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 - http://www.scopus.com/inward/record.url?scp=85126577286&partnerID=8YFLogxK
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 -