Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Anna Veprik; Geoffrey Denwood; Dong Liu; Rula Bany Bakar; Valentin Morfin; Kara McHugh; Nchimunya N. Tebeka; Laurène Vetterli; Ekaterina Yonova-Doing; Fiona Gribble; Frank Reimann; Kyle L. Hoehn; Piers A. Hemsley; Jonas Ahnfelt-Rønne; Patrik Rorsman; Quan Zhang; Heidi de Wet; James Cantley

doi:10.1038/s42003-022-03170-w

Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Anna Veprik
, Geoffrey Denwood
, Dong Liu
, Rula Bany Bakar
, Valentin Morfin
, Kara McHugh
, Nchimunya N. Tebeka
, Laurène Vetterli
, Ekaterina Yonova-Doing
, Fiona Gribble
, Frank Reimann
, Kyle L. Hoehn
, Piers A. Hemsley
, Jonas Ahnfelt-Rønne
, Patrik Rorsman
, Quan Zhang
, Heidi de Wet
, James Cantley (Lead / Corresponding author)

Plant Sciences

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Abstract

Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

Original language	English
Article number	238
Number of pages	13
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03170-w
Publication status	Published - 18 Mar 2022

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Homeostasis
Nutrient signalling
Type 2 diabetes

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry,Genetics and Molecular Biology
Medicine (miscellaneous)

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10.1038/s42003-022-03170-wLicence: CC BY

Final Published VersionFinal published version, 2.22 MBLicence: CC BY

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Veprik, A., Denwood, G., Liu, D., Bany Bakar, R., Morfin, V., McHugh, K., Tebeka, N. N., Vetterli, L., Yonova-Doing, E., Gribble, F., Reimann, F., Hoehn, K. L., Hemsley, P. A., Ahnfelt-Rønne, J., Rorsman, P., Zhang, Q., de Wet, H., & Cantley, J. (2022). Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion. Communications Biology, 5(1), Article 238. https://doi.org/10.1038/s42003-022-03170-w

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title = "Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion",

abstract = "Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.",

keywords = "Homeostasis, Nutrient signalling, Type 2 diabetes",

author = "Anna Veprik and Geoffrey Denwood and Dong Liu and \{Bany Bakar\}, Rula and Valentin Morfin and Kara McHugh and Tebeka, \{Nchimunya N.\} and Laur{\`e}ne Vetterli and Ekaterina Yonova-Doing and Fiona Gribble and Frank Reimann and Hoehn, \{Kyle L.\} and Hemsley, \{Piers A.\} and Jonas Ahnfelt-R{\o}nne and Patrik Rorsman and Quan Zhang and \{de Wet\}, Heidi and James Cantley",

note = "Funding Information: During the course of this work, AV was supported by a Novo Nordisk Postdoctoral Fellowship run in partnership with the University of Oxford; JC and QZ were supported by DiabetesUK RD Lawrence Fellowships (DUK-14/0004841 and DUK-14/0005128, respectively); KMcH was supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T00875X/1]; HdW held BBSRC grant funding (BB/P020666/1). Work in the Reimann/Gribble laboratory was supported by the Wellcome Trust (WT084210Z/07/Z and WT088357Z/09/Z) and the MRC (MRC\_MC\_UU\_12012/3). We thank Prof. David E. James FAA (University of Sydney) for providing ACC1 floxed mice, Prof. Daniel J. Drucker (Mount Sinai Hospital, Toronto) for supplying Glutag cells, Dr. Catriona Kelly (University of Ulster) for providing αTC9 cells, and Prof. Ewan Pearson (University of Dundee) for discussions on genetics. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = mar,

day = "18",

doi = "10.1038/s42003-022-03170-w",

language = "English",

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Veprik, A, Denwood, G, Liu, D, Bany Bakar, R, Morfin, V, McHugh, K, Tebeka, NN, Vetterli, L, Yonova-Doing, E, Gribble, F, Reimann, F, Hoehn, KL, Hemsley, PA, Ahnfelt-Rønne, J, Rorsman, P, Zhang, Q, de Wet, H & Cantley, J 2022, 'Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion', Communications Biology, vol. 5, no. 1, 238. https://doi.org/10.1038/s42003-022-03170-w

TY - JOUR

T1 - Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

AU - Veprik, Anna

AU - Denwood, Geoffrey

AU - Liu, Dong

AU - Bany Bakar, Rula

AU - Morfin, Valentin

AU - McHugh, Kara

AU - Tebeka, Nchimunya N.

