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J. Biol. Chem., Vol. 276, Issue 20, 16904-16910, May 18, 2001
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From the U465 INSERM, Centre de Recherches Biomédicales des
Cordeliers (Université Paris 6), 15 Rue de l'Ecole de
Médecine, 75270 Paris Cedex 06, France and the
Enlarged fat cells exhibit modified metabolic
capacities, which could be involved in the metabolic complications of
obesity at the whole body level. We show here that sterol regulatory
element-binding protein 2 (SREBP-2) and its target genes are induced in
the adipose tissue of several models of rodent obesity, suggesting
cholesterol imbalance in enlarged adipocytes. Within a particular fat
pad, larger adipocytes have reduced membrane cholesterol concentrations compared with smaller fat cells, demonstrating that altered cholesterol distribution is characteristic of adipocyte hypertrophy per
se. We show that treatment with methyl-
Cholesterol, a Cell Size-dependent Signal That
Regulates Glucose Metabolism and Gene Expression in
Adipocytes*,
,
,
Centre de Recherche Smithkline Beecham, 4 Rue du Chesnay
Beauregard, 35260 Saint Grégoire, France
-cyclodextrin, which
mimics the membrane cholesterol reduction of hypertrophied adipocytes, induces insulin resistance. We also produced cholesterol depletion by
mevastatin treatment, which activates SREBP-2 and its target genes. The
analysis of 40 adipocyte genes showed that the response to cholesterol
depletion implicated genes involved in cholesterol traffic (caveolin 2, scavenger receptor BI, and ATP binding cassette 1 genes) but also
adipocyte-derived secretion products (tumor necrosis factor
,
angiotensinogen, and interleukin-6) and proteins involved in energy
metabolism (fatty acid synthase, GLUT 4, and UCP3). These data
demonstrate that altering cholesterol balance profoundly modifies
adipocyte metabolism in a way resembling that seen in hypertrophied fat
cells from obese rodents or humans. This is the first evidence that
intracellular cholesterol might serve as a link between fat cell size
and adipocyte metabolic activity.
*
This work was supported by contract FAIR 97-3011 from the
European Community.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The on-line version of this article (available at
http://www.jbc.org) contains supplemental data.
§
To whom correspondence should be addressed. Tel.: 33 1 42 34 69 22/23/24; Fax: 33 1 40 51 85 86; E-mail:
idugail@bhdc.jussieu.fr.
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