    Article  CAS  Google Scholar 

  29. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS . Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1995; 1: 1311–1314.

    Article  CAS  Google Scholar 

  30. Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M . Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes 1996; 45: 695–698.

    Article  CAS  Google Scholar 

  31. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995; 1: 1155–1161.

    Article  CAS  Google Scholar 

  32. Velkoska E, Morris MJ, Burns P, Weisinger RS . Leptin reduces food intake but does not alter weight regain following food deprivation in the rat. Int J Obes Relat Metab Disord 2003; 27: 48–54.

    Article  CAS  Google Scholar 

  33. Pritchard JE, Nowson CA, Strauss BJ, Carlson JS, Kaymakci B, Wark JD . Evaluation of dual energy X-ray absorptiometry as a method of measurement of body fat. Eur J Clin Nutr 1993; 47: 216–228.

    CAS  PubMed  Google Scholar 

  34. Jecquier E . Leptin signaling, adiposity and energy balance. Ann NY Acad Sci 2002; 967: 379–388.

    Article  Google Scholar 

  35. Weisinger RS, Denton DA, Di Nicolantonio R, McKinley MJ . The effect of captopril or enalaprilic acid on Na-deplete rats. Clin Exp Physiol Pharmacol 1988; 15: 55–65.

    Article  CAS  Google Scholar 

  36. Sakaguchi K, Chai SY, Jackson B, Johnston CI, Mendelsohn FA . Differential angiotensin-converting enzyme inhibition in brain after oral administration of perindopril demonstrated by quantitative in vitro autoradiography. Neuroendocrinology 1988; 48: 223–228.

    Article  CAS  Google Scholar 

  37. Thunhorst RL, Xu Z, Cicha MZ, Zardetto-Smith AM, Johnson AK . Fos expression in rat brain during depletion-induced thirst and salt appetite. Am J Physiol 1998; 274: R1807–R1814.

    CAS  PubMed  Google Scholar 

  38. Gilliam-Davis S, Payne VS, Kasper SO, Tommasi EN, Robbins ME, Diz DI . Long-term AT1 receptor blockade improves metabolic function and provides renoprotection in Fischer 344 rats. Am J Physiol 2007; 293: H1327–H1333.

    Article  CAS  Google Scholar 

  39. Mifsud SA, Skinner SL, Cooper ME, Kelly DJ, Wilkinson-Berka JL . Effects of low-dose and early versus late perindopril treatment on the progression of severe diabetic nephropathy in (mREN-2)27 rats. J Am Soc Nephrol 2002; 13: 684–692.

    CAS  PubMed  Google Scholar 

  40. Morrison CD, White CL, Wang Z, Lee SY, Lawrence DS, Cefalu WT et al. Increased hypothalamic protein tyrosine phosphatase 1b contributes to leptin resistance with age. Endocrinology 2007; 148: 433–440.

    Article  CAS  Google Scholar 

  41. Weisinger HS, Begg DP, Egan GF, Jayasooriya AP, Lie F, Mathai ML et al. Angiotensin converting enzyme inhibition from birth reduces body weight and body fat in Sprague–Dawley rats. Physiol Behav 2008; 93: 820–825.

    Article  CAS  Google Scholar 

  42. Santos EL, Souza KD, Guimaraes PB, Reis FCG, Silva SMA, Costa-Neto CM et al. Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats. Int Immunopharmacol 2008; 8: 247–253.

    Article  CAS  Google Scholar 

  43. Carter CS, Onder G, Kritchevsky SB, Pahor M . Angiotensin-converting enzyme inhibition, body composition and physical performance in aged rats. J Gerontol A Biol Sci Med Sci 2005; 60: 1437–1446.

    Article  Google Scholar 

  44. Jayasooriya AP, Mathai ML, Walker LL, Begg DP, Denton DA, Cameron-Smith D et al. Mice lacking angiotensin converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance. Proc Natl Acad Sci (USA) 2008; 105: 6531–6536.

    Article  CAS  Google Scholar 

  45. Fruebis J, Tsao TS, Javorschi S, Ebets-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. Proc Natl Acad Sci (USA) 2001; 98: 2005–2010.

    Article  CAS  Google Scholar 

  46. Erbe DV, Gartrell K, Zhang YL, Suri V, Kirincich SJ, Will S et al. Molecular activation of PPAR-gamma by angiotensin type-1 receptor antagonists. Vascular Pharmacol 2006; 45: 154–162.

    Article  CAS  Google Scholar 

  47. Enalapril in Hypertension Study Group (UK). Enalapril in essential hypertension: a comparative study with propranolol. Br J Clin Pharmacol 1984; 18: 51–56.

    Article  Google Scholar 

  48. Masuo K, Mikami H, Ogihara T, Tuck ML . Weight reduction and pharmacologic treatment in obese hypertensives. Am J Hypertens 2001; 14: 530–538.

    Article  CAS  Google Scholar 

  49. Dixon JB, Strauss BJG, Laurie C, O'Brien PE . Changes in body composition with weight Loss: obese subjects randomized to surgical and medical programs. Obesity 2007; 15: 1187–1198.

    Article  Google Scholar 

Download references

Acknowledgements

MLM was supported by the G. Harald and Leila Y Mathers Charitable Foundation and the J Robert Jr and Helen C Kleberg Foundation. The support of grants from the Australia Research Council (DP0346830) and National Health and Medical Research Council (350313) is also gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M L Mathai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mathai, M., Naik, S., Sinclair, A. et al. Selective reduction in body fat mass and plasma leptin induced by angiotensin-converting enzyme inhibition in rats. Int J Obes 32, 1576–1584 (2008). https://doi.org/10.1038/ijo.2008.126

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2008.126

Keywords

This article is cited by

Search

Quick links