PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides

Gagnon, Jeffrey; Mayne, Janice; Chen, Andrew; Raymond, Angela; Woulfe, John; Mbikay, Majambu; Chrétien, Michel

doi:10.1016/j.lfs.2010.11.010

Cited by 16 publications

(14 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among such peptides, GLP‐1 especially exerts multiple biological functions including stimulation of insulin secretion from β ‐cells. Gagnon et al recently showed that circulating levels of GLP‐1 and GLP‐2 are indeed elevated in Pcsk2 −/− mice [13]. In Gcgr −/− mice, an approximately 25‐fold increase in total GLP‐1 in pancreas has been shown [3,14].…”

Section: Animal Models Defective For Glucagon Signallingmentioning

confidence: 99%

“…The difference in blood glucose levels is more pronounced in female than in male Gcg −/− mice [3]. Elevation of plasma GLP‐1 and GLP‐2 levels in Pcsk2 −/− , which is probably the consequence of the compensatory change in proglucagon expression for glucagon deficiency, is more pronounced in female mice than in male mice [13]. The underlying mechanism for this sexual dimorphism remains to be elucidated, but oestrogen is surely involved [31].…”

Section: Sexual Dimorphism In the Phenotype Of Animal Models Defectivmentioning

confidence: 99%

See 1 more Smart Citation

Metabolic impact of glucagon deficiency

Hayashi

2011

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

Multiple bioactive peptides are produced from proglucagon encoded by glucagon gene (Gcg). Glucagon is produced in islet α-cells through processing by prohormone convertase 2 (Pcsk2) and exerts its action through the glucagon receptor (Gcgr). Although it is difficult to produce a genetic model that harbours isolated glucagon deficiency without affecting the production of other peptides derived from proglucagon, three different animal models that harbour deficiencies in glucagon signalling have been generated by gene targeting strategy. Although both Pcsk2(-/-) and Gcgr(-/-) mice display lower blood glucose levels, homozygous glucagon-GFP knock-in mice (Gcg(gfp/gfp) ) display normoglycaemia despite complete glucagon deficiency. In Gcg(gfp/gfp) mice, the metabolic impact of glucagon deficiency is probably ameliorated by lower plasma insulin levels and glucagon-independent mechanisms that maintain gluconeogenesis. As both Pcsk2(-/-) and Gcgr(-/-) mice exhibit increased production of glucagon-like peptide-1 (GLP-1), which is absent in Gcg(gfp/gfp), GLP-1 is the likely cause of the difference in metabolic impact of glucagon deficiency in these animal models. Although all the three models display islet 'α'-cell hyperplasia, the mechanisms involved remain to be elucidated. Studies using Pcsk2(-/-), Gcgr(-/-) and Gcg(gfp/gfp) mice, especially in combination with α-cell ablation models such as pancreas-specific aristaless-related homeobox (ARX) knockout mice, should further clarify the physiological and pathological roles of glucagon in the regulation of metabolism and the control of islet cell differentiation and proliferation.

show abstract

Section: Animal Models Defective For Glucagon Signallingmentioning

confidence: 99%

Section: Sexual Dimorphism In the Phenotype Of Animal Models Defectivmentioning

confidence: 99%

Metabolic impact of glucagon deficiency

Hayashi

2011

Diabetes Obesity Metabolism

View full text Add to dashboard Cite

show abstract

“…However, because the blunted glucagon action in both Pcsk2 −/− and Gcgr −/− mice induces hyperplasia of α-cells and increases proglucagon production, the serum GLP-1 levels are increased in both types of mice (6,7). Because GLP-1 exerts multiple biological effects, including stimulation of insulin secretion and β-cell proliferation, the possible contribution of increased GLP-1 production to the metabolic phenotypes in these animal models cannot be ignored.…”

mentioning

confidence: 99%

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

Watanabe

Seino²,

Miyahira³

et al. 2011

Diabetes

View full text Add to dashboard Cite

Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon–green fluorescent protein (gfp) knock-in mice (Gcggfp/gfp: GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.

show abstract

“…Removal of AGRP/ NPY-expressing neurons at adult age does, however, cause severe hypophagia in mice (133,134). NPY, which is most likely a PC2 substrate (135)(136)(137)(138)(139), is coexpressed with AGRP in the same neuronal population of the Arc. NPY exerts orexigenic actions through the depolarization of POMC neurons, which results in an inhibition on the action of ␣-MSH.…”

Section: Pc1/3 Substrates Which Contribute To the Pc1/3 Null Phementioning

confidence: 98%

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

et al. 2016

View full text Add to dashboard Cite

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.

show abstract

PCSK2-null mice exhibit delayed intestinal motility, reduced refeeding response and altered plasma levels of several regulatory peptides

Cited by 16 publications

References 46 publications

Metabolic impact of glucagon deficiency

Metabolic impact of glucagon deficiency

Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders

Contact Info

Product

Resources

About