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Importance of ?-Catenin in glucose and energy homeostasis.

ABSTRACT: In settings of increased insulin demand, failure to expand pancreatic ?-cells mass leads to diabetes. Genome-wide scans of diabetic populations have uncovered several genes associated with susceptibility to type 2 diabetes and a number of them are part of the Wnt signaling. ?-Catenin, a Wnt downstream effector participates in pancreatic development, however, little is known about its action in mature ?-cells. Deletion of ?-Catenin in Pdx1 pancreatic progenitors leads to a decreased ?-cell mass and impaired glucose tolerance. Surprisingly, loss of ?-catenin made these mice resistant to high fat diet because of their increased energy expenditure and insulin sensitivity due to hyperactivity. The complexity of this phenotype was also explained in part by ectopic expression of Cre recombinase in the hypothalamus. Our data implicates ?-Catenin in the regulation of metabolism and energy homeostasis and suggest that Wnt signaling modulates the susceptibility to diabetes by acting on different tissues.

SUBMITTER: Elghazi L

PROVIDER: S-EPMC3457035 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Importance of β-Catenin in glucose and energy homeostasis.

Elghazi Lynda L Gould Aaron P AP Weiss Aaron J AJ Barker Daniel J DJ Callaghan John J Opland Darren D Myers Martin M Cras-Méneur Corentin C Bernal-Mizrachi Ernesto E

Scientific reports 20120925

In settings of increased insulin demand, failure to expand pancreatic β-cells mass leads to diabetes. Genome-wide scans of diabetic populations have uncovered several genes associated with susceptibility to type 2 diabetes and a number of them are part of the Wnt signaling. β-Catenin, a Wnt downstream effector participates in pancreatic development, however, little is known about its action in mature β-cells. Deletion of β-Catenin in Pdx1 pancreatic progenitors leads to a decreased β-cell mass a ...[more]

PMID: 23012647

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Project description:Aims/hypothesisThe brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium-glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.MethodsHere we used a high molecular mass glucose-biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose-ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand-receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology.ResultsAdgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis.Conclusions/interpretationAltogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.

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Importance of ?-Catenin in glucose and energy homeostasis.

Publications

Importance of β-Catenin in glucose and energy homeostasis.

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