Obesity leads to chronic, low-grade local inflammation in the liver and adipose tissue. This local inflammation eventually results in insulin resistance and the development of type 2 diabetes. American researcher Jonathan Mowers and his team1 explored the complex molecular pathways linking obesity, inflammation and diabetes. Their investigation identified two potential therapeutic targets.

Previously, these researchers observed that mRNA and protein expression levels of protein kinases IKKe and TBK1 were increased in adipose tissue from mice fed a high fat diet. This paper describes their exploration of the roles of these kinases in adipocytes and how they influence energy metabolism in these cells. The researchers conducted a number of experiments using adipose cell lines, co-expressed recombinant proteins, immunoprecipitation, kinase assays and LC-MS/MS. Some of their findings are as follows:

  • They observed that protein levels of IKKe and TBK1 were increased in TNFa-stimulated cells grown in culture.
  • They identified potential members of the IKKe signalling pathway and determined that IKKe overexpression represses lipolytic signalling through the b-adrenergic/cAMP pathway.
  • They determined that PDE3B, a phosphodiesterase, is a likely substrate of IKKe and TBK1.
  • They co-expressed the kinases and PDE3B, selectively immuno-enriched for PDE3B and then identified the phosphorylation sites using LC-MS/MS. They demonstrated that IKKe and TBK1 phosphorylate PDE3B on seven different serine residues.
  • The researchers created a PDE3B mutant by changing one of the phosphorylation sites from a serine to an alanine. This helped them determine that phosphorylation of PDE3B at this site is necessary for physiological activity of this protein.

This paper illustrates how difficult it is to delineate the different components of a signalling pathway. From the many different experiments conducted as part of this study, the researchers showed that the kinases IKKe and TBK1 are part of the molecular pathway that responds to adipocyte inflammation. They suggest that PDE3B is a physiological target of IKKe and TBK1, that it is phosphorylated on serine 318, and that it plays a role in cAMP regulation. In conclusion, they suggest that inhibiting IKKe and TBK1 may help treat obesity and type 2 diabetes

  1. Mowers J, Uhm M, Reilly SM, et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1. Elife. 2013 Dec 24;2:e01119. doi: 10.7554/eLife.01119.