Emerging role of protein kinase C in energy homeostasis: A brief overview

Abstract

Protein kinase C-β (PKCβ), a member of the lipid-activated serine/threonine PKC family, has been implicated in a wide range of important cellular processes. Very recently, the novel role of PKCβ in the regulation of triglyceride homeostasis via regulating mitochondrial function has been explored. In this review, I aim to provide an overview of PKCβ regarding regulation by lipids and recently gained knowledge on its role in energy homeostasis. Alterations in adipose PKCβ expression have been shown to be crucial for diet-induced obesity and related metabolic abnormalities. High-fat diet is shown to induce PKCβ expression in white adipose tissue in an isoform- and tissue-specific manner. Genetically manipulated mice devoid of PKCβ are lean with increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Available data support the model in which PKCβ functions as a "diet-sensitive" metabolic sensor whose induction in adipose tissue by high-fat diet is among the initiating event disrupting mitochondrial homeostasis via intersecting with p66(Shc) signaling to amplify adipose dysfunction and have systemic consequences. Alterations in PKCβ expression and/or function may have important implications in health and disease and warrants a detailed investigation into the downstream target genes and the underlying mechanisms involved. Development of drugs that target the PKCβ pathway and identification of miRs specifically controlling PKCβ expression may lead to novel therapeutic options for treating age-related metabolic disease including fatty liver, obesity and type 2 diabetes.

Keywords: High-fat diet; Insulin resistance; Mitochondrial function; Obesity; Signal transduction.

Figure 1

Domain composition of protein kinase C-β and its regulation at the transcriptional and posttranscriptional levels. A: Membrane-targeting modules (C1 and C2), pleckstrin homology domain, the pseudosubstrate region, the kinase core and the C-terminal tail; B: Schematic representation of promoter structure of protein kinase C-β gene. Approximate locations of known regulatory regions are indicated. ATP: Adenosine-5’-triphosphate; PHLPP: PH domain and leucine rich repeat protein phosphatases; PDK-1: 3-phosphoinositide-dependent protein kinase 1.

Figure 2

Proapoptotic signals, including reactive oxygen species, activate protein kinase C-β, which in turn phosphorylates p66^Shc at serine 36. Phosphorylated p66^Shc translocates to the inner mitochondrial membrane and acts as a redox enzyme to amplify oxidative stress by generating H₂O₂. Increased H₂O₂, in turn, causes opening of the mitochondrial permeability transition pore and apoptosis. Protein kinase C-β (PKCβ) activated by reactive oxygen species further induces p66^Shc phosphorylation. This event in turn perturbs mitochondria structure and function.