Endoplasmic Reticulum Stress Links Obesity, Insulin and Type 2 Diabetes

The investigators examined the molecular mechanisms of the metabolic (or dysmetabolic) syndrome of obesity, insulin resistance, hypertension and type 2 diabetes mellitus. Obesity results in “cellular stress” or metabolic dysfunction leading to insulin resistance, the mechanism(s) of which is unknown. The authors hypothesized that the endoplasmic reticulum (ER), the intracellular site of protein synthesis, may be insulted (ie, stressed) by obesity. This leads to the production of misfolded or unfolded proteins that accumulate in ER tubules and impair ER function. In reaction, the cell mounts an “unfolded protein response” (UPR) composed of increased activity of the pancreatic ER kinase (PERK) that phosphorylates eIF2α, the α subunit of translation initiation factor 2, c-Jun N-terminal kinase (JNK) - a serine phosphorylase, and glucose-regulated/binding immunoglobulin protein (GRP78). Obesity, whether dietary or genetic (ob/ob), results in increased hepatic and adipose tissue levels of phosphorylated PERK and eIF2α and JNK and GRP78 consistent with ER stress. The investigators then demonstrated that ER stress interfered with insulin action by decreasing insulin-stimulated phosphorylation of tyrosine-bearing insulin receptor substrate-1 (IRS1). This leads to propagation of the insulin signal by increasing serine phosphorylation of IRS1 through increased JNK activity; serine phosphorylation inhibits IRS1 propagation of intracellular insulin receptor signaling. The authors also demonstrated the important role of inositol-requiring kinase-1α (IRK1α) in activating (phosphorylating) JNK and serine phosphorylation of IRS1 and consequent inhibition of insulin action.

X-box-binding protein-1 (XBP1) is a transcription factor that regulates several genes that are altered in ER stress. In XBP^-/- cells in vitro, PERK phosphorylation, JNK activation, and serine phosphorylation of IRS1 were increased and insulin stimulated tyrosine phosphorylation of IRS1 was depressed. In XBP^+/- mice in vivo (XBP^-/- mice are not viable), there is impaired glucose metabolism. XBP^+/- mice fed a high fat diet developed hyperglycemia, glucose intolerance, and hyperinsulinemia consistent with insulin resistance, whereas XBP^+/+ mice did not. Molecular studies revealed elevated hepatic levels of phosphorylated PERK and JNK activity as well as increase in serine-phosphorylated IRS1. The insulin stimulated intracellular signaling cascade was suppressed in XBP^+/- mice fed a high fat diet. Thus, decrease in XBP1 activity leads both to decreased insulin action (down regulation of tyrosine phosphorylation of IRS1) and increased insulin resistance (up regulation of serine phosphorylation of IRS1). The authors concluded that obesity leads to ER stress resulting in decreased insulin action and hence insulin resistance and hyperglycemia.

No stress relief for the ER. The metabolic and inflammatory stresses of obesity disrupt the smooth operation of the ER and cause protein misfolding. The ER attempts to cope with stress by activating XBP-1, a transcriptional regulator of the unfolded protein response (UPR). If these responses fail to restore homeostasis, stress-induced IRE1 activates JNK1, a serine kinase that opposes insulin action. Impaired insulin signaling might serve to alleviate intracellular stress, but it does so at the expense of systemic glucose regulation. FFA, free fatty acids; ROS, reactive oxygen species.
CREDIT: KATHARINE SUTLIFF/SCIENCE

Editor’s Comment: The concept of endoplasmic reticular stress was a novel one to this writer. The ER is the cytoplasmic network of organelles (microsomes) in which translation of messenger (m)RNA to encoded protein occurs, and where the “naked” protein is subsequently modified to produce the mature 3-dimensional (glycosylated, phosphorylated, etc.) protein product. That it could come under “stress” was a provocative but perfectly reasonable thought. The current data offer a reasonable molecular explanation for the pathways through which obesity brings about insulin resistance. At the level of IRS1, insulin action is regulated by the “yin and yang” of whether IRS1 is phosphorylated on its tyrosine (activating) or serine (inactivating) residues and obesity-induced ER stress favors the latter. The data do not explain the initiating event(s) that brings about this sequence of adverse metabolic effects. Just how does obesity down regulate XBP1 function? Inflammatory stress mediated by tumor necrosis factor-α also activates JNK1 thereby increasing serine phosphorylation of IRS1. In this regard, these observations complement the review of the role of infection in the development of obesity published in Growth Genetics & Hormones.¹ The readers are strongly urged to read the paper by Ozcan and colleagues in its entirety and the accompanying commentary by Muoio and Newgard² that discusses the role that inflammatory cytokines may play in the genesis of insulin resistance.


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