Endoplasmic Reticulum Stress and the Unfolded Protein Response in Lipid Metabolism and Obesity

Disruptions in endoplasmic reticulum (ER) homeostasis lead to ER stress and activation of the unfolded protein response (UPR), which are implicated in the pathogenesis of many diseases including obesity and type 2 diabetes. In recent years, the ER stress sensors (IRE1α, PERK, and ATF6) and UPR target genes such as XBP1 have been assigned novel functions in the regulation of lipogenesis. Transgenic mouse models and tissue-specific loss of ER stress sensors/UPR target genes have led to identification of the importance of UPR activation in maintaining lipid and energy homeostasis under physiological and pathological conditions. Furthermore, the role of UPR pathways in adaptation to severe or persistent ER stress conditions, and their impact on development of obesity, diabetes, and hepatic steatosis, has been demonstrated. In the present chapter, the role of ER stress/UPR activation and alterations in specific UPR genes in the context of obesity, lipid metabolism, and fatty liver will be discussed.