AU - Vetterli, Laurène

AU - Yonova-Doing, Ekaterina

AU - Gribble, Fiona

AU - Reimann, Frank

AU - Hoehn, Kyle L.

AU - Hemsley, Piers A.

AU - Ahnfelt-Rønne, Jonas

AU - Rorsman, Patrik

AU - Zhang, Quan

AU - de Wet, Heidi

AU - Cantley, James

N1 - Funding Information: During the course of this work, AV was supported by a Novo Nordisk Postdoctoral Fellowship run in partnership with the University of Oxford; JC and QZ were supported by DiabetesUK RD Lawrence Fellowships (DUK-14/0004841 and DUK-14/0005128, respectively); KMcH was supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T00875X/1]; HdW held BBSRC grant funding (BB/P020666/1). Work in the Reimann/Gribble laboratory was supported by the Wellcome Trust (WT084210Z/07/Z and WT088357Z/09/Z) and the MRC (MRC_MC_UU_12012/3). We thank Prof. David E. James FAA (University of Sydney) for providing ACC1 floxed mice, Prof. Daniel J. Drucker (Mount Sinai Hospital, Toronto) for supplying Glutag cells, Dr. Catriona Kelly (University of Ulster) for providing αTC9 cells, and Prof. Ewan Pearson (University of Dundee) for discussions on genetics. Publisher Copyright: © 2022, The Author(s).

PY - 2022/3/18

Y1 - 2022/3/18

N2 - Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

AB - Dysregulated glucagon secretion from pancreatic alpha-cells is a key feature of type-1 and type-2 diabetes (T1D and T2D), yet our mechanistic understanding of alpha-cell function is underdeveloped relative to insulin-secreting beta-cells. Here we show that the enzyme acetyl-CoA-carboxylase 1 (ACC1), which couples glucose metabolism to lipogenesis, plays a key role in the regulation of glucagon secretion. Pharmacological inhibition of ACC1 in mouse islets or αTC9 cells impaired glucagon secretion at low glucose (1 mmol/l). Likewise, deletion of ACC1 in alpha-cells in mice reduced glucagon secretion at low glucose in isolated islets, and in response to fasting or insulin-induced hypoglycaemia in vivo. Electrophysiological recordings identified impaired KATP channel activity and P/Q- and L-type calcium currents in alpha-cells lacking ACC1, explaining the loss of glucose-sensing. ACC-dependent alterations in S-acylation of the KATP channel subunit, Kir6.2, were identified by acyl-biotin exchange assays. Histological analysis identified that loss of ACC1 caused a reduction in alpha-cell area of the pancreas, glucagon content and individual alpha-cell size, further impairing secretory capacity. Loss of ACC1 also reduced the release of glucagon-like peptide 1 (GLP-1) in primary gastrointestinal crypts. Together, these data reveal a role for the ACC1-coupled pathway in proglucagon-expressing nutrient-responsive endocrine cell function and systemic glucose homeostasis.

KW - Homeostasis

KW - Nutrient signalling

KW - Type 2 diabetes

UR - https://www.scopus.com/pages/publications/85126577286

U2 - 10.1038/s42003-022-03170-w

DO - 10.1038/s42003-022-03170-w

M3 - Article

C2 - 35304577

SN - 2399-3642

VL - 5

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 238

ER -

Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion

Abstract

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Keywords

ASJC Scopus subject areas

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