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. 2003 Jun 10;100(12):7265-70.
doi: 10.1073/pnas.1133870100. Epub 2003 May 19.

Monocyte chemoattractant protein 1 in obesity and insulin resistance

Peter Sartipy  1 , David J Loskutoff
Affiliations

Monocyte chemoattractant protein 1 in obesity and insulin resistance

Peter Sartipy et al. Proc Natl Acad Sci U S A. .

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, beta3-adrenergic receptor, and peroxisome proliferator-activated receptor gamma). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.

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Figures

Fig. 1.
Fig. 1.
Effect of insulin on MCP-1 gene expression in vitro. Mature adipocytes were incubated without insulin (Ctrl) or with 1,000 nM insulin (Ins) for 3 h. (A) MCP-1 mRNA levels were determined in normal (N) and IR 3T3-L1 adipocytes by using real-time RT-PCR and normalized to the expression of 18S rRNA. The data are expressed as relative mRNA level compared with the average expression level in normal cells incubated without insulin (=1). (Inset) The effect of TNF-α on insulin-stimulated glucose uptake was analyzed in mature 3T3-L1 adipocytes incubated without (C) or with 3 ng/ml TNF-α for 3 days. Insulin-stimulated 3H-2-deoxyglucose uptake was determined, and the data are expressed as percentage of the control (i.e., cells incubated without TNF-α). The error bars represent the SE (n = 5); ***, P < 0.0001 relative to control cells. (B) Secretion of MCP-1 protein from normal (N) and IR 3T3-L1 adipocytes was determined in conditioned media by using ELISA. Differentiated adipocytes were treated as described in A. The data were normalized to total cell protein. The error bars represent the SE (n = 3); **, P < 0.01 and ***, P < 0.001 relative to control cells.
Fig. 2.
Fig. 2.
Effect of TNF-α on MCP-1 gene expression in vitro. Differentiated normal 3T3-L1 adipocytes were cultured as described in Methods, and then incubated in the presence or absence of 5 ng/ml TNF-α for different times (A) or incubated for 3 h with different concentrations of TNF-α (B). MCP-1 gene expression was analyzed by using real-time RT-PCR and normalized to expression of 18S rRNA. The data are expressed as relative mRNA level compared with the average expression in cells incubated without TNF-α (=1). The error bars represent the SE (n = 3); ***, P < 0.001 relative to cells incubated without TNF-α.
Fig. 3.
Fig. 3.
Effect of MCP-1 on glucose uptake and gene expression in differentiated 3T3-L1 adipocytes. Basal (A) and insulin-stimulated (B) 3H-2-deoxyglucose uptake in differentiated 3T3-L1 adipocytes treated with MCP-1 (1 ng/ml) was measured as described in Methods. The data are expressed as percentage of control (i.e., cells incubated without MCP-1). Changes in expression of adipogenic genes in differentiated 3T3-L1 adipocytes treated with MCP-1 (5 ng/ml) were analyzed by using gene-specific primers and real-time RT-PCR. Genes analyzed include LpL (C), adipsin (D), GLUT-4 (E), aP2 (F), β3-adrenergic receptor (G), and PPAR-γ (H). The results were normalized to expression of 18S rRNA and are expressed as relative mRNA level compared with the average expression in cells incubated without MCP-1 (=1). The error bars represent the SE (n = 3–8); *, P < 0.05 and ***, P < 0.001 relative to control cells.
Fig. 4.
Fig. 4.
MCP-1 gene expression in vivo.(A) Basal levels of MCP-1 mRNA were determined in s.c. adipose tissue from sex- and age-matched WT and ob/ob mice by using real-time RT-PCR. The data are normalized to the expression of 18S rRNA and are expressed as relative mRNA level compared with the average expression in WT mice (=1). The error bars represent the SE (n = 6); ***, P < 0.0001. (B) Basal levels of MCP-1 mRNA were determined in different tissues from ob/ob mice by using real-time RT-PCR. The data are normalized to the expression of 18S rRNA and are expressed as relative mRNA levels compared with the average expression in s.c. adipose tissue (=1). The error bars represent the SE (n = 4); a, P < 0.001 in adipose tissue vs. liver, kidney, and lung.
Fig. 5.
Fig. 5.
Effect of exogenous insulin on MCP-1 gene expression in vivo. The effect of insulin on MCP-1 gene expression in s.c. adipose tissue from WT (A) and ob/ob (B) mice was determined. Female mice were injected i.p. with 10 units (WT) or 20 units (ob/ob) of human insulin or an equivalent volume of saline as control (shown at the 0-h time point). The mice were killed at different times, and MCP-1 gene expression was determined in the s.c. adipose tissue by using real-time RT-PCR. *, P < 0.05 and **, P < 0.01 relative to saline-treated mice. Plasma was collected from the same mice and analyzed for MCP-1 antigen (C) and glucose (D). ○, results from WT mice; •, ob/ob mice. a, P < 0.01 for WT vs. ob/ob mice at baseline (C), and a, P < 0.05 for WT vs. ob/ob mice at baseline (D); ***, P < 0.001 relative to saline-treated mice. The error bars indicate SE (n = 6).
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