Adipocyte/macrophage fatty acid–binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice
Masato Furuhashi, … , Haiming Cao, Gökhan S. Hotamisligil
Masato Furuhashi, … , Haiming Cao, Gökhan S. Hotamisligil
Published June 12, 2008
Citation Information: J Clin Invest. 2008;118(7):2640-2650. https://doi.org/10.1172/JCI34750.
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Research Article Metabolism

Adipocyte/macrophage fatty acid–binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice

Abstract

Adipose tissue inflammation is a characteristic of obesity. However, the mechanisms that regulate this inflammatory response and link adipose inflammation to systemic metabolic consequences are not fully understood. In this study, we have taken advantage of the highly restricted coexpression of adipocyte/macrophage fatty acid–binding proteins (FABPs) aP2 (FABP4) and mal1 (FABP5) to examine the contribution of these lipid chaperones in macrophages and adipocytes to local and systemic inflammation and metabolic homeostasis in mice. Deletion of FABPs in adipocytes resulted in reduced expression of inflammatory cytokines in macrophages, whereas the same deletion in macrophages led to enhanced insulin signaling and glucose uptake in adipocytes. Using radiation chimerism through bone marrow transplantation, we generated mice with FABP deficiency in bone marrow and stroma-derived elements in vivo and studied the impact of each cellular target on local and systemic insulin action and glucose metabolism in dietary obesity. The results of these experiments indicated that neither macrophages nor adipocytes individually could account for the total impact of FABPs on systemic metabolism and suggest that interactions between these 2 cell types, particularly in adipose tissue, are critical for the inflammatory basis of metabolic deterioration.

Authors

Masato Furuhashi, Raquel Fucho, Cem Z. Görgün, Gürol Tuncman, Haiming Cao, Gökhan S. Hotamisligil

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Figure 1

Coculture experiments.

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Coculture experiments. (A) Protein expression of aP2 and mal1 in adipocy...
(A) Protein expression of aP2 and mal1 in adipocyte cell lines (WT-Ad, KO-Ad, KO+aP2-Ad, KO+GFP-Ad, and 3T3-L1), mouse macrophage cell lines (WT-Mac and KO-Mac), and thioglycollate-elicited primary macrophages from Ap2+/+Mal1+/+ (WT-pMac) and Ap2–/–Mal1–/– (KO-pMac) mice. (B) Dibutyryl cAMP–stimulated lipolysis (4-hour stimulated FFA release) in adipocyte cell lines. (C) Basal FFA release into the conditioned medium (CM) in adipocytes examined under the same conditions of coculture experiments for 16 hours. (D) Expression of Mcp1 in macrophages, WT-Mac or KO-Mac, incubated with conditioned medium from WT-Ad or KO-Ad adipocytes. Data were normalized to those in untreated macrophages. (E) Expression of Mcp1 in primary macrophages, WT-pMac or KO-pMac, incubated with conditioned medium from KO+GFP-Ad (FABP-deficient) or KO+aP2-Ad (FABP-reconstituted) adipocytes. Data were normalized to those in macrophages incubated with the conditioned medium from KO+GFP-Ad adipocytes. (F) Insulin-stimulated glucose uptake in 3T3-L1 adipocytes incubated in contact with immortalized macrophages, WT-Mac or KO-Mac. (G) Insulin-stimulated phosphorylation of Akt in 3T3-L1 adipocytes incubated in contact with immortalized macrophages. The graph on the right shows the quantification. (H) Insulin-stimulated phosphorylation of Akt in adipocyte cell lines, KO+GFP-Ad and KO+aP2-Ad, incubated in contact with primary macrophages, WT-pMac or KO-pMac. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01.