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J. Biol. Chem., Vol. 279, Issue 48, 49747-49754, November 26, 2004

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Ligand-independent Activation of Peroxisome Proliferator-activated Receptor- by Insulin and C-peptide in Kidney Proximal Tubular Cells

DEPENDENT ON PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY^*

Nawal M. Al-Rasheed, Ravinder S. Chana, Richard J. Baines¶, Gary B. Willars, and Nigel J. Brunskill¶||

From the Department of Cell Physiology and Pharmacology, University of Leicester, Leicester LE1 9HN, United Kingdom, the ^¶Department of Infection Immunity and Inflammation, University of Leicester, Leicester LE1 9HN, United Kingdom, and the Department of Pharmacology, King Saud University, Riyadh, Saudi Arabia

Peroxisome proliferator-activated receptor (PPAR) has key roles in the regulation of adipogenesis, inflammation, and lipid and glucose metabolism. C-peptide is believed to be inert and without appreciable biological functions. Recent studies suggest that C-peptide possesses multiple functions. The present study investigated the effects of insulin and C-peptide on PPAR transcriptional activity in opossum kidney proximal tubular cells. Both insulin and C-peptide induced a concentration-dependent stimulation of PPAR transcriptional activity. Both agents substantially augmented thiazolidinedione-stimulated PPAR transcriptional activity. Neither insulin nor C-peptide had any effect on the expression levels of PPAR. GW9662, a PPAR antagonist, blocked PPAR activation by thiazolidinediones but had no effect on either insulin- or C-peptide-stimulated PPAR transcriptional activity. Co-transfection of opossum kidney cells with dominant negative mitogen-activated protein kinase kinase significantly depressed basal PPAR transcriptional activity but had no effect on that induced by either insulin or C-peptide. Both insulin- and C-peptide-stimulated PPAR transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol (PI) 3-kinase p85 regulatory subunit. In addition PI 3-kinase-dependent phosphorylation of PPAR was observed after stimulation by C-peptide or insulin. C-peptide effects but not insulin on PPAR transcriptional activity were abolished by pertussis toxin pretreatment. Finally both C-peptide and insulin positively control the expression of the PPAR-regulated CD36 scavenger receptor in human THP-1 monocytes. We concluded that insulin and C-peptide can stimulate PPAR activity in a ligand-independent fashion and that this effect is mediated by PI 3-kinase. These results support a new and potentially important physiological role for C-peptide in regulation of PPAR-related cell functions.

Received for publication, July 21, 2004 , and in revised form, September 15, 2004.

^* 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.

^|| To whom correspondence should be addressed: Dept. of Cell Physiology and Pharmacology, Medical Sciences Bldg., University of Leicester, University Rd., Leicester, LE1 9HN, United Kingdom. Tel.: 44-116-258-8043; Fax: 44-116-258-4764; E-mail: njb18{at}le.ac.uk.

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