Coordinating Organismal Physiology Through the Unfolded Protein Response by R. Luke Wiseman & Cole M. Haynes

Author:R. Luke Wiseman & Cole M. Haynes
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

2.3 The UPR in Adipose Tissue

Adipose tissue is a type of connective tissue primarily composed of adipocytes specialized in storing excess fat in the form of triglycerides in lipid droplets. Apart from storing energy-rich fatty acids, adipose tissue is highly flexible in their storage and release by hormonal signals and energetic needs of the organism and thus maintains energy homeostasis. Insulin plays an important role in adipocyte metabolism and promotes synthesis and storage of triglycerides. When there is ample glucose supply in the circulation, high levels of circulating insulin bind to their receptors on adipocytes and signal cytosol to cell membrane translocation of glucose transporters (GLUT-4), which in turn enhances glucose flux into cells. Glucose undergoes glycolysis and produces dihydroxyacetone phosphate as intermediates, which serves as a substrate for triglycerides to be stored in adipocytes.

Whereas the uptake, esterification of fatty acids into triglycerides, their storage, and the consequential expansion of adipose tissue represent an adaptive response to over nutrition, its limitless expansion leads to obesity-related symptoms such as cardiovascular disease, insulin resistance, and type 2 diabetes (Gregor and Hotamisligil 2007). Furthermore, the IRE1α–XBP1, PERK–eIF2α, and ATF6α pathways play roles in adipogenesis and lipid accumulation. Among these UPR pathways, the inhibitory role of the PERK–eIF2α pathway was demonstrated, while IRE1α and ATF6α were shown to promote adipogenesis (Rutkowski et al. 2015). The presence of insulin resistance in obese conditions, which is a prominent symptom during ER stress, suggests that ER stress may be one cause of obesity. An examination of genetic or diet-induced (high-fat diet) obese mouse model indicated the activation of PERK and IRE1α by their phosphorylation, JNK activation, and elevated GRP78/BiP expression in adipose tissue of these mice compared to the lean mice suggested that obesity induces ER stress. In order to test the role of XBP1 in insulin signaling, XBP1 gain or loss of function models was established in mouse embryonic fibroblasts. Subsequent to insulin stimulation, a reduced level of tyrosine phosphorylation on the insulin receptor substrate 1 (IRS1) was evident in Xbp1 −/− fibroblasts with the concomitant increase in serine phosphorylation indicative of a compromised insulin signaling (Özcan et al. 2004). Besides modulating insulin signaling, XBP1 was also shown to control adipogenesis by regulating the WNT10b and β catenin (WNT/β) signaling. In preadipocytes, WNT/β-catenin suppresses adipogenic factors C/EBPα and PPARγ and hence maintains cells in an undifferentiated state. However, during adipogenesis, overexpression of XBP1s and C/EBPα is observed. Subsequently, XBP1s inhibits the transcription of WNT10b and simultaneously antagonizes the anti-adipogenic β-catenin signaling pathway, leading to an unrestrained adipogenesis (Cho et al. 2013).

Han et al. demonstrated the upregulation of canonical UPR markers in 3T3-L1 cells and suggested a physiological role of the UPR during adipogenesis (Han et al. 2013). During day 4 of adipogenesis, in addition to the adipocyte-specific gene expression, there was an increased level of phosphorylated and total eIF2α, phosphorylated and total IRE1α, spliced and native Xbp1, as well as CHOP. However, pharmacological induction of ER stress by Tm or by hypoxic conditions attenuated adipogenesis in spite of elevated eIF2α phosphorylation (Zhang et al.

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