Glucagon-like Peptide-2 Acts through Central GLP-2R and MC4R in Mobilizing Stored Lipids from the Intestine
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ABSTRACT:
PROVIDER: PRJNA1208518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31944300_1.fastq.gz | Fastqsanger.gz | |||
| SRR31944300_2.fastq.gz | Fastqsanger.gz | |||
| SRR31944301_1.fastq.gz | Fastqsanger.gz | |||
| SRR31944301_2.fastq.gz | Fastqsanger.gz | |||
| SRR31944302_1.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulated gut lipid handling contributes to atherogenic dyslipidemia, a cardiovascular disease risk factor for patients with diabetes. The gut hormone glucagon-like peptide-2 (GLP-2) plays significant roles in intestinal lipid handling. In post-absorptive state, GLP-2 mobilizes pre-formed chylomicrons that are stored in the intestine from previous meals, the mechanisms of which are not fully understood. Our previous study demonstrated the involvement of a gut-brain neural pathway in this effect, but the key components of this pathway remain unknown. Here, we evaluated central GLP-2 receptor (GLP-2R) and melanocortin 4 receptor (MC4R) as important players in the pathway. Mesenteric lymph duct cannulated rats received intracerebroventricular infusion of a GLP-2R antagonist (GLP-2(11-33)), an MC4R antagonist (SHU9119), or saline as control. Post-absorptive lipid output from the intestine in response to peripheral GLP-2 was assessed. Spatial transcriptomics analysis was performed to determine the changes in mRNA expression among treatment groups. Blockade of central GLP-2R or MC4R attenuated the effects of GLP-2 in stimulating lymph triglyceride output. Treatments differentially affected key genes in jejunal endothelial cells, smooth muscle cells and neuronal cells. These results support the critical roles of central GLP-2R and MC4R in a neural pathway for peripheral GLP-2 in mobilizing lipids stored in the intestine during post-absorptive state.
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Project description:Human MC4R mutations can increase or decrease obesity risk. Other than intracellular signaling, MC4R function is also influenced by its levels. However, the genetic programs that govern MC4R transcription in the brain remain largely unknown. Moreover, it is unclear whether human genetic variants exist that affect Mc4r expression and obesity risk. Here, we identify the homeodomain transcription factor Otp as one regulator of Mc4r expression in a specific subset of hypothalamic neurons. Selective loss of Otp in these neurons during development or adulthood results in reduced Mc4r expression and excessive body weight gain. Moreover, OTP interacts with upstream regulatory sequences of Mc4r to modulate its transcription.
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Project description:Human MC4R mutations can increase or decrease obesity risk. Other than intracellular signaling, MC4R function is also influenced by its levels. However, the genetic programs that govern MC4R transcription in the brain remain largely unknown. Moreover, it is unclear whether human genetic variants exist that affect Mc4r expression and obesity risk. Here, we identify the homeodomain transcription factor Otp as one regulator of Mc4r expression in a specific subset of hypothalamic neurons. Selective loss of Otp in these neurons during development or adulthood results in reduced Mc4r expression and excessive body weight gain. Moreover, OTP interacts with upstream regulatory sequences of Mc4r to modulate its transcription.
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Project description:We analysed the effect of the deficiency Df(2R)ED3921 and Df(2R)ED50000 on gene expression in embryos (stage 0-11), and wing imaginal discs and brains from 3rd instar larvae. Df(2R)ED3921 and Df(2R)ED50000 were described in Ragab et al. (2005) Genetics 172:1069-1078 2005. RNA from Df(2R)ED3921 and Df(2R)ED50000 embryos was compared to a pool of RNA extracted from wild-type embryos at the same stage. For each genotype, 4 independent biological replicates were performed (2 of these dyes swapped with respect to the other two). The same experimental protocol and genotypes were used for the analysis in dissected wing imaginal discs and brains from 3rd instar larvae.
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Project description:ObjectiveGlucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown.MethodsWe investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of Tgr5, Glp2r, and Glp1r was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, Glp2r-/- and Tgr5-/- mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized ex vivo.ResultsAcute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous Glp2r in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in Tgr5-/- mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in Glp2r-/- but not in Tgr5-/- mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM ex vivo, in a tetrodotoxin-sensitive manner.ConclusionsOur data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease.
| S-EPMC5444019 | biostudies-literature