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PPAR?-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation.


ABSTRACT: Obesity poses an increased risk of developing metabolic syndrome and closely associated nonalcoholic fatty liver disease, including liver cancer. Satiety hormone leptin-deficient (ob/ob) mice, considered paradigmatic of nutritional obesity, develop hepatic steatosis but are less prone to developing liver tumors. Sustained activation of peroxisome proliferator-activated receptor ? (PPAR?) in ob/ob mouse liver increases fatty acid oxidation (FAO), which contributes to attenuation of obesity but enhances liver cancer risk. To further evaluate the role of PPAR?-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPAR?-deficient ob/ob (PPAR?(?)ob/ob) mice. These mice become strikingly more obese compared to ob/ob littermates, with increased white and brown adipose tissue content and severe hepatic steatosis. Hepatic steatosis becomes more severe in fasted PPAR?(?)ob/ob mice as they fail to up-regulate FAO systems. PPAR?(?)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPAR? agonist Wy-14,643. Although PPAR?(?)ob/ob mice are severely obese, there was no significant increase in liver tumor incidence, even when maintained on a diet containing Wy-14,643. We conclude that sustained PPAR? activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPAR? in ob/ob mice aggravates obesity and hepatic steatosis. However, it does not lead to liver tumor development because of reduction in FAO and energy burning.

SUBMITTER: Gao Q 

PROVIDER: S-EPMC4419205 | BioStudies | 2015-01-01T00:00:00Z

REPOSITORIES: biostudies

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