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Am J Physiol Regul Integr Comp Physiol 295: R1097, 2008; doi:10.1152/ajpregu.90633.2008
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LETTER TO THE EDITOR

ENDOCRINE PHYSIOLOGY AND METABOLISM

HIF-1{alpha} protein rather than mRNA as a marker of hypoxia in adipose tissue in obesity: focus on "Inflammation is associated with a decrease of lipogenic factors in omental fat in women," by Poulain-Godefroy et al.

WE WERE INTERESTED TO SEE the article by Poulain-Godefroy et al. (4) in which a global decrease in lipogenic markers was associated with the enhancement of inflammation in human adipose tissue, a relationship accentuated in diabetic subjects. The authors further show that expression levels of the inflammatory markers CD14 and IL-18 are increased in omental compared with subcutaneous adipose tissue, the depot differences being particularly evident for IL-18. This suggests that subcutaneous fat is less susceptible to inflammation than the visceral tissue, consistent with the link between visceral fat and the diseases associated with obesity.

Poulain-Godefroy et al. (4) also examined the hypothesis that hypoxia may occur in clusters of adipocytes distant from the vasculature in adipose tissue in obesity, thus underpinning the inflammatory response that develops as fat mass expands (6, 7). However, no increase in the level of the mRNA encoding the {alpha}-subunit of the key hypoxia-inducible transcription factor HIF-1 was found in adipose tissue of lean and obese subjects; nor were there depot differences in HIF-1{alpha} mRNA level (4). At first glance, this appears incompatible with the "hypoxia hypothesis" (6, 7), although a previous study observed increased HIF-1{alpha} mRNA levels in adipose tissue of obese subjects, which fell with weight loss (1), and there is now direct evidence of hypoxia in adipose tissue of genetic and dietary-induced obese animals together with an increase in HIF-1{alpha} protein (3, 5, 10).

A key question is whether HIF-1{alpha} mRNA is a good indicator of hypoxia in adipose tissue. While changes in mRNA level are normally paralleled by subsequent alterations in the amount of the encoded protein, this does not seem to be the case for HIF-1{alpha} in human adipocytes (6). Indeed, our studies on human fat cells in culture have shown that hypoxia (1% O2 or chemically-induced) leads to a marked increase (up to 8-fold) in HIF-1{alpha} protein, while HIF-1{alpha} mRNA level falls (by up to 4-fold) (8, 9). There are parallels in other systems, for example, THP-1 human monocytes where the HIF-1{alpha} mRNA level fell in undifferentiated cells (and was unchanged in differentiated cells) in response to hypoxia while HIF-1{alpha} protein increased (2). The explanation for this is not clear, but stabilization of HIF-1{alpha} protein may feed back to transcriptional regulation of the HIF-1{alpha} gene.

There is emerging evidence in support of the hypoxia hypothesis in obese animals (3, 5, 10) and from studies on adipocytes in culture, as recently reviewed (6). We suggest that it is important to measure the amount of HIF-1{alpha} protein, rather than the mRNA level, as a key marker in studies examining whether hypoxia occurs in adipose tissue in human obesity.

FOOTNOTES


Address for reprint requests and other correspondence: P. Trayhurn, Obesity Biology Research Unit, School of Clinical Sciences, Univ. of Liverpool, Duncan Bldg., Liverpool L69 3GA, U.K. (e-mail: p.trayhurn{at}liverpool.ac.uk)

REFERENCES

  1. Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clément K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54: 2277–2286, 2005.[Abstract/Free Full Text]
  2. Frede S, Stockmann C, Freitag P, Fandrey J. Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-{kappa}B. Biochem J 396: 517–527, 2006.[CrossRef][Web of Science][Medline]
  3. Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901–911, 2007.[Abstract/Free Full Text]
  4. Poulain-Godefroy O, Lecoeur C, Pattou F, Frühbeck G, Froguel P. Inflammation is associated with a decrease of lipogenic factors in omental fat in women. Am J Physiol Regul Integr Comp Physiol 295: R1–R7, 2008.[Abstract/Free Full Text]
  5. Rausch ME, Weisberg SP, Vardhana P, Tortorielllo DV. Obesity in C57BL/6J mice is characterised by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obesity 32: 451–463, 2008.[CrossRef][Web of Science]
  6. Trayhurn P, Wang B, Wood IS. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 100: 227–235, 2008.[Web of Science][Medline]
  7. Trayhurn P, Wood IS. Adipokines: Inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92: 347–355, 2004.[CrossRef][Web of Science][Medline]
  8. Wang B, Wood IS, Trayhurn P. Dysregulation of the expression and secretion of inflammation-related adipokines by hypoxia in human adipocytes. Pflügers Archiv Eur J Physiol 455: 479–492, 2007.[CrossRef][Web of Science][Medline]
  9. Wang B, Wood IS, Trayhurn P. PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochem Biophys Res Commun 368: 88–93, 2008.[CrossRef][Web of Science][Medline]
  10. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293: E1118–E1128, 2007.[Abstract/Free Full Text]

Paul Trayhurn
Bohan Wang
I. Stuart Wood
 Obesity Biology Research Unit
School of Clinical Sciences
University of Liverpool
Duncan Building
Liverpool
United Kingdom




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Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
O. Poulain-Godefroy and P. Froguel
Response to the letter to the editor: "HIF-1{alpha} protein rather than mRNA as a marker of hypoxia in adipose tissue in obesity," by Trayhurn et al.
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1098 - R1098.
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