ER Stress in Adipocytes Inhibits Insulin Signaling, Represses Lipolysis, and Alters the Secretion of Adipokines Without Inhibiting Glucose Transport

Abstract

The endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK), which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signaling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulininduced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signaling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E beta-cells dependent on the degree of ER stress. It appears that ER stress in adipocytes might initially lead to changes resembling early prediabetic stages, which at least in part support the regulation of systemic energy homeostasis. ABSTRACTThe endoplasmic reticulum (ER) is the intra-cellular site, where secreted and membrane proteins are synthesized. ER stress and activation of the unfolded protein response (UPR) contribute to insulin resistance and the development of diabetes in obesity. It was shown previously in hepatocytes that the UPR activates c-jun N-terminal kinase (JNK) which phosphorylates insulin receptor substrate (IRS) proteins on serine residues thereby inhibiting insulin signal transduction. Here we describe how ER stress affects insulin signalling and the biological function of adipocytes. In addition to inhibition of IRS we found that ER stress downregulates the expression of the insulin receptor. Concomitantly, insulin-induced activation of Akt/PKB and of ERK1/2 was strongly inhibited. Ectopic expression of IRS1 or IRS2 strongly counteracted the inhibitory effect of ER stress on insulin signalling while pharmacological inhibition of JNK with SP600125 resulted only in a mild improvement. ER stress decreased the secretion of the adipokines adiponectin and leptin, but strongly increased secretion of IL-6. ER stress inhibited expression and insulin-induced phosphorylation of AS160, reduced lipolysis but did not inhibit glucose transport. Finally, supernatants collected from 3T3-L1 adipocytes undergoing ER stress improved or impaired proliferation when used to condition the culture medium of INS-1E -cells dependen...

Endothelial Cells From Visceral Adipose Tissue Disrupt Adipocyte Functions in a Three-Dimensional Setting: Partial Rescue by Angiopoietin-1

“…Notably, ER stress induces a decreased secretion of leptin and adiponectin, an alteration of insulin signaling and lipolysis, and inflammation in these cells (29). Here, we observed an ER stress in cocultured cells, which could be linked to the adipocyte dysfunctions.…”

Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

“…Second, recent evidence suggests that the UPR might participate in hepatic insulin resistance in different ways [24,25]. Third, ER stress is involved in adipose insulin resistance [26]. Finally, ER stress also leads to muscle insulin resistance [27].…”

From signal transduction to signal interpretation: An alternative model for the molecular function of insulin receptor substrates

“…The PKC family consists of 12 isoforms classified as follows: Atypical PKCs (ζ and λ), conventional PKCs (α, β and γ), novel PKCs (δ, ε, η and θ), and protein kinase Ns (PKN1, PKN2 and PKN3), from which PKCδ, PKCλ/ζ and PKCθ are known to target IRS. A well-studied case is the activation of JNK downstream of ER stress and the unfolded protein response (Ozcan et al, 2004;Xu et al, 2010). Obesity in humans and rodents was shown to be associated with the development of ER stress in hepatocytes and adipocytes leading to JNK-dependent phosphorylation/inhibition of IRS1 on Ser307 (Aguirre et al, 2000).…”

“…Grp78/Bip is an important component of the intra-cellular system that ensures homeostasis in the endoplasmic reticulum (ER). As described above, the accumulation of unfolded proteins in the lumen of the ER (ER stress) with concomitant activation of the unfolded protein response (UPR) has been described to underlie obesity-associated insulin resistance in hepatocytes and adipocytes (Ozcan et al, 2004;Xu et al, 2010) dependent on activation of JNK. It is therefore tempting to speculate that interaction between IRS and Grp78/Bip might physically link activation of the UPR with (the downregulation of) insulin signalling and that prevention of this interaction could specifically improve insulin sensitivity in fat or liver, respectively.…”

“…glucose transport. Cases in which insulin's ability to elicit biological effects in target cells does not correlate well with the amount of intra-cellular PKB/Akt activity have been reported (Hoehn et al, 2008;Whitehead et al, 2001;Xu et al, 2010). For example, the maximal effect of insulin on GLUT4 translocation in L6 myotubes was observed at concentrations where only 5% of the total Akt/PKB pool was phosphorylated (Hoehn et al, 2008) and we described that insulin-induced glucose transport can be normal in 3T3-L1 adipocytes at very low levels of Akt/PKB activation (Xu et al, 2010), indicating that yet undefined qualitative differences might exist.…”