Deletion of brain-specific isoforms of adapter protein SH2B1 protects mice from obesity in a non-leptin-mediated manner
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ABSTRACT:
PROVIDER: PRJNA606294 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11074549_1.fastq.gz | Fastqsanger.gz | |||
| SRR11074549_2.fastq.gz | Fastqsanger.gz | |||
| SRR11074550_1.fastq.gz | Fastqsanger.gz | |||
| SRR11074550_2.fastq.gz | Fastqsanger.gz | |||
| SRR11074551_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Obesity is associated with increased ovarian inflammation and the establishment of local leptin resistance. We presently investigated the role of leptin signalling on Nod-Like Receptor Protein 3 (NLPR3) inflammasome and macrophage prevalence in the pathophysiology of ovarian failure of obese mice. Methods: We collected ovaries from: (i) diet induced obese (DIO) mice fed chow diet (CD) or high-fat diet (HFD) for 4 or 16 weeks (wk); (ii) mice lacking the long-isoform of leptin receptor (ObRb; db/db); (iii) mice lacking leptin (ob/ob); and (iv) pharmacologically hyperleptinemic (LEPT) mice for protein and mRNA expression analysis. Next, granulosa cells (GCs) from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Results: We observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice, as well as in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob -/- and 16 wk HFD mice. Transcriptional analysis revealed opposing profiles between genetic models, with genes associated with steroid metabolism and prostaglandin action in db/db mice and genes controlling extracellular matrix in ob/ob mice being downregulated, despite both processes being crucial for follicular development and ovulation. Conclusions: Leptin signalling regulated NLRP3 inflammasome activation and expression of M1 markers in ovaries of obese mice, in an ObRb-dependent and -independent manner. Absence of changes in the expression of leptin signalling and proinflammatory mediators in GCs from db/db and ob/ob mice was associated with impaired folliculogenesis.
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Project description:Undernutrition increases susceptibility to diarrheal diseases. The adipocytokine leptin imparts protection from amebiasis. We tested the role of leptin signaling in cellular resistance to E. histolytica cytotoxicity in HEK cells transfected to express the leptin receptor. Protection from amebic killing was conferred by the leptin receptor. It required activation of the transcriptional regulator STAT3 by the leptin receptor, as mutation of the STAT3 activation domain of the receptor, or addition of a STAT3 small-molecule inhibitor, reversed protection. In contrast, a leptin receptor containing a common polymorphism (Q223R) known to increase susceptibility to amebiasis in humans provided significantly less protection. Consistent with the importance of STAT3, the Q223R polymorphism decreased l leptin-dependent STAT3 activation by 21% relative to the WT receptor (P=0.035). Microarray analysis identified potential downstream effectors of STAT3-mediated protection, most importantly TRIB1 and SOCS3, which appear to having opposing roles in the regulation of E. histolytica induced apoptosis. Together these data demonstrated that leptin increased the resistance of host cells to E. histolytica cytotoxicity via a STAT3-dependent mechanism. Additionally we found that the Q223R polymorphism in the leptin receptor, known to increase susceptibility to E. histolytica infection, decreased STAT3 activation and decreased host resistance to amebic cytotoxicity. This is the first demonstration of a host-signaling pathway that restricts amebic pathogenesis. Additionally, this finding represents an important advance in our mechanistic understanding of the role of leptin in the relationship between undernutrition and increased susceptibility to infection.
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Project description:Genome wide association studies (GWAS) in obesity have identified a large number of noncoding loci located near genes expressed in the central nervous system. However, due to the difficulties in isolating and characterizing specific neuronal subpopulations, very few obesity-associated SNPs have been functionally characterized. Leptin responsive neurons in the hypothalamus are essential in controlling energy homeostasis and body weight. Here, we show that by combining FACS-sorting of leptin-responsive hypothalamic neuron nuclei with genomic approaches (RNA-seq, ChIP-seq, ATAC-seq), we can provide a comprehensive map of leptin-response specific regulatory elements, several of which overlap obesity-associated GWAS variants. Further demonstrating the robustness of our leptin-response neuron regulome, we functionally characterize a novel enhancer near Socs3, a leptin response-associated transcription factor. Combined, our results provide a comprehensive map of active genomic regions in leptin-responsive neurons and present a blueprint for functionally characterizing obesity-associated SNPs in the hypothalamus.
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Project description:Obesity induces profound transcriptome changes in adipocytes; recent evidence suggests that lncRNAs play key roles in this process. Here, we performed a comprehensive transcriptome study by RNA-Seq in adipocytes isolated from interscapular brown, inguinal and epididymal white adipose tissues in diet-induced obese mice. Our analysis reveals a set of obesity-dysregulated lncRNAs, many of which exhibit dynamic changes in fed vs. fasted state, potentially serving as novel molecular markers reflecting adipose energy status. Among the most prominent ones is Lnc-leptin, an lncRNA transcribed from an enhancer region upstream of Leptin. Expression of Lnc-leptin is sensitive to insulin and closely correlates to Leptin expression across diverse pathophysiological conditions. Functionally, induction of Lnc-leptin is essential for adipogenesis, and its presence is required for a loop formation between exon2 of Lnc-leptin and promoter of Leptin in mature adipocytes and the maintenance of Leptin expression in vitro and in vivo. Our study establishes Lnc-leptin as a new regulator of Leptin.
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