Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice.
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., p85α/p55α/p50α) are highly induced in AT from high-fat diet-fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), 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 αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH(2)-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ 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.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA. carrie.mccurdy@ucdenver.edu
Carrie E
CE
McCurdy
Simon
S
Schenk
Michael J
MJ
Holliday
Andrew
A
Philp
Julie A
JA
Houck
David
D
Patsouris
Paul S
PS
MacLean
Susan M
SM
Majka
Dwight J
DJ
Klemm
Jacob E
JE
Friedman
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D059305:Diet, High-Fat; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*
D016207:Cytokines; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase