Conjugated linoleic acid activates AMP-activated protein kinase and reduces adiposity more effectively when used with metformin in mice.
Trans-10, cis-12 (t10c12) conjugated linoleic acid (CLA) reduces lipid levels in adipocytes, but the mechanisms involved are still emerging. The hypotheses of this study were that t10c12 CLA treatment activated AMP-activated protein kinase (AMPK) and that the effectiveness of a low dose of t10c12 CLA would be increased when combined with an AMPK activator. We demonstrated t10c12 CLA, directly or indirectly, activated AMPK and increased the amount of phosphorylated acetyl-CoA carboxylase (ACC) in 3T3-L1 adipocytes. Compound C, a potent inhibitor of AMPK, attenuated the phosphorylation of ACC, integrated stress response (ISR), inflammatory response, reduction in key lipogenic transcription factors, and triglyceride (TG) reduction that otherwise occurred in t10c12 CLA-treated adipocytes. Treatment of adipocytes or mice with a low dose of t10c12 CLA in conjunction with the AMPK activator metformin resulted in more TG loss than treatment with the individual chemicals. Additionally, although an inflammatory response was required for robust TG reduction, the combination of t10c12 CLA with AMPK activators had a similar TG loss with a reduced inflammatory response. A microarray analysis of the transcriptional response to either t10c12 CLA, metformin, or the combination, indicated the responses were very similar, with a correlation coefficient of 0.91 or better for genes in the ISR or lipid-related pathways. Altogether, these results support our hypotheses that t10c12 CLA activates AMPK, directly or indirectly, and that metformin increases the effectiveness of t10c12 CLA in reducing TG amounts in adipocytes.
Jiang
Shan
S
Department of Animal Science, University of Nebraska, Lincoln, NE 68502, USA.
Wang
Zhigang
Z
Riethoven
Jean-Jack
JJ
Xia
Yuannan
Y
Miner
Jess
J
Fromm
Michael
M
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D055372:AMP-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers; D005227:Fatty Acids / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017931:DNA Primers; D005227:Fatty Acids; D044243:Linoleic Acids, Conjugated; D012333:RNA, Messenger; D014280:Triglycerides; D008687:Metformin; D055372:AMP-Activated Protein Kinases