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Phosphoproteomics-directed manipulation reveals SEC22B as an hepatocellular signaling node governing metabolic actions of glucagon

ABSTRACT: The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmocotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little of how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we conducted in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. On pathway analysis of the thousands of phosphopeptides identified, we identified “vesicle transport” as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments revealed that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identified several protein binding partners of SEC22B affected by glucagon, some of which were only bound with SEC22B-S137 phosphorylation. In summary, here we demonstrate that phosphorylation of SEC22B is an hepatocellular signaling node mediating the metabolic actions of glucagon, and provide a rich resource for future investigations on the biology of glucagon action.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Ralf Schittenhelm

LAB HEAD: Adam Rose

PROVIDER: PXD049186 | Pride | 2024-08-29

REPOSITORIES: Pride

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			Action	DRS
	P1CH20190814_DIA_Phos_S1.raw	Raw
	P1CH20190814_DIA_Phos_S10.raw	Raw
	P1CH20190814_DIA_Phos_S11.raw	Raw
	P1CH20190814_DIA_Phos_S12.raw	Raw
	P1CH20190814_DIA_Phos_S13.raw	Raw

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Phosphoproteomics-directed manipulation reveals SEC22B as an hepatocellular signaling node governing metabolic actions of glucagon

Project description:The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmocotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little of how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we conducted in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. On pathway analysis of the thousands of phosphopeptides identified, we identified “vesicle transport” as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments revealed that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identified several protein binding partners of SEC22B affected by glucagon, some of which were only bound with SEC22B-S137 phosphorylation. In summary, here we demonstrate that phosphorylation of SEC22B is an hepatocellular signaling node mediating the metabolic actions of glucagon, and provide a rich resource for future investigations on the biology of glucagon action.

2024-08-30 | PXD052303 | Pride

Phosphoproteomics-directed manipulation reveals SEC22B as an hepatocellular signaling node governing metabolic actions of glucagon

2024-08-29 | PXD049203 | Pride

Glucagon contributes to liver zonation in mice [Gcg infusion]

Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.

2018-03-01 | GSE110673 | GEO

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Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice

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Transcriptome-Wide Analysis of PGC-1α-Binding RNAs Identifies Genes Linked to Glucagon Metabolic Action

Project description:PGC-1α is a transcriptional coactivator that controls expression of metabolic/energetic genes programming cellular responses to nutrient and environmental adaptations such as fasting, cold or exercise. Unlike most other coactivators, PGC-1α contains protein domains involved in RNA binding and processing such as serine/arginine (SR) and RNA Recognition (RRM) motifs. However, little is known regarding the specific RNAs that bind PGC-1α to possibly control specific metabolic and energetic functions. To address this, we have performed single-end enhanced crosslinking and immunoprecipitation (seCLIP)-based transcriptome-wide analysis to identify specific RNA sequences that bind to PGC-1α. Primary hepatocytes were used to perform seCLIP experiments with glucagon-induced endogenous PGC-1α. RNA sequencing reveals that a large fraction of the RNAs bound to PGC-1α were intronic sequences related to genes involved in transcriptional, signaling or metabolic function linked to glucagon and fasting responses, but were not the canonical direct transcriptional targets of PGC-1α, such as OXPHOS or gluconeogenic genes. Validation of this analysis confirmed that among the top scoring RNA sequences bound to PGC-1α were Sik1, Camk1d, Ppard, Klf15, Gfra1 and Slc25a25. PGC-1α depletion decreased a fraction of mRNA transcript levels of these glucagon-induced genes. Importantly, knock-down of these genes affected glucagon-dependent glucose production, a PGC-1α-regulated metabolic pathway. These studies show that PGC-1α largely binds to intronic RNA sequences, some of them controlling transcript levels associated with glucagon action.

2020-08-14 | GSE152303 | GEO

Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

Project description:Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

2024-06-11 | GSE243681 | GEO

Glucagon regulates Hepatic Kisspeptin1 to Impair Insulin Secretion in Diabetes Mellitus

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A glucagon variant, glucagon 1-61, identified in man, controls blood glucose through regulation of insulin secretion and hepatic glucose production

Project description:Glucagon is secreted from pancreatic α-cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma by high-resolution-proteomics, we identified several glucagon variants among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 was secreted in obese subjects before and as well after gastric bypass surgery with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β-cells demonstrated that PG 1-61 dose-dependently increased levels of cAMP, through the glucagon receptor, and increased insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. As a consequence, PG 1-61 increased blood glucose and plasma insulin and decreased plasma levels of amino acids in vivo. Glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

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A Metabolomic Signature of Glucagon Action in Healthy Individuals with Overweight/Obesity Humans

Project description:Objective: We sought to identify the circulating metabolites that would serve as markers of glucagon action. Design: In this study, we performed a continuous 72-hour glucagon infusion in healthy individuals with overweight/obesity. Participants were randomized to either glucagon (12.5 ng/kg/min) (GCG 12.5) or glucagon (25 ng/kg/min) GCG 25 or a placebo control were included. A comprehensive metabolomics analysis was then performed from plasma isolated at several time points during the infusion to identify markers of glucagon activity.

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