Insulin signaling and insulin sensitizing in muscle and liver of obese monkeys: peroxisome proliferator-activated receptor gamma agonist improves defective activation of atypical protein kinase C.
Obesity, the metabolic syndrome, and aging share several pathogenic features in both humans and non-human primates, including insulin resistance and inflammation. Since muscle and liver are considered key integrators of metabolism, we sought to determine in biopsies from lean and obese aging rhesus monkeys the nature of defects in insulin activation and, further, the potential for mitigation of such defects by an in vivo insulin sensitizer, rosiglitazone, and a thiazolidinedione activator of the peroxisome proliferator-activated receptor gamma. The peroxisome proliferator-activated receptor gamma agonist reduced hyperinsulinemia, improved insulin sensitivity, lowered plasma triglycerides and free fatty acids, and increased plasma adiponectin. In muscle of obese monkeys, previously shown to exhibit defective insulin signaling, the insulin sensitizer improved insulin activation of atypical protein kinase C (aPKC), the defective direct activation of aPKC by phosphatidylinositol (PI)-3,4,5-(PO₄)₃, and 5'-AMP-activated protein kinase and increased carnitine palmitoyltransferase-1 mRNA expression, but it did not improve insulin activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase (IRS-1/PI3K), protein kinase B, or glycogen synthase. We found that, although insulin signaling was impaired in muscle, insulin activation of IRS-1/PI3K, IRS-2/PI3K, protein kinase B, and aPKC was largely intact in liver and that rosiglitazone improved insulin signaling to aPKC in muscle by improving responsiveness to PI-3,4,5-(PO₄)₃.
Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Heidi K
HK
Ortmeyer
Mini P
MP
Sajan
Atsushi
A
Miura
Yoshinore
Y
Kanoh
Jose
J
Rivas
Yongxiang
Y
Li
Mary L
ML
Standaert
Alice S
AS
Ryan
Noni L
NL
Bodkin
Robert V
RV
Farese
Barbara C
BC
Hansen
D000818:Animals; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; D047495:PPAR gamma; C115015:PKC-3 protein; D011493:Protein Kinase C