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Sci. Signal., 9 February 2010
Vol. 3, Issue 108, p. ec47
[DOI: 10.1126/scisignal.3108ec47]

EDITORS' CHOICE

Metabolism Do Pathogen Sensors Make You Fat?

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

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]

Citation: W. Wong, Do Pathogen Sensors Make You Fat? Sci. Signal. 3, ec47 (2010).



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