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High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

ABSTRACT: To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122279 | GEO | 2021/08/24

REPOSITORIES: GEO

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GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

Project description:A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

2020-07-11 | GSE154217 | GEO

Molecular data integration reveals Growth Hormone Receptor as an alternative candidate oncogenic signaling pathway in glioblastoma

Project description:Our laboratory has identified the Growth Hormone Receptor (GHR) as a candidate oncogenic pathway involved in GBM oncogenicity. In order to study further the role of GHR in GBM, we have generated GHR overexpressing patient-derived cell lines (PDCL) from PDCL established by GlioTEx team (Institut du Cerveau et de la Moelle, Paris, France). An analysis of the global proteome of each variant was then undertaken. The wild-type (GHR WT) and constitutively activated (GHR CA) GHR expression vectors were generous gifts from Mike Waters and Peter Brooks (University of Queensland, Australia). The constitutively activated GHR vector was generated by fusing the transmembrane and cytoplasmic domains of rabbit GHR (to ensure the absence of human GH stimulation) to Jun zippers in order to achieve GH-independent forced dimerization in absence of the extracellular domain. The control GFP vector was obtained from Addgene . These vectors were then inserted in lentiviral vectors. Cells were transduced with multiplicity of infection of 20 and transduced cells were selected with puromycin.

2022-06-23 | PXD004969 | Pride

Growth hormone resistance exacerbates cholestasis-induced murine liver fibrosis

Project description:Growth hormone (GH) resistance has been associated with liver cirrhosis in humans but its contribution to the disease remains controversial. In order to elucidate whether GH resistance plays a causal role in the establishment and development of liver fibrosis, or rather represents a major consequence thereof, we challenged mice lacking the Growth hormone receptor gene (Ghr-/-, a model for GH resistance) by crossing them with Mdr2 knockout mice (Mdr2-/-), a mouse model of inflammatory cholestasis and liver fibrosis. Ghr-/-;Mdr2-/- mice showed elevated serum markers associated with liver damage and cholestasis, extensive bile duct proliferation and increased collagen deposition relative to Mdr2 -/- mice, thus suggesting a more severe liver fibrosis phenotype. Additionally, Ghr-/-;Mdr2-/- mice had a pronounced down-regulation of hepato-protective genes Hnf6, Egfr and Igf-1, and significantly increased levels of ROS and apoptosis in hepatocytes, compared to control mice. Moreover, single knockout mice (Ghr-/-) fed with a diet containing 1% cholic acid displayed an increase in hepatocyte ROS production, hepatocyte apoptosis and bile infarcts compared to their wildtype littermates, indicating that loss of Ghr renders hepatocytes more susceptible to toxic bile acid accumulation. Surprisingly, and despite their severe fibrotic phenotype, Ghr-/-;Mdr2-/- mice displayed a significant decrease in tumour incidence compared to Mdr2-/- mice, indicating that loss of Ghr signaling may slow the progression from fibrosis/cirrhosis to cancer in the liver.

2020-06-20 | GSE58908 | GEO

Pathways involved in pony body size development

Project description:The mechanism of body growth in mammals is poorly understood. Here, we report the regulatory networks involved in body growth through analyzing transcriptomes of pituitary and epiphyseal tissues of Debao ponies and Mongolian horses at juvenile and adult stages. We found that GHR was expressed little in long bones though GH was highly expressed in Debao ponies compared with Mongolian horses. Moreover, m-RAS and ATF3, involved in the GHR pathway, were found to be significantly downregulated in juvenile ponies, which slowed the proliferation of bone osteocytes. However, WNT2 and PLCβ2 were obviously upregulated in juvenile Debao ponies, which led to premature mineralization of bone extracellular matrix. Furthermore, we found that the WNT/Ca2+ pathway may be responsible for the regulation of body growth. We then demonstrated that GHR was lacking in long bones of Debao ponies using RT-qPCR and Western blot. Treatment with WNT antagonist 1 decreased expression of the WNT pathway (P≤0.05) in vitro. The transduction of ATDC5 cells with GHR-RNAi lentivirus decreased expression of the GHR pathway (P≤0.05). Additionally, detection of plasma hormone concentrations showed that the ponies had higher levels of IGF-1 as juveniles and GH in adulthood than Mongolian horses, indicating that the hormone regulation in Debao ponies differs from that in Mongolian horses. Our work provides an insight into the genetic regulation for dwarf growth in mammals and a reference for therapeutic strategy for dwarfism

