Singular effects of PPAR agonists on nonalcoholic fatty liver disease of diet-induced obese mice.
OBJECTIVE
To assess the effects of peroxisome proliferator-activated receptor (PPAR) agonists on glucose tolerance and hepatic lipid metabolism in diet-induced obese mice.


METHODS
Male C57BL/6 mice received a standard chow diet (SC, 10% energy as lipids) or high-fat diet (HF, 50% energy as lipids) for 10 weeks, after which treatment was initiated, forming the groups: SC group, HF group, HF-BZ group (HF + bezafibrate, pan-PPAR agonist), HF-WY group (HF + WY-14643, PPARalpha agonist) and HF-GW group (HF + GW1929, PPARgamma agonist). Treatments lasted for four weeks. Insulin resistance and liver remodeling were evaluated by biochemical and molecular approaches.


RESULTS
The HF and HF-GW mice were overweight. Conversely, the HF-BZ and HF-WY mice presented with body masses equal to those of the SC mice. All treatments restored insulin sensitivity and blood lipid and adiponectin levels. Hepatic steatosis was prevented in the HF-WY and HF-BZ mice as shown by the elevated mRNA levels of PPARalpha and Carnitine palmitoyl transferase-1a in both groups, which favored enhanced beta-oxidation. Marked decreases in liver triacylglycerol levels confirmed these findings. In contrast, the HF-GW mice exhibited increased PPARgamma and fatty acid translocase/CD136 mRNA levels, contributing to enhanced hepatic lipogenesis.


CONCLUSIONS
The WY14643 and bezafibrate treatments most effectively improved the adverse metabolic and hepatic effects caused by obesity and IR. The results reinforce the central role of PPARalpha, as well as its contrary relationship to PPARgamma in the regulation of metabolic homeostasis and lipolytic pathways in the liver.
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: sandrabarbosasilva@gmail.com.
Sandra
S
Barbosa-da-Silva
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: v.souzamello@gmail.com.
Vanessa
V
Souza-Mello
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: dc.magliano@gmail.com.
D'Angelo Carlo
DC
Magliano
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: thatymarinho@gmail.com.
Thatiany de Souza
Tde S
Marinho
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: marciaguila@gmail.com.
Marcia Barbosa
MB
Aguila
Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Brazil. Electronic address: mandarim@uerj.br.
Carlos Alberto
CA
Mandarim-de-Lacerda
D054392:Adipokines / Q000378:metabolism; D000818:Animals; D001577:Benzophenones / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D002149:Energy Intake / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D009765:Obesity / Q000150:complications*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D054392:Adipokines; D001577:Benzophenones; D001786:Blood Glucose; D047493:PPAR alpha; D014443:Tyrosine; C120099:GW 1929
Bezafibrate; Mice; NAFLD; Obesity; PPARalpha; PPARgamma