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Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (liver bulk RNA seq)

ABSTRACT: Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese mouse and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.

ORGANISM(S): Mus musculus

PROVIDER: GSE263187 | GEO | 2024/04/30

REPOSITORIES: GEO

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Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (pituitary scRNA seq)

Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.

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Project description:Nonalcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world’s population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD express normal or low body mass index; thus, the condition is called nonobese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in nonobese individuals. Furthermore, preclinical results from nonobese animal models with NAFLD are unclear. Gut microbiota and their metabolites in nonobese/lean NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora and intestinal metabolites in a nonobese NAFLD mouse model established using a methionine-choline deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16s RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes/Bacteroidota ratio was increased. g_Tuzzerella, s_Bifidobacterium pseudolongum and s_Faecalibaculum rodentium were the predominant species in nonobese NAFLD mice. Fecal metabolomics using LC-MS/MS revealed the potential biomarkers for the prognosis and diagnosis of nonobese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME and pantetheine 4'-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid and estriol. Our findings could be useful to identify and develop drugs to treat nonobese NAFLD and lean NAFLD.

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