A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.
To directly assess the role of beta cell lipolysis in insulin secretion and whole-body energy homeostasis, inducible beta cell-specific adipose triglyceride lipase (ATGL)-deficient (B-Atgl-KO) mice were studied under normal diet (ND) and high-fat diet (HFD) conditions.



Atglflox/floxmice were cross-bred with Mip-Cre-ERT mice to generate Mip-Cre-ERT/+;Atglflox/floxmice. At 8 weeks of age, these mice were injected with tamoxifen to induce deletion of beta cell-specific Atgl (also known as Pnpla2), and the mice were fed an ND or HFD.



ND-fed male B-Atgl-KO mice showed decreased insulinaemia and glucose-induced insulin secretion (GSIS) in vivo. Changes in GSIS correlated with the islet content of long-chain saturated monoacylglycerol (MAG) species that have been proposed to be metabolic coupling factors for insulin secretion. Exogenous MAGs restored GSIS in B-Atgl-KO islets. B-Atgl-KO male mice fed an HFD showed reduced insulinaemia, glycaemia in the fasted and fed states and after glucose challenge, as well as enhanced insulin sensitivity. Moreover, decreased insulinaemia in B-Atgl-KO mice was associated with increased energy expenditure, and lipid metabolism in brown (BAT) and white (WAT) adipose tissues, leading to reduced fat mass and body weight.



ATGL in beta cells regulates insulin secretion via the production of signalling MAGs. Decreased insulinaemia due to lowered GSIS protects B-Atgl-KO mice from diet-induced obesity, improves insulin sensitivity, increases lipid mobilisation from WAT and causes BAT activation. The results support the concept that fuel excess can drive obesity and diabetes via hyperinsulinaemia, and that an islet beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Camille
C
Attané
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Marie-Line
ML
Peyot
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Roxane
R
Lussier
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Pegah
P
Poursharifi
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.|UT Southwestern Medical Center, Dallas, TX, USA.
Shangang
S
Zhao
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.|Diabetes Research Center, Beijing University of Chinese Medicine, Beijing, China.
Dongwei
D
Zhang
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Johane
J
Morin
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Marco
M
Pineda
Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, QC, Canada.
Shupei
S
Wang
University Nice Sophia Antipolis, Nice, France.|Inserm, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), Aging and Diabetes Team, Nice, France.|CNRS, UMR7284, IRCAN, Nice, France.
Olivier
O
Dumortier
Departments of Medicine and Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.|Diabetes Unit, Boston Medical Center, Boston, MA, USA.
Neil B
NB
Ruderman
Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, Montreal, QC, Canada.
Grant A
GA
Mitchell
SCIEX, Concord, Ontario, Canada.
Brigitte
B
Simons
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
S R Murthy
SR
Madiraju
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada.
Erik
E
Joly
Montreal Diabetes Research Center, CRCHUM, 900 St-Denis (Viger Tower), Room R08-412, Montreal, QC, H1W 4A4, Canada. marc.prentki@umontreal.ca.
Marc
M
Prentki
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D000217:Acyltransferases
D002118:Calcium; D007328:Insulin; D008049:Lipase; D013629:Tamoxifen; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
ATGL; Beta cell; Brown adipose tissue; Energy expenditure; High-fat diet fed mice; Insulin secretion; Insulin sensitivity; Lipolysis; Monoacylglycerol; White adipose tissue
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