Conjugated linoleic acid reduces adiposity and increases markers of browning and inflammation in white adipose tissue of mice

Abstract

The objective of this study was to examine the mechanism by which conjugated linoleic acid (CLA) reduces body fat. Young male mice were fed three combinations of fatty acids at three doses (0.06%, 0.2%, and 0.6%, w/w) incorporated into AIN76 diets for 7 weeks. The types of fatty acids were linoleic acid (control), an equal mixture of trans-10, cis-12 (10,12) CLA plus linoleic acid, and an equal isomer mixture of 10,12 plus cis-9, trans-11 (9,11) CLA. Mice receiving the 0.2% and 0.6% dose of 10,12 CLA plus linoleic acid or the CLA isomer mixture had decreased white adipose tissue (WAT) and brown adipose tissue (BAT) mass and increased incorporation of CLA isomers in epididymal WAT and liver. Notably, in mice receiving 0.2% of both CLA treatments, the mRNA levels of genes associated with browning, including uncoupling protein 1 (UCP1), UCP1 protein levels, and cytochrome c oxidase activity, were increased in epididymal WAT. CLA-induced browning in WAT was accompanied by increases in mRNA levels of markers of inflammation. Muscle cytochrome c oxidase activity and BAT UCP1 protein levels were not affected by CLA treatment. These data suggest a linkage between decreased adiposity, browning in WAT, and low-grade inflammation due to consumption of 10,12 CLA. The objective of this study was to examine the mechanism by which conjugated linoleic acid (CLA) reduces body fat. Young male mice were fed three combinations of fatty acids at three doses (0.06%, 0.2%, and 0.6%, w/w) incorporated into AIN76 diets for 7 weeks. The types of fatty acids were linoleic acid (control), an equal mixture of trans-10, cis-12 (10,12) CLA plus linoleic acid, and an equal isomer mixture of 10,12 plus cis-9, trans-11 (9,11) CLA. Mice receiving the 0.2% and 0.6% dose of 10,12 CLA plus linoleic acid or the CLA isomer mixture had decreased white adipose tissue (WAT) and brown adipose tissue (BAT) mass and increased incorporation of CLA isomers in epididymal WAT and liver. Notably, in mice receiving 0.2% of both CLA treatments, the mRNA levels of genes associated with browning, including uncoupling protein 1 (UCP1), UCP1 protein levels, and cytochrome c oxidase activity, were increased in epididymal WAT. CLA-induced browning in WAT was accompanied by increases in mRNA levels of markers of inflammation. Muscle cytochrome c oxidase activity and BAT UCP1 protein levels were not affected by CLA treatment. These data suggest a linkage between decreased adiposity, browning in WAT, and low-grade inflammation due to consumption of 10,12 CLA. Obesity is recognized as the most widespread nutritional disease in the United States (1World Health Organization. Obesity and overweight. Accessed January 25, 2013, at www.who.int/mediacentre/factsheets/fs311/en/index.html.Google Scholar). Excess body fat increases chronic disease risk and mortality (2Centers for Disease Control and Prevention. US obesity trends. Accessed January 25, 2013, at http://www.cdc.gov/obesity/data/trends.htmlGoogle Scholar). Many Americans are consuming dietary supplements to lose weight or prevent weight gain, including supplements containing equal mixtures of cis-9, trans-11 (9,11) conjugated linoleic acid (CLA) and trans-10, cis-12 (10,12) CLA. Indeed, consuming a mixture of these CLA isomers, or 10,12 CLA alone, reduced body fat in many animal (reviewed in Ref. 3Kennedy A. Martinez K. Schmidt S. Mandrup S. Lapoint K. McIntosh M. Antiobesity mechanisms of action of conjugated linoleic acid.J. Nutr. Biochem. 2010; 21: 171-179Crossref PubMed Scopus (194) Google Scholar) and human studies (4Whigham L.D. Watras A.C. Schoeller D.A. Efficacy of conjugated linoleic acid for reducing fat mass: a meta-analysis in humans.Am. J. Clin. Nutr. 2007; 85: 1203-1211Crossref PubMed Scopus (265) Google Scholar). Rodents that consumed higher amounts of the CLA than humans (e.g., 0.5–1.5% CLA in the diet or 600–1,800 mg/kg body weight) lost body fat more rapidly but concurrently developed side effects, including chronic inflammation, insulin resistance, and lipoatrophy (5Poirier H. Niot I. Clement L. Guerre-Millo M. Besnard P. Development of conjugated linoleic acid (CLA)-mediated lipoatrophic syndrome in the mouse.Biochimie. 2005; 87: 73-79Crossref PubMed Scopus (74) Google Scholar). Notably, intermediate levels of CLA isomers w/w) reduced in mice weight or P. A. doses of linoleic acid fat gain, insulin adipose tissue in mice fed a 2010; PubMed Scopus Google Scholar). isomers were not the of in in the was and mechanisms were not P. A. doses of linoleic acid fat gain, insulin adipose tissue in mice fed a 2010; PubMed Scopus Google Scholar). doses of CLA (e.g., or mg/kg body the in is not as or as in the higher doses in that the 10,12 CLA isomer reduces or at doses side in mice (5Poirier H. Niot I. Clement L. Guerre-Millo M. Besnard P. Development of conjugated linoleic acid (CLA)-mediated lipoatrophic syndrome in the mouse.Biochimie. 