Role of adipose and hepatic atypical protein kinase C lambda (PKCλ) in the development of obesity and glucose intolerance

Abstract

PKCλ, an atypical member of the multifunctional protein kinase C family, has been implicated in the regulation of insulin-stimulated glucose transport and of the intracellular immune response. To further elucidate the role of this cellular regulator in diet-induced obesity and insulin resistance, we generated both liver (PKC-Alb) and adipose tissue (PKC-Ap2) specific knockout mice. Body weight, fat mass, food intake, glucose homeostasis and energy expenditure were evaluated in mice maintained on either chow or high fat diet (HFD). Ablation of PKCλ from the adipose tissue resulted in mice that were indistinguishable from their wild-type littermates. However, PKC-Alb mice were resistant to diet-induced obesity (DIO). Surprisingly this DIO resistance was not associated with either a reduction in caloric intake or an increase in energy expenditure as compared with their wild-type littermates. Furthermore, these mice displayed an improvement in glucose tolerance. When maintained on chow diet, these mice were similar to wild types in respect to body weight and fat mass, yet insulin sensitivity was impaired compared with wt littermates. Taken together these data suggest that hepatic PKCλ is modulating insulin-mediated glucose turnover and response to high fat diet feeding, thus offering a deeper understanding of an important target for anti-obesity therapeutics.

Impairment of insulin-stimulated glucose transport and ERK activation by adipocyte-specific knockout of PKC-λ produces a phenotype characterized by diminished adiposity and enhanced insulin suppression of hepatic gluconeogenesis

“…It may be noted that AλKO mice, derived from the same line of PKC-λ-floxed mice used in our study, have also been studied by another group, 20 and, as in our study, were found to have normal glucose tolerance and a trend to diminished food intake. These AλKO mice were also found to have energy expenditure, respiratory quotients, and locomoter activity indistinguishable from that of wild-type mice 20 .…”

TGF-β receptor 1 regulates progenitors that promote browning of white fat

“…aP2-Cre mice have been generated by at least four independent laboratories and widely used in studies targeting adipose tissue in vivo [30] that resulted in seminal findings about the adipose-tissue specific roles of several key genes, including the insulin receptor (FIRKO mouse), Glut4 , PKC λ, etc. [1] , [6] , [19] , [30] , [52] . Over the past few years, studies have reported the observations of aP2-Cre activity in other cell types.…”

Circulating HDL levels control hypothalamic astrogliosis via apoA-I

“…Plasma cholesterol levels were determined using the Infinity cholesterol kit (Thermo Scientific Inc., Rockford, IL) as described (16). An intraperitoneal pyruvate tolerance test was conducted by injection of sodium pyruvate (2 g/kg; Sigma-Aldrich, St. Louis, MO) in 0.9% w/v NaCl, as described previously (17). Tail blood glucose levels (milligrams per deciliter) were measured with a TheraSense Freestyle glucometer (Abbott Diabetes Care, Inc., Alameda, CA) before (0 min) and at 15, 30, 45, 60, and 120 min after injection.…”