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Diabetes 56:e18 2007
DOI: 10.2337/db07-1003
© 2007 by the American Diabetes Association
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Letter to the Editor

Response to Comment on: Harmancey et al. (2007) Adrenomedullin Inhibits Adipogenesis Under Transcriptional Control of Insulin: Diabetes 56:553–563

Romain Harmancey, and Fatima Smih

From the I2MR Institut National de la Santé Et de La Recherche Médicale (INSERM) U858, Obesity and Heart Failure Team, Université Paul Sabatier (UPS), Institut Louis Bugnard IFR31, Toulouse, France

Address correspondence to Fatima Smih, PhD, I2MR INSERM U858, Obesity and Heart Failure Team, Faculté de Médecine, Université Paul Sabatier, 37 allées Jules Guesde, 31000 Toulouse, France. E-mail: fatima.smih{at}toulouse.inserm.fr

We thank Dr. Takahashi for his interest (1,2). First, the main reason for using 100 nmol/l adrenomedullin was to compensate for the uncontrolled catabolism of exogenously added adrenomedullin. Several reports point out that human adipocytes express neprilysin, one of the main enzymes that degrade adrenomedullin (3,4). The metalloprotease is also expressed by 3T3-F442A preadipocytes during differentiation (R.H., F.S., unpublished data). Moreover, we observed in preliminary experiments that omapatrilat, a dual vasopeptidase inhibitor of neprilysin and ACE, increased adipogenesis in 3T3-F442A preadipocytes.

We also reported weak adrenomedullin secretion by adipose cells in a previous study (5), but one should keep in mind that traditional Sep-Pak C18 purification procedures before radioimmunoassay do not take into account the adrenomedullin fraction bound to complement factor H (6). This has been demonstrated as a particular bias in the estimation of circulating adrenomedullin levels. We also think that it may affect adrenomedullin assay of cell culture media containing serum (7).

Second, electroporation of differentiated adipocytes is difficult because they are prone to collapse, and other efficient transfection methods that utilize cationic lipid reagents are suspected of inhibiting insulin signaling (8). Isolated human adipocytes treated with insulin showed that adrenomedullin expression is downregulated in fully differentiated cells (see Fig. 5B in ref. 2).

Third, the discrepancy between murine adipose cell lines and human mesenchymal stem cells may be due to variations in the treatments used to induce adipogenesis; however, it suggests that adipocytes have mechanisms to both upregulate and downregulate adrenomedullin gene expression during differentiation. Recent advances in the field of adipogenesis point out the many facets of the effect of insulin. In addition to the recent discovery of cyclic AMP response element–binding protein activation (9), we think that adrenomedullin downregulation could contribute to the proadipogenic action of insulin, although this will effectively require further investigation.

Finally, we agree with Dr. Takahashi that the relation between plasma adrenomedullin and insulin levels might have been different with insulin-resistant obese subjects. We believe that the development of insulin resistance during obesity may lead to an effective increase in adrenomedullin plasma concentration because the peptide would no longer be negatively controlled by insulin. This hypothesis is supported by recent results, demonstrating a positive correlation of adrenomedullin levels in omental adipose tissue with BMI and homeostasis model assessment index in obese patients with no endocrine, cardiovascular, hepatic, renal, or inflammatory disease (10).

Data and results presented in the article are drawn from 10 patients in each group: 5 male and 5 female patients in the lean group and 4 male and 6 female patients in the obese group.

REFERENCES

  1. Takahashi K: Comment on: Harmancey et al. (2007) Adrenomedullin inhibits adipogenesis under transcriptional control of insulin: Diabetes 56:553–563. Diabetes 56:e15, 2007. DOI: 10.2337/db07-0592
  2. Harmancey R, Senard JM, Rouet P, Pathak A, Smih F: Adrenomedullin inhibits adipogenesis under transcriptional control of insulin. Diabetes 56:553–563, 2007.[Abstract/Free Full Text]
  3. Schling P, Schafer T: Human adipose tissue cells keep tight control on the angiotensin II levels in their vicinity. J Biol Chem 277:48066–48075, 2002[Abstract/Free Full Text]
  4. Linscheid P, Seboek D, Zulewski H, Keller U, Muller B: Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology 146:2699–2708, 2005[Abstract/Free Full Text]
  5. Harmancey R, Senard JM, Pathak A, Desmoulin F, Claparols C, Rouet P, Smih F: The vasoactive peptide adrenomedullin is secreted by adipocytes and inhibits lipolysis through NO-mediated beta-adrenergic agonist oxidation. Faseb J 19:1045–1047, 2005[Abstract/Free Full Text]
  6. Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F: Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 276:12292–12300, 2001[Abstract/Free Full Text]
  7. Peake PW, O’Grady S, Pussell BA, Charlesworth JA: Detection and quantification of the control proteins of the alternative pathway of complement in 3T3–L1 adipocytes. Eur J Clin Invest 27:922–927, 1997[Medline]
  8. Pramfalk C, Lanner J, Andersson M, Danielsson E, Kaiser C, Renstrom IM, Warolen M, James SR: Insulin receptor activation and down-regulation by cationic lipid transfection reagents. BMC Cell Biol 5:7, 2004[Medline]
  9. Klemm DJ, Leitner JW, Watson P, Nesterova A, Reusch JE, Goalstone ML, Draznin B: Insulin-induced adipocyte differentiation: activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation. J Biol Chem 276:28430–28435, 2001[Abstract/Free Full Text]
  10. Paulmyer-Lacroix O, Desbriere R, Poggi M, Achard V, Alessi MC, Boudouresque F, Ouafik L, Vuaroqueaux V, Labuhn M, Dutourand A, Grino M: Expression of adrenomedullin in adipose tissue of lean and obese women. Eur J Endocrinol 155:177–185, 2006[Abstract/Free Full Text]

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This Article
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