2005; 87: 73-79Crossref PubMed Scopus (74) Google Scholar) and humans P. K. with dietary trans-10, cis-12 conjugated linoleic acid isomer insulin in with the PubMed Scopus Google M. P. S. mixture with trans-10, cis-12 conjugated linoleic acid increases markers of inflammation and in with cis-9, trans-11 conjugated linoleic acid in Nutr. PubMed Scopus Google Scholar). the CLA isomer and S. A. of cis-9, trans-11 conjugated linoleic acid in white adipose 2007; PubMed Scopus Google and insulin in mice of conjugated linoleic acid isomers in Nutr. Biochem. 2010; 21: PubMed Scopus Google Scholar). the and of CLA adiposity, of and of this an is the of CLA to or prevent obesity and side mechanisms of 10,12 CLA increased and decreased decreased and increased inflammation, and (reviewed in Ref. 3Kennedy A. Martinez K. Schmidt S. Mandrup S. Lapoint K. McIntosh M. Antiobesity mechanisms of action of conjugated linoleic acid.J. Nutr. Biochem. 2010; 21: 171-179Crossref PubMed Scopus (194) Google Scholar). linkage of these mechanisms to body fat inflammation and is browning of white adipose tissue an increased brown is associated with risk of obesity in mice K. K. S. brown adipose tissue in a mechanism for in risk of syndrome in 2007; PubMed Scopus Google Scholar) and humans S. I. A. and of brown adipose tissue in J. PubMed Scopus Google Scholar). that 10,12 CLA increases and in human K. A. M. McIntosh M. conjugated linoleic acid inflammation in human with 2010; PubMed Scopus Google which associated with of brown in WAT A. K. I. A. J. in mice by of brown 2010; PubMed Scopus Google L. I. P. of brown in white adipose tissue is 2010; PubMed Scopus Google a between inflammation and with this levels of an equal mixture of 10,12 and CLA A. linoleic acid uncoupling protein 1 in white adipose tissue of PubMed Scopus Google or 10,12 CLA J. of by trans-10, cis-12 conjugated linoleic acid in a of 2005; 21: PubMed Scopus Google J. S. cis-12 conjugated linoleic acid inflammation and of white adipose tissue in a and PubMed Scopus Google markers of brown including uncoupling protein 1 in WAT in these levels of 10,12 CLA or CLA isomers side as these to in mice the to which 10,12 CLA or a CLA isomer mixture at an dose in intermediate the and doses the fatty acids and and the of WAT browning and inflammation in the of CLA. this that an intermediate dose of 10,12 CLA 10,12 CLA plus linoleic or the CLA isomer mixture 10,12 CLA plus incorporated into WAT and decreased WAT increased the mRNA levels of markers of browning, browning and low-grade inflammation, and increased the protein levels of and and the activity of cytochrome c oxidase in epididymal WAT or or insulin male mice were at of and in in a of was by the and 1 of to a mice were to of dietary mice for 7 in this three levels of fatty acids and three types of fatty The types of fatty acids were linoleic acid as in the and 10,12 CLA and CLA The three doses of fatty acids in the diet were 0.2% and 0.6% to and mg/kg body a of The diets were with linoleic acid, 10,12 CLA plus linoleic acid, or 10,12 CLA plus CLA. 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Development of conjugated linoleic acid (CLA)-mediated lipoatrophic syndrome in the mouse.Biochimie. 2005; 87: 73-79Crossref PubMed Scopus (74) Google the of three doses of CLA these The but not the or intermediate of both CLA increased levels not and levels of a that to WAT. levels of were in the intermediate dose of the CLA isomer mixture Notably, of the CLA increased levels of or not increased levels or These data suggest that is a dose 10,12 CLA plus linoleic acid or 0.2% CLA for both CLA in mice that dose of CLA increases levels of and a linoleic acid 10,12 CLA plus linoleic 10,12 CLA plus CLA reduces adiposity, the mRNA levels of genes associated with browning and fatty acid in and WAT. 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S. and of brown in the and human adipose tissue 2010; PubMed Scopus Google Scholar). Notably, of A. K. I. A. J. in mice by of brown 2010; PubMed Scopus Google L. I. P. of brown in white adipose tissue is 2010; PubMed Scopus Google Scholar) is a of that and the uncoupling with or I. L. M. K. S. The of brown in white fat is by white to brown J. 2010; PubMed Scopus Google Scholar). studies that doses of a mixture of CLA isomers A. linoleic acid uncoupling protein 1 in white adipose tissue of PubMed Scopus Google Scholar) or 10,12 J. of by trans-10, cis-12 conjugated linoleic acid in a of 2005; 21: PubMed Scopus Google Scholar) decreased and increased UCP1 and in or WAT, the that CLA body at in by uncoupling in WAT. with the intermediate dose of 10,12 CLA or the CLA isomer mixture increased mRNA or protein markers of browning fatty acid cytochrome c oxidase and in WAT mRNA markers of browning were not increased by the dose of CLA in WAT, this dose decreased the Indeed, J. 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