Promoting Glucose Homeostasis with an ER Stress Response

Science Signaling  18 Oct 2011:
Vol. 4, Issue 195, pp. ec294
DOI: 10.1126/scisignal.4195ec294

Metabolic conditions such as obesity and diabetes can cause the accumulation of unfolded proteins and endoplasmic reticulum (ER) stress at the cellular level, which can trigger defects in glucose homeostasis at the organismal level. ER stress generates the spliced, active form of the transcription factor Xbp1s (X-box binding protein 1s), which then transcriptionally activates genes encoding factors involved in coping with ER stress. Lee et al. investigated the role of the stress-activated protein kinase (SAPK) p38, which is generally activated by various types of cellular stress, in regulating Xbp1s activity. In mouse embryo fibroblasts infected with an adenovirus encoding Xbp1s, Xbp1s protein abundance was increased by treatments that activated SAPKs, such as anisomycin. Anisomycin treatment increased the stability of Xbp1s mRNA and stimulated the phosphorylation of Xbp1s at Thr48 and Ser61, which promoted its nuclear translocation. The anisomycin-induced increase in Xbp1s protein abundance was blocked by treatments that reduced p38 activity, whereas expression of a constitutively active form of the kinase upstream of p38, MKK6 (MKK6Glu), increased Xbp1s protein abundance in the absence of anisomycin treatment. The abundance of Xbp1s increases in the liver when mice are refed after fasting, and p38 activity (as assessed by phosphorylation of p38) and phosphorylation of Xbp1s at Thr48 and Ser61 were increased in lean, but not obese, mice that were refed after fasting. Nuclear translocation of Xbp1s and the transcript abundance of the Xbp1s target gene Hspa5 were reduced in lean mice that had been treated with the p38 inhibitor before the fasting and refeeding paradigm. The activity of p38 was reduced in obese mice or mice fed a high-fat diet, and the metabolic status of ob/ob mice (a model for diabetes) was improved by injection with adenovirus expressing MKK6Glu to increase the activity of p38. In addition, the livers of ob/ob mice injected with MKK6Glu showed increased p38 activity, higher protein abundance of Xbp1s, increased phosphorylation of Xbp1s at Thr48 and Ser61, and reduced phosphorylation of inositol-requiring enzyme 1 α (IRE1-α), a marker of ER stress. Compared with ob/ob mice injected with LacZ-expressing adenovirus, ob/ob mice injected with MKK6Glu-expressing adenovirus exhibited enhanced signaling events downstream of the insulin receptor and decreased expression of genes encoding gluconeogenic enzymes in response to insulin infusions. Blood glucose concentrations were decreased by injecting ob/ob mice with an adenovirus expressing wild-type Xbp1s, but not one expressing a form of Xbp1s that could not be phosphorylated by p38 at the two residues required for nuclear translocation. Thus, p38 phosphorylation of Xbp1s is required for the nuclear translocation of Xbp1s during ER stress, and this pathway promotes glucose homeostasis and may be defective in obesity and diabetes.

J. Lee, C. Sun, Y. Zhou, J. Lee, D. Gokalp, H. Herrema, S. W. Park, R. J. Davis, U. Ozcan, p38 MAPK–mediated regulation of Xbp1s is crucial for glucose homeostasis. Nat. Med. 17, 1251–1260 (2011). [PubMed]