Attenuated Pik3r1 Expression Prevents Insulin Resistance and Adipose Tissue Macrophage Accumulation in Diet-Induced Obese Mice

被引:54
作者
McCurdy, Carrie E. [1 ,2 ,3 ]
Schenk, Simon [4 ]
Holliday, Michael J. [1 ,2 ,3 ]
Philp, Andrew [5 ]
Houck, Julie A. [1 ,2 ,3 ]
Patsouris, David [6 ]
MacLean, Paul S. [2 ]
Majka, Susan M. [2 ,3 ]
Klemm, Dwight J. [2 ,3 ]
Friedman, Jacob E. [1 ,7 ]
机构
[1] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA
[2] Univ Colorado, Sch Med, Dept Med, Aurora, CO USA
[3] Univ Colorado, Sch Med, Charles C Gates Ctr Regenerat Med & Stem Cell Bio, Aurora, CO USA
[4] Univ Calif San Diego, Dept Orthopaed Surg, La Jolla, CA 92093 USA
[5] Univ Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA
[6] Univ Lyon 1, INSERM, U1060, Fac Med Lyon Sud, Oullins, France
[7] Univ Colorado, Sch Med, Dept Biochem & Mol Genet, Aurora, CO USA
基金
美国国家卫生研究院;
关键词
HIGH-FAT DIET; PHOSPHOINOSITIDE; 3-KINASE; P85-ALPHA SUBUNIT; GLUCOSE-UPTAKE; PHOSPHATIDYLINOSITOL; REGULATORY SUBUNIT; SKELETAL-MUSCLE; CELLS; INFLAMMATION; SENSITIVITY;
D O I
10.2337/db11-1433
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85 alpha/p55 alpha/p50 alpha) are highly induced in AT from high-fat diet fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (alpha HZ), but not knockout of Pik3r2 (p85 beta), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese alpha HZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese alpha HZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT. Diabetes 61:2495-2505, 2012
引用
收藏
页码:2495 / 2505
页数:11
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