Proc Natl Acad Sci U S A 100(12): 7265-7270

Monocyte chemoattractant protein 1 in obesity and insulin resistance

Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, VB-3, La Jolla, CA 92037

^{To whom correspondence should be addressed. E-mail:}ude.sppircs@fotuksol.

Edited by Jeffrey M. Friedman, The Rockefeller University, New York, NY

Received 2002 Jun 28; Accepted 2003 Apr 8.

Abstract

This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and in vivo in IR obese mice (ob/ob). Thus, MCP-1 resembles other previously described genes (e.g., PAI-1 and SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues. In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (LpL, adipsin, GLUT-4, aP2, β3-adrenergic receptor, and peroxisome proliferator-activated receptor γ). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.

Abstract

Obesity poses a serious health hazard and contributes to the increased morbidity and mortality in Western societies where it has reached epidemical proportions (1). Despite the magnitude and cost of this problem, the molecular changes in obesity that lead to poor health remain to be defined. Obesity frequently is accompanied by related metabolic perturbations such as dyslipidemia, hypertension, insulin resistance, hyperinsulinemia, and the development of a procoagulant state, and these changes contribute to an increased risk for cardiovascular diseases (2). Importantly, insulin resistance is also central to the pathophysiology of type II diabetes (3). Although the molecular mechanisms leading to development of insulin resistance also are not fully understood, there appears to be an association between insulin resistance and both the accumulation of abdominal visceral fat (4) and the presence of specific genetic components (5).

Insulin affects a number of biological processes including glucose transport, glucose/lipid metabolism, cell growth, protein synthesis, and gene expression (6). Although insulin resistance, by definition, describes an impaired biological responsiveness to insulin, it is frequently used to describe a defect in insulin-stimulated glucose uptake by muscle and adipocytes and/or a decrease in gluconeogenesis by the liver. The degree to which the other actions of insulin (e.g., gene expression) remain normal or become resistant in type II diabetes is not clear.

In addition to their role in fat storage, adipocytes synthesize and secrete a variety of bioactive proteins (7). During the development of obesity and type II diabetes these cells increase in size and number and their metabolic activity is dramatically altered. It is conceivable that some of the adipocyte-derived factors could underlie the association of insulin resistance with a prothrombotic state and the increased risk for coronary heart disease (8). In this regard, plasminogen activator inhibitor 1 (PAI-1) is elevated in human obesity and type II diabetes (9, 10). Tumor necrosis factor α (TNF-α) is also elevated in obesity and may contribute to many aspects of adipose tissue biology including development of insulin resistance and abnormalities in lipid metabolism (11).

Studies of genetically obese mice and cultured adipocytes demonstrate that insulin and TNF-α are two mediators that regulate PAI-1 expression in the adipocyte in vivo (12). Interestingly, these studies also reveal that insulin-resistant (IR) adipocytes and mice remained sensitive to insulin in terms of PAI-1 gene expression, possibly because glucose homeostasis and PAI-1 gene expression are regulated by different insulin signaling pathways (13). Consistent with this hypothesis, Shimomura and colleagues (14) demonstrated that in murine leptin-deficient states insulin signaling in the liver also diverges along two pathways and they showed that the transcription factor SREBP-1c is another gene that remains sensitive to insulin in these IR mice. Similar selective insulin resistance also has been described in human and rodent muscle (15, 16). Collectively, these observations raise the possibility that in the situation of metabolic insulin resistance accompanied by hyperinsulinemia, the expression of certain insulin-responding genes may dramatically increase in insulin target tissues. Characterization of such genes could provide valuable information about the molecular basis for the association of insulin resistance and type II diabetes with cardiovascular disease.

To begin to define the cluster of genes that remain responsive to insulin in metabolic IR states, microarray analysis was performed. By comparing gene expression profiles between normal and IR 3T3-L1 adipocytes treated with exogenous insulin, we have identified a number of genes that continue to respond normally to insulin in cultured IR adipocytes (unpublished work). One such gene is monocyte chemoattractant protein 1 (MCP-1), a member of the chemokine family. It has been studied in a number of pathological conditions characterized by monocyte infiltration (17) and is expressed by a variety of activated cells (e.g., endothelial cells, monocytes, and smooth muscle cells) exposed to inflammatory stimuli (18). However, information about the role of MCP-1 in obesity and the development of insulin resistance is lacking. This chemokine was recently detected in cultured human adipocytes (19).

In the present study, we show that MCP-1 mRNA is overexpressed in the adipose tissue of genetically obese mice compared with WT littermates and that it continues to respond to exogenous insulin in IR adipocytes and mice. Additional in vitro studies suggest that MCP-1 may contribute to the development of insulin resistance and that it also induces adipocyte dedifferentiation.

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Acknowledgments

We thank Marcia McRae for preparing the manuscript. This work was supported in part by a grant from Novartis Pharmaceuticals and National Institutes of Health Grant HL59459 (to D.J.L.). P.S. was supported by a postdoctoral fellowship from the Henning and Johan Throne-Holst Foundation. This is The Scripps Research Institute manuscript no. 14956-CB.

Acknowledgments

Notes

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PAI-1, plasminogen activator inhibitor 1; TNF-α, tumor necrosis factor α; IR, insulin-resistant; MCP-1, monocyte chemoattractant protein 1; PPAR, peroxisome proliferator-activated receptor.

Notes

This paper was submitted directly (Track II) to the PNAS office.

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