Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice.
Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of Rosi and CLA on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed male C57Bl/6 mice. CLA alone suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of Rosi attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase and fatty acid translocase (FAT/CD36) mRNA, suggesting inhibition of fatty acid uptake into adipose; addition of Rosi completely rescued this effect. In addition, CLA alone increased markers of macrophage infiltration, F4/80, and CD68 mRNA levels, without inducing TNF-alpha in epididymal adipose tissue. The ratio of Bax to Bcl2, a marker of apoptosis, was significantly increased in adipose of the CLA-alone group and was partially prevented by treatment of Rosi. Immunohistochemistry of F4/80 demonstrates a proinflammatory response induced by CLA in epididymal adipose. In the liver, CLA alone induced microsteatotic liver but surprisingly increased the rate of very-low-density lipoprotein-triglyceride production without inducing inflammatory mediator-TNF-alpha and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36, and fatty acid synthase. The combined administration of CLA and Rosi reduced hepatic liver triglyceride content as well as lipogenic gene expression compared with CLA alone. In summary, dietary CLA prevented weight gain in Rosi-treated mice without attenuating the beneficial effects of Rosi on insulin sensitivity. Rosi ameliorated CLA-induced lipodystrophic disorders that occurred in parallel with rescued expression of adipocytokine and adipocytes-abundant genes.
Liu
Li-Fen
LF
Dept. of Human Nutrition, The Ohio State Univ., 1787 Neil Ave., Columbus, OH 43210, USA.
Purushotham
Aparna
A
Wendel
Angela A
AA
Belury
Martha A
MA
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000097:blood; D044243:Linoleic Acids, Conjugated / Q000009:adverse effects / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D044243:Linoleic Acids, Conjugated; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D000077154:Rosiglitazone