Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice.

Abstract

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.

• Authors: Martina Schweiger, Matthias Romauch, Renate Schreiber, Gernot F Grabner, Sabrina Hütter, Petra Kotzbeck, Pia Benedikt, Thomas O Eichmann, Sohsuke Yamada, Oskar Knittelfelder, Clemens Diwoky, Carina Doler, Nicole Mayer, Werner De Cecco, Rolf Breinbauer, Robert Zimmermann, Rudolf Zechner
• Journal: Nature communications (Nat Commun) Vol. 8 Pg. 14859 (03 22 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 28327588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phenylurea Compounds
• atglistatin
• Lipase
• Glucose

Topics

• Adipose Tissue, White (enzymology)
• Animals
• Body Weight (drug effects)
• Diet, High-Fat
• Fatty Liver (blood, drug therapy, enzymology, prevention & control)
• Feeding Behavior
• Glucose (metabolism)
• Homeostasis (drug effects)
• Humans
• Insulin Resistance
• Lipase (antagonists & inhibitors, metabolism)
• Lipolysis (drug effects)
• Male
• Mice, Inbred C57BL
• Obesity (drug therapy, enzymology, pathology)
• Phenylurea Compounds (pharmacology, therapeutic use)