Potential role of dietary fat‐ and obesity‐sensitive adipose PKCbeta signaling in pathophysiology of adipose dysfunction

Abstract

Excess delivery of nutrients to adipose tissue in obesity results in an increase in adipose tissue mass, followed by an increase in stress signals, and thereby an altered production of proinflammatory adipokines, ultimately leading to the progression of chronic inflammation and development of insulin‐resistance. Although the features of chronic inflammation in obese adipose tissue are clearly defined, the signals and mechanisms that trigger chronic inflammation (origin or mechanism of initiation of inflammatory signaling) and maintenance are not well understood and remains a critical area of research. There is clear evidence that the inflammatory trigger is metabolic and a strong correlation between adipocyte size and macrophage infiltration has also been reported. Importantly, specialized metabolic cells (such as adipocytes) are the cells that sustain the insult and whose expansion begins the inflammatory program. Accordingly, adipocyte hypertrophy and local hypoxia are implicated in immune cell infiltration, cytokine secretion and disruption of different signaling cascades. Our recent study suggested that protein kinase C beta (PKC beta) might be a pivotal protein regulating triglyceride storage and could be a target for the pathogenesis of adipose dysfunction in response to nutritional changes. Accordingly, a systemic PKC beta deficiency protects mice from diet‐induced adiposity and development of insulin‐resistance. To determine how PKC beta deficiency exerts its effect, we determined high‐fat diet‐PKC beta interaction and the impact of PKC beta deficiency on relevant adipose signaling pathways and metabolism. Here, we report that dietary fat strongly increased adipose PKC beta expression in a time‐dependent manner. The induction was observed at 2–6 weeks, peaked at 10 weeks, and remained elevated for at least 16 weeks (the last time point measured). We and others have reported involvement of PKC beta in regulating phosphorylation of retinoblastoma, I kappa b kinase, insulin‐receptor substrate, and p66shc, as well as dictates autophagy levels, we therefore compared changes in phosphorylation of these proteins and autophagy levels in different adipose tissues of above mice. The time‐dependent changes were also compared using adipose tissues from PKC beta‐deficient mice fed same high‐fat diet for identical periods. The available results support the possibility that adipocyte PKC beta is a key sensor to detect dangerous dietary signal, whose activation initiates adipose inflammation by sequential events consisting of PKC beta‐induced changes, thus mediating the interface between metabolic input and inflammatory output in the expanding adipose tissue. This study opens the possibility that modulation of PKC beta activity in the adipose tissue may be an effective approach to attenuate adipose dysfunction.Support or Funding InformationHL079091