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J. Biol. Chem., Vol. 281, Issue 43, 32796-32805, October 27, 2006

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Bone Marrow Plasminogen Activator Inhibitor-1 Influences the Development of Obesity^*

From the Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232

Plasma levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in obesity and correlate with body mass index. The increase in PAI-1 associated with obesity likely contributes to increased cardiovascular risk and may predict the development of type 2 diabetes mellitus. Although adipocytes are capable of synthesizing PAI-1, the bulk of evidence indicates that cells residing in the stromal fraction of visceral fat are the primary source of PAI-1. We hypothesized that bone marrow-derived PAI-1, e.g. derived from macrophages located in visceral fat, contributes to the development of diet-induced obesity. To test this hypothesis, male C57BL/6 wild-type mice and C57BL/6 PAI-1 deficient mice were transplanted with either PAI-1^-/-, PAI-1^+/-, or PAI-1^+/+ bone marrow. The transplanted animals were subsequently fed a high fat diet for 24 weeks. Our findings show that only the complete absence of PAI-1 protects from the development of diet-induced obesity, whereas the absence of bone marrow-derived PAI-1 protects against expansion of the visceral fat mass. Remarkably, there is a link between the PAI-1 levels, the degree of inflammation in adipose tissue, and the development of obesity. Based on these findings we suggest that bone marrow-derived PAI-1 has an effect on the development of obesity through its effect on inflammation.

Received for publication, June 29, 2006 , and in revised form, August 14, 2006.

^* This study was supported by NHLBI, National Institutes of Health Grants HL-51387, HL-65192, and P50HL081089. 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 383 Preston Research Bldg., 2220 Pierce Ave., Nashville, TN 37232. Tel.: 615-936-1719; Fax: 615-936-2936; E-mail: Douglas.e.vaughan{at}vanderbilt.edu.

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