Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis

Cell Metabolism (Impact Factor: 17.57). 07/2014; 20(3). DOI: 10.1016/j.cmet.2014.06.002
Source: PubMed


The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.

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Available from: Kevin W Williams, Dec 16, 2014
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    • "This adaptive cellular response to food deprivation in AGRP neurons is different to what has been found using whole hypothalamus analysis, where UPR signaling has been primarily associated with overnutrition states (Ozcan et al., 2009). Interestingly, overexpression of Xbp1s in POMC neurons has been shown to facilitate the function of those neurons (Williams et al., 2014), and a similar effect may be operating in AGRP neurons. In addition, we found that anti-apoptotic pathways were also prominently increased in AGRP neurons during food-deprivation, which is also indicative of considerable cellular stress and the importance of protecting against cell death for this critical energy homeostasis neuron population. "
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