2021-01-27 | GSE146145 | GEO

Adult-onset loss of hepatocyte growth hormone receptor (GHR) signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance

Project description:RNA-seq analysis of livers from control mice, mice with adult onset, hepatocyte-specific GH receptor (GHR) deficiency, and GHR-deficient mice combined with IGF1 expression or expression of constitutively active ('CA') STAT5b. This dataset is part of a large study showing that adult-onset loss of hepatocyte GHR signaling increases steatosis, associated with enhanced glucokinase activity, de novo lipogenesis (DNL) and pathway selective hepatic insulin resistance.

2023-08-21 | GSE222513 | GEO

Holistic proteome analyses of heart samples from GHR-deficient (GHR-KO) pigs

Project description:A proteomics analysis of heart samples from GH receptor deficient (GHR-KO) pigs has been performed. This animal model is unique to study consequences of lacking GH actions. In this study, we used LC-MS/MS to capture alterations in the heart proteome of this clinically relevant large animal model.

2020-12-01 | PXD019852 | Pride

Proteomic changes of the liver in the absence of growth hormone (GH) actions

Project description:The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH actions in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying consequences of lacking GH actions. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model.

2020-03-30 | PXD017671 | Pride

Systems Signature Reveals Unique Remission-path of Diabetes Generated by Gastric Bypass Surgery

Project description:Gastric bypass surgery (GBP) emerging as a powerful tool for treatment of obesity has been applied for remission of diabetes. However, the GBP global molecular effects on diabetes remission independent of weight loss remain largely unknown. We profiled plasma metabolites and proteins of 10 normoglycemic obese (NO) and 9 diabetic obese (DO) patients at 1-week, 3-months and 1-year stages after Roux-en-Y gastric bypass (RYGB) as well pre-RYGB stage, by which 146 proteins and 128 metabolites were detected from both NO and DO groups at all four stages. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the representing physiological states (called the edge-states, in contrast to the traditional node-states) and the related molecular networks of NO and DO patients, respectively. The PCA results and hubnetworks of NO subjects were significantly different from those of DO patients; particularly, the hub-network rearrangement of both groups differentially went through after RYGB. In conclusion, by developing network-based systems signatures rather than relying on individual molecules, we for the first time reveal that RYGB generates a unique recovering-path for diabetes remission independent of weight loss.

2017-12-13 | PXD008071 | Pride

Domestication and growth hormone transgenesis cause similar changes in gene expression profiles in coho salmon

Project description:By directly comparing gene expression in wild type, domestic, and GH transgenic strains of salmon, we have found that domestication and GH transgenesis are modifying similar genetic pathways. Genes in many different physiological pathways show modified expression in domestic and GH transgenic strains relative to wild-type, but effects are strongly correlated. Genes specifically involved in growth regulation (IGF-I, GHR, IGF-II, THR) are also concordantly regulated in domestic and transgenic fish, and both strains show elevated levels of circulating IGF-I. Muscle expression of GH in nontransgenic strains was found to be elevated in domesticated fish relative to wild type, providing a possible mechanism for growth enhancement. These data have implications for genetic improvement of existing domesticated species as well as regulation of emerging transgenic strains. Keywords: Expression profiling by array Microarray analyses were performed on four or five individual fish per group of wild type, domesticated, and GH transgenic salmon hybridized (one slide per individual) against a common wild-type RNA pool.

2009-03-08 | E-GEOD-13846 | biostudies-arrayexpress

Structural and proteomic repercussions of growth hormone receptor deficiency on the pituitary gland – lessons from a translational pig model

Project description:Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 but high, non-functional GH levels. This study investigates the histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old GHR-KO pigs and control animals were compared using a quantitative stereological approach and label-free proteomics.

2023-05-12 | PXD035833 | Pride

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