Mice with global deficiency in protein kinase C epsilon (PKCε) are strongly protected against high fat diet (HFD)-induced glucose intolerance. Improved suppression of hepatic glucose output (HGO) has shown to be a major effect, which leads to the proposal that the kinase inhibits proximal insulin signalling in the liver.
To compare the direct and indirect effects of PKCε, we used “floxed” PKCε mice to generate whole body-, liver- and adipose tissue-specific PKCε knockout (KO) mice, and examined glucose tolerance, as well as insulin action during euglycaemic-hyperinsulinaemic clamps, following chow or HFD for up to 16 weeks. Adipose tissue mRNA was analysed by RT-PCR and Affymetrix gene array. The conditioned media proteome from adipose tissue explants, subjected to normoxia or hypoxia, or from mice fed a HFD, was analysed by mass spectrometry.
Surprisingly, liver-specific PKCε KO did not recapitulate the protective effects of global PKCε KO on glucose homeostasis in fat-fed mice. In contrast, adipocyte-specific PKCε KO did improve glucose tolerance and partly improved the suppression of HGO. Further examination showed that despite a lack of alteration in the key enzymes of proteins of lipid metabolism and inflammation of the adipose tissue, there was a widespread upregulation of genes involved in the complement and coagulation cascade in the fat-fed adipose-specific PKCε KO. Conditioned media from adipose tissue explants inhibited insulin signalling in cultured hepatocytes, and proteomic analysis of this media indicated alterations in several proteins of the complement and coagulation cascade.
Collectively, our in vivo and in vitro data suggest a role for PKCε in diet-induced insulin resistance mediated in adipose tissue but not directly in liver, possibly through alterations in the secretion of proteins of the complement and coagulation cascade, which in turn leads to a beneficial crosstalk with the liver.