Metabolic functions of atypical protein kinase C: good and bad as defined by nutritional status

Farese RV, Sajan MP. Metabolic functions of atypical protein kinase C: good and bad as defined by nutritional status. Am J Physiol Endocrinol Metab 298: E385-E394, 2010. First published December 8, 2009; doi:10.1152/ajpendo.00608.2009.-Atypical protein kinase C (aPKC) isoforms mediate insulin effects on glucose transport in muscle and adipose tissues and lipid synthesis in liver and support other metabolic processes, expression of enzymes needed for islet insulin secretion and hepatic glucose production/release, CNS appetite suppression, and inflammatory responses. In muscle, selective aPKC deficiency impairs glucose uptake and produces insulin resistance and hyperinsulinemia, which, by activating hepatic aPKC, provokes inordinate increases in lipid synthesis and produces typical metabolic syndrome features. In contrast, hepatic aPKC deficiency diminishes lipid synthesis and protects against metabolic syndrome features. Unfortunately, aPKC is deficient in muscle but paradoxically conserved in liver in obesity and type 2 diabetes mellitus; this combination is particularly problematic because it promotes lipid and carbohydrate abnormalities. Accordingly, metabolic effects of aPKCs can be good or bad, depending upon nutritional status; thus, muscle glucose uptake, islet insulin secretion, hepatic glucose and lipid production/release, and adipose fat synthesis/storage would be important for survival during periods of limited food availability and therefore be good. However, during times of food surfeit, excessive activation of hepatic aPKC, whether caused by overnutrition or impairments in extrahepatic effects of insulin, would lead to inordinate increases in hepatic lipid synthesis and metabolic syndrome features and therefore be bad. In keeping with these ideas, the inhibition of hepatic aPKC markedly ameliorates lipid and carbohydrate abnormalities in experimental models of obesity and type 2 diabetes. We postulate that a similar approach may be useful for treating humans.