title: PPARα-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 α (PPARα) 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 PPARα-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPARα-deficient ob/ob (PPARα(Δ)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 PPARα(Δ)ob/ob mice as they fail to up-regulate FAO systems. PPARα(Δ)ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPARα agonist Wy-14,643. Although PPARα(Δ)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 PPARα activation-related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPARα 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.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Shaanxi, China.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Prajwal C
authors.initials: PC
authors.lastname: Boddu
authors.affiliation: Department of Pediatrics, Child Health Research Institute, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Bryon
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Saiprasad
authors.initials: S
authors.lastname: Narsingam
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Zhu
authors.affiliation: Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Bayar
authors.initials: B
authors.lastname: Thimmapaya
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: jkreddy@northwestern.edu.
authors.forename: Janardan K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000172:deficiency*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha