In the context of obesity and glucose homeostasis, the protein kinase C (PKC) family of lipid-activated kinases is largely viewed as a class of pathogenic enzymes that interfere with proximal insulin signalling. This is exemplified by PKC epsilon (PKCe) which has been reported to phosphorylate the insulin receptor and impair insulin action directly in the liver. However, studies of mice with whole body or tissue-specific deletion of PKCe indicate the importance of other mechanisms. We showed that liver-specific deletion of PKCe does not protect against glucose intolerance in fat-fed mice, but deletion either in adipose tissue or in AgRP neurons of the hypothalamus provides partial protection, with evidence of crosstalk with the liver. In addition, this does not involve changes in insulin sensitivity measured during euglycaemic-hyperinsulinaemic clamps. Together with the broader PKC literature indicating that these kinases are regulators of metabolism at many levels, these findings transcend the oversimplified concept that PKC action is detrimental to insulin signalling.