Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice.
Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Martina
0000-0002-3419-1007
M
Schweiger
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Matthias
M
Romauch
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Renate
R
Schreiber
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Gernot F
GF
Grabner
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Sabrina
S
Hütter
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Petra
P
Kotzbeck
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Pia
P
Benedikt
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Thomas O
TO
Eichmann
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Sohsuke
S
Yamada
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Oskar
O
Knittelfelder
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Clemens
C
Diwoky
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
Carina
C
Doler
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
Nicole
N
Mayer
Institute of Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria.
Werner
W
De Cecco
Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria.
Rolf
0000-0001-6009-7359
R
Breinbauer
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Robert
R
Zimmermann
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, 8010 Graz, Austria.
Rudolf
R
Zechner
D052436:Adipose Tissue, White / Q000201:enzymology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology* / Q000517:prevention & control; D005247:Feeding Behavior; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use
D010671:Phenylurea Compounds; C585749:atglistatin; D008049:Lipase; D005947:Glucose