A novel mechanism regulating insulin secretion involving Herpud1 in mice

Wong, Nicole; Morahan, Grant; Stathopoulos, Maria; Proietto, Joseph; Andrikopoulos, Sofianos

doi:10.1007/s00125-013-2908-y

Cited by 20 publications

(18 citation statements)

References 33 publications

(44 reference statements)

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“…As the BXDs have extensive historical phenotype and metabolite data available on GeneNetwork (Wang et al, 2003), we performed a phenome-wide association study to determine if any collected phenotype data mapped at least suggestively (likelihood ratio statistic [LRS] ≥ 12) as clinical QTLs (cQTL) to the same loci. A handful of phenotypic connections in the BXDs were supported by literature, including a link between Nnt and insulin (Wong et al, 2013) and between Car3 and subcutaneous adipose mass (Mitterberger et al, 2012). However, for the majority of pQTLs, no established cQTLs mapped to the same loci.…”

Section: Resultsmentioning

confidence: 82%

“…For these genes, Nnt, Car3, Dhtkd1 , and Bckdhb , coding differences between B6 and D2 alleles were linked to robust differences at both the transcript level and protein level, leading to shared cis -regulatory eQTLs and pQTLs and then to phenotypic consequences. While Nnt has been previously attributed as causal to differences in insulin secretion in the BXDs (Wong et al, 2013), the other pQTLs are novel, including Car3 , which was previously linked to adiposity only in knockout mice (Mitterberger et al, 2012). For Bckdhb , strains carrying the B6 allele have a ~50% reduction in enzyme levels, which leads to a buildup of BCAA levels and a decrease in alanine levels, as in the intermittent form of MSUD.…”

Section: Discussionmentioning

confidence: 99%

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Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Williams

Dubuis

et al. 2014

Cell

225

241

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SUMMARY The manner by which genotype and environment affect complex phenotypes is one of the fundamental questions in biology. In this study, we quantified the transcriptome—a subset of the metabolome—and, using targeted proteomics, quantified a subset of the liver proteome from 40 strains of the BXD mouse genetic reference population on two diverse diets. We discovered dozens of transcript, protein, and metabolite QTLs, several of which linked to metabolic phenotypes. Most prominently, Dhtkd1 was identified as a primary regulator of 2-aminoadipate, explaining variance in fasted glucose and diabetes status in both mice and humans. These integrated molecular profiles also allowed further characterization of complex pathways, particularly the mitochondrial unfolded protein response (UPRmt). UPRmt shows strikingly variant responses at the transcript and protein level that are remarkably conserved among C. elegans, mice, and humans. Overall, these examples demonstrate the value of an integrated multilayered omics approach to characterize complex metabolic phenotypes.

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Section: Resultsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Williams

Dubuis

et al. 2014

Cell

225

241

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“…HMGB2 is also critically involved in regulatory mechanisms that, control DNA damage [125], cell senescence [126], innate immune responses and neuroinflammation [127, 128] as well as stem cell proliferation and neurogenesis [129]. In addition to the specific GIT2-dependent alteration of HMG proteins multiple additional proteins that regulate age-related energy metabolism (Prcp [130], age-related DNA damage (Bach2 [131], age-related hematopoietic network regulation (Irf8 [132], immunosenescence (Pecam1 [133] and ER stress/amyloid related regulation of insulin secretion (Herpud1 [134-136]) were altered in GIT2KOs. From our work it was evident that GIT2 deletion in our models was potentially associated with cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

Siddiqui

Lustig²,

Carter³

et al. 2017

Aging

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Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of ‘neurometabolic’ integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2−/− mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2−/− (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical ‘organ’, i.e. ‘parathymic lobes’. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe – suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature ‘aging’ phenotype of GIT2KO mice.

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“…The BXD recombinant inbred mice, which have been derived from the cross of DBA/2J and C57Bl6/J mice, form a particularly useful genetic reference population (Andreux et al., 2012, Chesler et al., 2004, Peirce et al., 2007, Rosen et al., 2007). These mice have been successfully used to identify genes involved in various physiological processes such as sleep (Franken et al., 2001), aging (Houtkooper et al., 2013), blood pressure (Koutnikova et al., 2009), or beta-cell function (Wong et al., 2013). …”

Section: Introductionmentioning

confidence: 99%

A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

et al. 2016

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SummaryThe counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.

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A novel mechanism regulating insulin secretion involving Herpud1 in mice

Abstract: We conclude that Herpud1 regulates insulin secretion via control of Nnt expression.

Cited by 20 publications

References 33 publications

Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Multilayered Genetic and Omics Dissection of Mitochondrial Activity in a Mouse Reference Population

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

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