Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance

被引:710
作者
Odegaard, Justin I. [1 ,2 ]
Ricardo-Gonzalez, Roberto R. [1 ,2 ]
Eagle, Alex Red [1 ,3 ]
Vats, Divya [1 ]
Morel, Christine R. [1 ]
Goforth, Matthew H. [1 ]
Subramanian, Vidya [4 ]
Mukundan, Lata [1 ]
Ferrante, Anthony W. [4 ]
Chawla, Ajay [1 ,2 ]
机构
[1] Stanford Univ, Sch Med, Dept Med, Div Endocrinol Metab& Gerontol, Stanford, CA 94305 USA
[2] Stanford Univ, Sch Med, Grad Program Immunol, Stanford, CA 94305 USA
[3] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA
[4] Columbia Univ Coll Phys & Surg, Naomi Berrie Diabet Ctr, Dept Med, New York, NY 10032 USA
关键词
D O I
10.1016/j.cmet.2008.04.003
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Macrophage infiltration and activation in metabolic tissues underlie obesity-induced insulin resistance and type 2 diabetes. While inflammatory activation of resident hepatic macrophages potentiates insulin resistance, the functions of alternatively activated Kupffer cells in metabolic disease remain unknown. Here we show that in response to the Th2 cytokine interleukin-4 (IL-4), peroxisome proliferator-activated receptor delta (PPAR delta) directs expression of the alternative phenotype in Kupffer cells and adipose tissue macrophages of lean mice. However, adoptive transfer of PPAR delta(-/-) (Ppard(-/-)) bone marrow into wildtype mice diminishes alternative activation of hepatic macrophages, causing hepatic dysfunction and systemic insulin resistance. Suppression of hepatic oxidative metabolism is recapitulated by treatment of primary hepatocytes with conditioned medium from PPAR delta(-/-) macrophages, indicating direct involvement of Kupffer cells in liver lipid metabolism. Taken together, these data suggest an unexpected beneficial role for alternatively activated Kupffer cells in metabolic syndrome and type 2 diabetes.
引用
收藏
页码:496 / 507
页数:12
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