Isomer-specific regulation of metabolism and PPARγ signaling by CLA in human preadipocytes

Abstract

Trans-10,cis-12 conjugated linoleic acid (CLA) has previously been shown to be the CLA isomer responsible for CLA-induced reductions in body fat in animal models, and we have shown that this isomer, but not the cis-9,trans-11 CLA isomer, specifically decreased triglyceride (TG) accumulation in primary human adiopcytes in vitro. Here we investigated the mechanism behind the isomerspecific, CLA-mediated reduction in TG accumulation in differentiating human preadipocytes. Trans-10,cis-12 CLA decreased insulin-stimulated glucose uptake and oxidation, and reduced insulin-dependent glucose transporter 4 gene expression. Furthermore, trans-10,cis-12 CLA reduced oleic acid uptake and oxidation when compared with all other treatments. In parallel to CLA's effects on metabolism, trans-10,cis-12 CLA decreased, whereas cis-9,trans-11 CLA increased, the expression of peroxisome proliferator-activated receptor γ (PPARγ) and several of its downstream target genes when compared with vehicle controls. Transient transfections demonstrated that both CLA isomers antagonized ligand-dependent activation of PPARγ. Collectively, trans-10,cis-12, but not cis-9, trans-11, CLA decreased glucose and lipid uptake and oxidation and preadipocyte differentiation by altering preadipocyte gene transcription in a manner that appeared to be due, in part, to decreased PPARγ expression. Supplementary key wordsconjugated linoleic acid; fatty acids; lipid metabolism; glucose metabolism; triglycerides; peroxisome proliferator-activated receptor gamma Abbreviations ACBP, acyl-CoA binding protein; ACC, acetyl-CoA carboxylase; aP2/FABP, adipocyte fatty acid binding protein; BCA, bicinchoninic acid; BMI, body mass index; BSA, bovine serum albumin; CD-36, fatty acid translocase; C/EBPα, CAAT/enhancer binding protein α; CLA, conjugated linoleic acid; GC, gas chromatography; GLUT4, insulin-dependent glucose transporter 4; GPDH, glycerol-3-phosphate dehydrogenase; HSL, hormone-sensitive lipase; IBMX, isobutylmethylxanthine; LA, linoleic acid; LPL, lipoprotein lipase; MUFA, monounsaturated fatty acid; ORO, oil red O; PPAR, 1 To whom correspondence should be addressed. e-mail:mkmcinto@uncg.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; SCD-1, stearoyl-CoA desaturase-1; SFA, saturated fatty acid; SV, stromal vascular; TG, triglyceride Conjugated linoleic acid (CLA) refers to a group of geometric and positional dienoic isomers of linoleic acid (LA) [18:2(n-6)]. The two predominant isomers of CLA found in food and commercial preparations are cis-9,trans-11 CLA and trans-10,cis-12 CLA. CLA is found in ruminant meats, pasteurized cheeses, and dairy products, and therefore is a natural part of the diet. CLA has been extensively studied due to its potentially beneficial effects on carcinogenesis (1-3), diabetes (4,5), atherosclerosis (6,7), immune function (8-10), and body composition (11)(12)(13)(14)(15)(16).Collectivel...

Conjugated linoleic acid (CLA) and obesity

“…Trans-10,cis-12 CLA also inhibits the expression of glucose transporter-4 (GLUT-4) 37,38 and increases the activity of carnitine palmitoyltransferase (CPT), enhancing fatty acid oxidation 10 . Trans-10,cis-12 CLA reduces lipogenesis in human 37 and mice adipocytes, decreasing sterol regulatory element-binding protein-1 (SREBP-1) expression in vivo 39 .…”

“…Trans-10,cis-12 CLA also inhibits the expression of glucose transporter-4 (GLUT-4) 37,38 and increases the activity of carnitine palmitoyltransferase (CPT), enhancing fatty acid oxidation 10 . Trans-10,cis-12 CLA reduces lipogenesis in human 37 and mice adipocytes, decreasing sterol regulatory element-binding protein-1 (SREBP-1) expression in vivo 39 . Trans-10,cis-12 CLA also induces adipocyte apoptosis in mice [39][40][41][42][43] , perhaps mediated by an increase in tumour necrosis factor alpha (TNFa) 39 , but the effects of CLA on lipolysis in vivo and in vitro are conflicting 10,38 .…”

“…Trans-10,cis-12 CLA also induces adipocyte apoptosis in mice [39][40][41][42][43] , perhaps mediated by an increase in tumour necrosis factor alpha (TNFa) 39 , but the effects of CLA on lipolysis in vivo and in vitro are conflicting 10,38 . Data regarding its effects on preadipocyte differentiation are inconclusive, possibly depending on species, CLA isomer and experimental conditions 4,37 . Chronic treatment with trans-10,cis-12 CLA significantly reduces the expression of several adipocytespecific genes, including PPARa and PPARg target genes, partly due to an increase in nuclear factor kappa B (NFkB) activity and subsequent induction of interleukin-6 44 , therefore explaining at least part of its effects on glucose and lipid metabolism.…”

Os efeitos do ácido linoléico conjugado no metabolismo animal: avanço das pesquisas e perspectivas para o futuro

“…A maioria dos estudos objetivando buscar os alvos moleculares da ação redutora da gordura corporal pelo CLA em adipócitos, reúne dados que permitem concluir que a inibição de PPAR γ, particularmente pelo trans-10, cis-12 CLA, levaria à redução da gordura corporal pela modulação da expressão gênica no sentido de inibir a diferenciação celular e alterar a atividade de proteínas envolvidas na lipogênese e na lipólise 109,136 . É importante a ressalva de que, nos estudos citados anteriormente, o tempo de exposição dos adipó-citos aos isômeros de CLA até os efeitos serem observados foi superior a 5 dias, confirmando que, em longo prazo, segundo Evans et al 136 , o efeito do trans-10, cis-12 CLA é de fato inibir PPAR γ. Um dado interessante é o do trabalho de Brown et al 138 , segundo o qual quando as células foram expostas ao isômero cis-9, trans-11, houve aumento de PPAR γ e, conseqüentemente, das proteínas codificadas pelos genes que estão sob seu controle transcricional, promovendo a adipogê-nese. Tal achado traz contribuições ímpares a respeito da suplementação com misturas de isômeros de CLA.…”

Production of Lean Beef Containing a High Content oftrans-10,cis-12Conjugated Linoleic Acid by Feeding a High-Temperature-Micro-Time-Treated Diet with Extruded Soybean

“…14) Cis-9, trans-11 CLA is an anticancer isomer, 15) and trans-10, cis-12 CLA is an antilipogenesis isomer. [16][17][18] These two CLA isomers occur naturally in foods derived from ruminants, and they are the major source of CLA in the human diet. 19,20) However, a high intake of ruminant fats can lead to obesity, because they have more saturated fatty acids.…”