ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

Kavaljit H. Chhabra; Siresha Bathina; Tumininu S. Faniyan; Dennis J. Samuel; Muhammad Ummear Raza; Leticia Maria de Souza Cordeiro; Gonzalo Viana Di Prisco; Brady K. Atwood; Jorge Robles; Lauren Bainbridge; Autumn Davis

doi:10.1007/s00125-023-06010-6

ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

Kavaljit H. Chhabra, Siresha Bathina, Tumininu S. Faniyan, Dennis J. Samuel, Muhammad Ummear Raza, Leticia Maria de Souza Cordeiro, Gonzalo Viana Di Prisco, Brady K. Atwood, Jorge Robles, Lauren Bainbridge, Autumn Davis

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Aims/hypothesis: The 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. Methods: Here 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 Adgrl1 ^Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 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/interpretation: Altogether, 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. Graphical Abstract: [Figure not available: see fulltext.].

Original language	English
Pages (from-to)	170-189
Number of pages	20
Journal	Diabetologia
Volume	67
Issue number	1
DOIs	https://doi.org/10.1007/s00125-023-06010-6
State	Published - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Funding

This study received funding from the following sources: National Institutes of Health grants DK124619, DK122190 and DK113115 to KHC; Startup funds, Department of Medicine, University of Rochester to KHC; The Del Monte Institute for Neuroscience Pilot Research Award, University of Rochester to KHC; University Research Award, Office of the Vice President for Research, University of Rochester to KHC; National Institutes of Health instrument grant OD025242 to University of Rochester Mass Spectrometry Resource Laboratory; National Institutes of Health grant DK093000 to the University of Massachusetts Chan Medical School; Stark Neurosciences Research Institute, Indiana University to BKA. We thank N. Bovin, Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, for help with the synthesis of glucose–biotin–PAA; J. Kim and R. Friedline, UMass Chan Medical School and NIDDK Mouse Metabolic Phenotyping Centers ( http://www.mmpc.org ), for help with hyperinsulinaemic–euglycaemic clamps; V. K. Thomas and J. Zhang, URMC Center for Advanced Light Microscopy and Nanoscopy, for help with microscopy; K. Welle and K. Swovick, University of Rochester Mass Spectrometry Resource Laboratory for proteomics analyses; M. Schaff, ProteoGenix, for help with the SPRi technique; S. Espitia, HDBiosciences, for the ADGRL1 signalling assays. The EE ANCOVA analysis done for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers using their Energy Expenditure Analysis page ( http://www.mmpc.org/shared/regression.aspx ) and supported by grants DK076169 and DK115255.

Funders	Funder number
Department of Medicine, University of Rochester
Stark Neurosciences Research Institute
University of Rochester Mass Spectrometry Resource Laboratory	DK093000
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases	DK076169, DK115255
National Institute of Diabetes and Digestive and Kidney Diseases
University of Southern Indiana
University of Massachusetts Medical School
University of Minnesota Rochester	OD025242
University of Minnesota Rochester
Division of Diabetes, Endocrinology, and Metabolic Diseases	DK113115, DK122190, DK124619
Division of Diabetes, Endocrinology, and Metabolic Diseases

Keywords

Diabetes
Glucose receptor
Glucose sensing
Hypothalamus
Mouse models
Obesity

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-023-06010-6

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abstract = "Aims/hypothesis: The 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. Methods: Here 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 Adgrl1 Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 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/interpretation: Altogether, 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. Graphical Abstract: [Figure not available: see fulltext.].",

keywords = "Diabetes, Glucose receptor, Glucose sensing, Hypothalamus, Mouse models, Obesity",

author = "Chhabra, {Kavaljit H.} and Siresha Bathina and Faniyan, {Tumininu S.} and Samuel, {Dennis J.} and Raza, {Muhammad Ummear} and {de Souza Cordeiro}, {Leticia Maria} and {Viana Di Prisco}, Gonzalo and Atwood, {Brady K.} and Jorge Robles and Lauren Bainbridge and Autumn Davis",

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doi = "10.1007/s00125-023-06010-6",

language = "English",

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AU - Chhabra, Kavaljit H.

AU - Bathina, Siresha

AU - Faniyan, Tumininu S.

AU - Samuel, Dennis J.

AU - Raza, Muhammad Ummear

AU - de Souza Cordeiro, Leticia Maria

AU - Viana Di Prisco, Gonzalo

AU - Atwood, Brady K.

AU - Robles, Jorge

AU - Bainbridge, Lauren

AU - Davis, Autumn

PY - 2024/1

Y1 - 2024/1

N2 - Aims/hypothesis: The 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. Methods: Here 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 Adgrl1 Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 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/interpretation: Altogether, 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. Graphical Abstract: [Figure not available: see fulltext.].

AB - Aims/hypothesis: The 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. Methods: Here 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 Adgrl1 Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology. Results: Adgrl1 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/interpretation: Altogether, 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. Graphical Abstract: [Figure not available: see fulltext.].

KW - Diabetes

KW - Glucose receptor

KW - Glucose sensing

KW - Hypothalamus

KW - Mouse models

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ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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