mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action

J Koska, N Stefan, S Dubois, C Trinidad, R V Considine, T Funahashi, J C Bunt, E Ravussin, P A Permana, J Koska, N Stefan, S Dubois, C Trinidad, R V Considine, T Funahashi, J C Bunt, E Ravussin, P A Permana

Abstract

Objective: To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals.

Design: Cross-sectional inpatient study.

Subjects: Obese Pima Indians with normal glucose tolerance.

Measurements: Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1alpha, MIP1beta and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1alpha, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m(-2) min(-1)) (all n=34).

Results: MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action.

Conclusions: Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

Trial registration: ClinicalTrials.gov NCT00410800.

Figures

Figure 1
Figure 1
Correlation of the mRNA concentrations of MIF in freshly isolated adipocytes and cultured preadipocytes from subcutaneous abdominal adipose tissue with mean adipocyte diameter. Symbols: close circles – males, open circles – females.
Figure 2
Figure 2
Spearman correlation between the expression levels of MIF gene in freshly isolated adipocytes or cultured preadipocytes from subcutaneous abdominal adipose tissue and fasting plasma insulin, insulin-mediated glucose disposal (M), and endogenous glucose production (EGP) during the clamp. Symbols: close circles – males, open circles – females.
Figure 3
Figure 3
Spearman correlations between the expression levels of MIF gene in freshly isolated adipocytes or cultured preadipocytes from subcutaneous abdominal adipose tissue and fasting serum MIF and plasma adiponectin concentrations. Symbols: close circles – males, open circles – females.

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