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.

Download full-text


Available from: Kevin W Williams, Dec 16, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.
    Full-text · Article · Sep 2015 · eLife Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: Maintenance of organismal homeostasis depends on the integration of intracellular and external signals, involving the ability to detect molecular perturbations. An explosion of studies in model organisms indicates the occurrence of dynamic communication between alarm pathways engaged by protein-folding stress in neurons that activate adaptive programs in peripheral organs to control cellular proteostasis. Here we review emerging concepts that highlight the contribution of the proteostasis network to the regulation of several aspects of animal physiology through central integration of signals spanning multiple tissues and organs. These recent findings uncover a new layer of functional interrelation between cells that handle and orchestrate the global maintenance of the proteome at the organismal level in a cell-nonautonomous manner.
    No preview · Article · Aug 2014 · Trends in Cell Biology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in hypothalamic neurons are common features of obesity, resulting in leptin and insulin resistance. In this issue, Williams et al. (2014) demonstrate, for the first time, cell-nonautonomous UPR signaling between brain and liver in the context of glucoregulation.
    No preview · Article · Sep 2014 · Cell Metabolism
Show more