Differential regulation of the unfolded protein response in outbred deer mice and susceptibility to metabolic disease

Endoplasmic reticulum (ER) stress has been causatively linked to the onset of various pathologies. However, whether and how inherent variations in the resulting unfolded protein response (UPR) affect predisposition to ER-stress-associated metabolic conditions remains to be established. By using genetically diverse deer mice (Peromyscus maniculatus) as a model, we show that the profile of tunicamycin-induced UPR in fibroblasts isolated at puberty varies between individuals and predicts deregulation of lipid metabolism and diet-induced hepatic steatosis later in life. Among the different UPR targets tested, CHOP (also known as Ddit3) more consistently predicted elevated plasma cholesterol and hepatic steatosis. Compared with baseline levels or inducibility, the maximal intensity of the UPR following stimulation best predicts the onset of pathology. Differences in the expression profile of the UPR recorded in cells from different populations of deer mice correlate with the varying response to ER stress in altitude adaptation. Our data suggest that the response to ER stress in cultured cells varies among individuals, and its profile early in life might predict the onset of ER-stress-associated disease in the elderly. This article has an associated First Person interview with the first author of the paper.