Editors' ChoiceMetabolism

Do Pathogen Sensors Make You Fat?

Sci. Signal.  09 Feb 2010:
Vol. 3, Issue 108, pp. ec47
DOI: 10.1126/scisignal.3108ec47

Inflammation and cellular stress responses occur in metabolic diseases, such as obesity and type 2 diabetes. Nakamura et al. looked for molecules involved in pathogen sensing that also regulated metabolism. They found that the double-stranded RNA-dependent protein kinase (PKR) was activated in mice by metabolic stress, whether it was caused by genetically induced obesity or a high-fat diet. Treatment with palmitic acid (a free fatty acid that can trigger insulin resistance in vivo) activated PKR in mouse embryonic fibroblasts (MEFs). PKR can activate c-Jun N-terminal kinase (JNK), which in turn phosphorylates insulin receptor substrate 1 (IRS1) at Ser307, a phosphorylation event that inhibits insulin signaling. In wild-type MEFs exposed to palmitic acid or thapsigargin [an agent that causes endoplasmic reticulum (ER) stress], JNK activity and phosphorylation of Ser307 in IRS1 were higher than in MEFs deficient in PKR kinase activity (Pkr–/–), and activation of PKR by palmitic acid or thapsigargin required its ability to bind to RNA. Pkr–/– mice gained less weight on a high-fat diet than did wild-type mice; furthermore, serum leptin and blood glucose concentrations, liver triglyceride content, and mRNA abundance in white adipose tissue for various inflammatory cytokines were lower in Pkr–/– mice compared with wild-type mice. Pkr–/– mice also showed greater insulin sensitivity and higher glucose disposal rates in response to lipid infusion than wild-type mice. Thus, PKR integrates responses to pathogens, nutrients, and ER stress, and manipulation of its activity in vivo may represent a possible therapeutic approach to treating metabolic diseases.

T. Nakamura, M. Furuhashi, P. Li, H. Cao, G. Tuncman, N. Sonenberg, C. Z. Gorgun, G. S. Hotamisligil, Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140, 338–348 (2010). [Online Journal]