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Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

ABSTRACT: Adaptation of liver to the postprandial state requires coordinate regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR-signaling, Xbp1-splicing, increased expression of ER-stress genes and phosphatidylcholine synthesis, which translate into a rapid morphological ER-remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increase upon nutrient supply. Sensory food perception activates POMC-neurons in the hypothalamus, optogenetic activation of POMC-neurons activates hepatic mTOR-signaling and Xbp1-splicing and lack of MC4R-expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinatly primes postprandrial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s-axis

ORGANISM(S): Mus musculus

PROVIDER: GSE118973 | GEO | 2018/10/31

REPOSITORIES: GEO

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Glycogen Metabolism Drives Sensory Activation of Pomc Neurons

Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.

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2024-03-28 | PXD044227 | Pride

Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

Project description:Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

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2024-02-12 | GSE248391 | GEO

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XBP1 coregulates unfolded protein response, acute phase response and DNA damage response during mouse liver regeneration

Project description:Partial hepatectomy (PH) imposes increased protein synthesis demands on remaining hepatocytes. Activation of IRE1α, a key sensor of endoplasmic reticulum (ER) stress, elicits XBP1 mRNA splicing and production of XBP1 protein, a main trigger of the unfolded protein response (UPR). Using genome-wide ChIPseq analysis we have explored the role of XBP1 during liver regeneration. XBP1 was induced in liver at 6h after PH in an IL-6 dependent manner. After PH, XBP1 silencing caused persistent ER stress, defective acute phase response (APR), increased hepatocellular damage and regenerative delay. At 6h post-PH, XBP1 bound an increased number of genes implicated in proteostasis, APR, metabolism, antioxidant defense and DNA damage response (DDR). ). XBP1 was linked to regulatory sequences containing canonical UPR motifs as well as motifs characteristic of other nuclear factors suggesting molecular interactions during liver regeneration. Upon PH, XBP1 bound the promoter of STAT3, a molecule downregulated in XBP1-silenced livers. XBP1 was indispensable for ser727-STAT3 phosphorylation, a post-translational modification implicated in cell proliferation and DNA damage repair. During active DNA replication XBP1 deficient livers showed high levels of the DNA double-strand break marker γ-H2AX, in association with defective upregulation of Eme1 and Fen1, two main executors of DDR. In conclusion, XBP1 is induced after PH and co-regulates UPR, APR and DDR during liver regeneration.

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2021-08-11 | GSE157117 | GEO

CARM1 determines endoplasmic reticulum stress response by controlling XBP1 in ovarian cancer [RNA-seq]

2021-08-11 | GSE157116 | GEO

The IRE1α/XBP1 pathway expression is impaired in pediatric cholestatic liver disease explants

Project description:Background/Aims: Cholestatic liver diseases (CLD) are the leading indication for pediatric liver transplantation. Increased intrahepatic bile acid concentrations cause endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) is activated to maintain homeostasis. UPR dysregulation, including the inositol-requiring enzyme 1α/X-box protein 1 (IRE1α/XBP1) pathway, is associated with several adult liver diseases. We evaluated hepatic UPR expression in pediatric patients with end-stage CLD and hypothesize that an inability to appropriately activate the hepatic IRE1α/XBP1 pathway is associated with the pathogenesis of CLD. Methods: We evaluated 34 human liver explants. Cohorts included: pediatric CLD (Alagille, ALGS, and progressive familial intrahepatic cholestasis, PFIC), pediatric non-cholestatic liver disease controls (autoimmune hepatitis, AIH), adult CLD, and normal controls. We performed RNA-seq, quantitative PCR, and western blotting to measure expression differences of the hepatic UPR and other signaling pathways. Results: Metascape pathway analysis demonstrated that the KEGG ‘protein processing in ER’ pathway was downregulated in pediatric CLD compared to normal controls. Pediatric CLD had decreased hepatic IRE1α/XBP1 pathway gene expression and decreased protein expression of p-IRE1α compared to normal controls. These CLD changes were not disease-specific to ALGS or PFIC. IRE1α/XBP1 pathway gene expression was decreased in pediatric CLD compared to AIH disease controls. Conclusion: Pediatric CLD explants have decreased gene and protein expression of the protective IRE1α/XBP1 pathway and down-regulated KEGG protein processing in the ER pathways. IRE1α/XBP1 pathway expression differences occur when compared to both normal and non-cholestatic disease controls. Attenuated expression of the IRE1α/XBP1 pathway is associated with cholestatic diseases and could be targeted to treat pediatric CLD.

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