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J. Biol. Chem., Vol. 279, Issue 34, 36093-36102, August 20, 2004

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Regulated Production of a Peroxisome Proliferator-activated Receptor- Ligand during an Early Phase of Adipocyte Differentiation in 3T3-L1 Adipocytes^*

Iphigenia Tzameli, Hui Fang, Mario Ollero¶||, Hang Shi, Jonathan K. Hamm, Paul Kievit, Anthony N. Hollenberg, and Jeffrey S. Flier**

From the Divisions of Endocrinology and ^¶Gastroenterology, Department of Medicine, and the ^||Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

Peroxisome proliferator-activated receptor- (PPAR) is a nuclear hormone receptor that is critical for adipogenesis and insulin sensitivity. Ligands for PPAR include some polyunsaturated fatty acids and prostanoids and the synthetic high affinity antidiabetic agents thiazolidinediones. However, the identity of a biologically relevant endogenous PPAR ligand is unknown, and limited insight exists into the factors that may regulate production of endogenous PPAR ligands during adipocyte development. To address this question, we created a line of 3T3-L1 preadipocytes that carry a -galactosidase-based PPAR ligand-sensing vector system. In this system, induction of adipogenesis resulted in elevated -galactosidase activity that signifies activation of PPAR via its ligand-binding domain (LBD) and suggests generation and/or accumulation of a ligand moiety. The putative endogenous ligand appeared early in adipogenesis in response to increases in cAMP, accumulated in the medium, and dissipated later in adipogenesis. Organically extracted and high pressure liquid chromatography-fractionated conditioned media from differentiating cells, but not from mature adipocytes, were enriched in this activity. One or more components within the organic extract activated PPAR through interaction with its LBD, induced lipid accumulation in 3T3-L1 cells as efficiently as the differentiation mixture, and competed for binding of rosiglitazone to the LBD of PPAR. The active species appears to be different from other PPAR ligands identified previously. Our findings suggest that a novel biologically relevant PPAR ligand is transiently produced in 3T3-L1 cells during adipogenesis.

Received for publication, May 13, 2004

^* This work was supported in part by grants from Takeda Chemicals Industries and National Institutes of Health Grant DKR3728082 (to J. S. F.) and by National Institutes of Health Grant 2P30 DK46200-11 (I. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Pharmacology and Molecular Biology Research Labs., Sankyo Co., Ltd., Tokyo 140-8710, Japan.

^** To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, Finard 202, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-9050; Fax: 617-667-9054; E-mail: jflier{at}caregroup.harvard.edu.

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