Adipose triglyceride lipase is implicated in fuel- and non-fuel-stimulated insulin secretion.
Reduced lipolysis in hormone-sensitive lipase-deficient mice is associated with impaired glucose-stimulated insulin secretion (GSIS), suggesting that endogenous beta-cell lipid stores provide signaling molecules for insulin release. Measurements of lipolysis and triglyceride (TG) lipase activity in islets from HSL(-/-) mice indicated the presence of other TG lipase(s) in the beta-cell. Using real time-quantitative PCR, adipose triglyceride lipase (ATGL) was found to be the most abundant TG lipase in rat islets and INS832/13 cells. To assess its role in insulin secretion, ATGL expression was decreased in INS832/13 cells (ATGL-knockdown (KD)) by small hairpin RNA. ATGL-KD increased the esterification of free fatty acid (FFA) into TG. ATGL-KD cells showed decreased glucose- or Gln + Leu-induced insulin release, as well as reduced response to KCl or palmitate at high, but not low, glucose. The K(ATP)-independent/amplification pathway of GSIS was considerably reduced in ATGL-KD cells. ATGL(-/-) mice were hypoinsulinemic and hypoglycemic and showed decreased plasma TG and FFAs. A hyperglycemic clamp revealed increased insulin sensitivity and decreased GSIS and arginine-induced insulin secretion in ATGL(-/-) mice. Accordingly, isolated islets from ATGL(-/-) mice showed reduced insulin secretion in response to glucose, glucose + palmitate, and KCl. Islet TG content and FFA esterification into TG were increased by 2-fold in ATGL(-/-) islets, but glucose usage and oxidation were unaltered. The results demonstrate the importance of ATGL and intracellular lipid signaling for fuel- and non-fuel-induced insulin secretion.
Peyot
Marie-Line
ML
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Guay
Claudiane
C
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Latour
Martin G
MG
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Lamontagne
Julien
J
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Lussier
Roxane
R
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Pineda
Marco
M
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Ruderman
Neil B
NB
Departments of Medicine and Physiology and Biophysics, Boston University School of Medicine and Diabetes Unit, Section of Endocrinology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts 02118.
Haemmerle
Guenter
G
Institute of Molecular Biosciences, Karl-Franzens-University, Graz 8010, Austria.
Zechner
Rudolf
R
Institute of Molecular Biosciences, Karl-Franzens-University, Graz 8010, Austria.
Joly
Érik
É
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Madiraju
S R Murthy
SRM
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada.
Poitout
Vincent
V
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada; Departments of Nutrition, Montreal, Quebec H1W 4A4, Canada; Medicine, University of Montreal, Montreal, Quebec H1W 4A4, Canada.
Prentki
Marc
M
From the Molecular Nutrition Unit and the Montreal Diabetes Research Center, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H1W 4A4, Canada; Departments of Nutrition, Montreal, Quebec H1W 4A4, Canada. Electronic address: marc.prentki@umontreal.ca.
D000818:Animals; D001483:Base Sequence; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005215:Fasting / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008049:Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases
D002265:Carboxylic Ester Hydrolases; D005230:Fatty Acids, Nonesterified; D005947:Glucose; D007328:Insulin; D008049:Lipase; D034741:RNA, Small Interfering; D014280:Triglycerides; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases