PKCzeta-regulated inflammation in the nonhematopoietic compartment is critical for obesity-induced glucose intolerance.
Obesity-induced inflammation is critical for the development of insulin resistance. Here, we show that genetic inactivation of PKCzeta in vivo leads to a hyperinflammatory state in obese mice that correlates with a higher glucose intolerance and insulin resistance. Previous studies implicated PKCzeta in the regulation of type 2 inflammatory responses in T cells. By using ex vivo and in vivo experiments, we demonstrate that although PKCzeta is involved in the alternative (M2) activation of macrophages, surprisingly, PKCzeta ablation in the nonhematopoietic compartment but not in the hematopoietic system is sufficient to drive inflammation and IL-6 synthesis in the adipose tissue, as well as insulin resistance. Experiments using PKCzeta/IL-6 double-knockout mice demonstrated that IL-6 production accounts for obesity-associated glucose intolerance induced by PKCzeta deficiency. These results establish PKCzeta as a critical negative regulator of IL-6 in the control of obesity-induced inflammation in adipocytes.
Lee
Sang Jun
SJ
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267, USA.
Kim
Ji Young
JY
Nogueiras
Ruben
R
Linares
Juan F
JF
Perez-Tilve
Diego
D
Jung
Dae Young
DY
Ko
Hwi Jin
HJ
Hofmann
Susanna M
SM
Drew
Angela
A
Leitges
Michael
M
Kim
Jason K
JK
Tschöp
Matthias H
MH
Diaz-Meco
Maria T
MT
Moscat
Jorge
J
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D018149:Glucose Intolerance / Q000209:etiology*; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D015850:Interleukin-6; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta