This review highlights the inflammatory and insulin-antagonizing effects of saturated fatty acids (SFA), which contribute to the development of metabolic syndrome. Mechanisms responsible for these unhealthy effects of SFA include: 1) accumulation of diacylglycerol and ceramide; 2) activation of nuclear factor-kappaB, protein kinase C-, and mitogen-activated protein kinases, and subsequent induction of inflammatory genes in white adipose tissue, immune cells, and myotubes; 3) decreased PPARgamma coactivator-1 alpha/beta activation and adiponectin production, which decreases the oxidation of glucose and fatty acids (FA); and 4) recruitment of immune cells like macrophages, neutrophils, and bone marrow-derived dendritic cells to WAT and muscle. Several studies have demonstrated potential health benefits of substituting SFA with unsaturated FA, particularly oleic acid and (n-3) FA. Thus, reducing consumption of foods rich in SFA and increasing consumption of whole grains, fruits, vegetables, lean meats and poultry, fish, low-fat dairy products, and oils containing oleic acid or (n-3) FA is likely to reduce the incidence of metabolic disease.

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), a family of fatty acids found in beef, dairy foods, and dietary supplements, reduces adiposity in several animal models of obesity and in some humans. However, the isomer-specific antiobesity mechanisms of action of CLA are unclear, and its use in humans is controversial. This review will summarize in vivo and in vitro findings from the literature regarding potential mechanisms by which CLA reduces adiposity including its impact on 1) energy metabolism, 2) adipogenesis, 3) inflammation, 4) lipid metabolism, and 5) apoptosis.

Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of nonadipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e.g. IL-6, TNF-alpha, and IL-1beta) and chemokines (e.g. IL-8, monocyte chemoattractant protein-1) occurred primarily in the nonadipocyte fraction of newly differentiated human adipocytes. Nonadipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 and adipocyte enhancer protein-1 and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from approximately 0-90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor-kappaB and MAPK signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with: 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor (PPAR)-gamma reporter construct and increased phosphorylation of PPARgamma, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces nuclear factor-kappaB- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPARgamma activity and insulin responsiveness in human adipocytes.

We previously demonstrated that trans-10, cis-12 conjugated linoleic acid (CLA) reduced the triglyceride content of human adipocytes by activating mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) signaling via interleukins (IL) 6 and 8. However, the upstream mechanism is unknown. Here we show that CLA increased (>6 h) the secretion of IL-6 and IL-8 in cultures containing both differentiated adipocytes and stromal vascular (SV) cells, non-differentiated SV cells, and adipose tissue explants. CLA isomer-specific induction of IL-6 and tumor necrosis factor-␣ was associated with the activation of nuclear factor B (NFB) as evidenced by 1) phosphorylation of IB␣, IB␣ kinase, and NFB p65, 2) IB␣ degradation, and 3) nuclear translocation of NFB. Pretreatment with selective NFB inhibitors and the MEK/ ERK inhibitor U0126 blocked CLA-mediated IL-6 gene expression. Trans-10, cis-12 CLA suppression of insulin-stimulated glucose uptake at 24 h was associated with decreased total and plasma membrane glucose transporter 4 proteins. Inhibition of NFB activation or depletion of NFB by RNA interference using small interfering NFB p65 attenuated CLA suppression of glucose transporter 4 and peroxisome proliferator-activated receptor ␥ proteins and glucose uptake. Collectively, these data demonstrate for the first time that trans-10, cis-12 CLA promotes NFB activation and subsequent induction of IL-6, which are at least in part responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator-activated receptor ␥ target gene expression and insulin sensitivity in mature human adipocytes. Conjugated linoleic acid (CLA)2 is a collective term used to refer to positional and geometric isomers of linoleic acid (C18:2) with a conjugated double bond. The two predominant isomers of CLA, cis-9, trans-11 and trans-10, cis-12, are naturally found in dairy products and ruminant meats, with cis-9, trans-11 CLA being the most abundant isomer (e.g. 80% cis-9, trans-11 CLA, 10% trans-10, cis-12 CLA). CLA is also available commercially as a dietary supplement for weight loss, with both isomers reported to be present at equal amounts (e.g. ϳ35% each). A great deal of attention has been centered on trans-10, cis-12 CLA due to its reported anti-obesity actions in animal models (for review, see Ref.1) and some humans (for review, see Ref.2). We have reported that trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, inhibited human preadipocyte differentiation (3) and caused delipidation of newly differentiated human adipocytes (4). CLA isomer-specific delipidation of adipocytes was due largely to decreased glucose and fatty acid uptake and TG synthesis as opposed to increased oxidation. Interestingly, CLA suppression of glucose and fatty acid uptake was positively correlated with activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) and G protein-coupled receptor (GPCR) signaling and robust secretion of the proinflammatory cytokines interleukin-6 (IL-6) an...

Four sets of experiments were conducted to examine the influence of conjugated linoleic acid (CLA) isomers during proliferation and differentiation of cultures of 3T3-L1 preadipocytes using physiological culturing conditions. Cultures treated with either albumin [bovine serum albumin (BSA) vehicle] or linoleic acid (LA) served as controls. For the proliferation study (Expt.1), cells were cultured in media containing a crude mixture of CLA isomers or pure LA at 0, 10, 50, or 200 microM for 4 d. Preadipocyte proliferation (cell number, 3H-thymidine incorporation into DNA) decreased as the level of CLA increased in the cultures. In contrast, LA had no impact on DNA synthesis. In Experiment 2a, postconfluent cultures were grown in media containing a crude mixture of CLA isomers or LA at 0, 10, 50, or 200 microM for the next 6 d. Postconfluent cultures supplemented with 50-200 microM CLA had less triglyceride (TG) and were smaller in size than cultures supplemented with similar amounts of LA. In Experiment 2b, postconfluent cultures supplemented with 200 microM of a crude mixture of CLA isomers or LA were harvested on days 1, 3, 6, or 9. Differences in TG content of cultures supplemented with 200 microM CLA compared to control and LA-supplemented cultures became apparent after 3 d of culture. Experiments 3a and 3b examined whether the fatty acid vehicle (BSA vs. ethanol) or the vitamin E status (+/-0.2 mM alpha-tocopherol) of the cultures altered CLA's impact on preadipocyte TG content. In Experiment 3a, ethanol-treated cultures had more TG than non-ethanol-treated cultures regardless of the fatty acid treatment. In Experiment 3b, cultures treated with 100 microM of either a crude mixture of CLA or the trans-10,cis-12 CLA isomer without supplemental vitamin E for 6 d had less TG than CLA-treated cultures containing vitamin E. In Experiment 4, postconfluent cultures were grown in media containing 100 microM LA or either a crude mixture of CLA isomers or the trans-10,cis-12 CLA isomer for 24-96 h to assess CLA's influence on the cell cycle and indices of apoptosis. Cultures treated with 100 microM CLA for 24-96 h had more apoptotic cells than BSA- or LA-treated cultures. Furthermore, cultures treated for 48 h with CLA had fewer cells in the S-phase than control cultures. The effects of the trans-10,cis-12 CLA isomer were more pronounced than those of the crude mixture of CLA isomers. These data suggest that CLA may exert its antiobesity effects by inhibiting proliferation, attenuating TG content, and/or inducing apoptosis in (pre)adipocytes.

Obesity and metabolic disease-related health problems (e.g., type 2 diabetes, atherosclerosis, and hypertension) are the most prevalent nutrition-related issues in the United States. An emerging feature of obesity and type 2 diabetes is their linkage with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential strategy to reduce inflammation and insulin resistance is consumption of polyphenol-rich foods like grapes or their by-products, which have anti-inflammatory properties. Polyphenols commonly found in grape products have been reported to reduce inflammation by (a) acting as an antioxidant or increasing antioxidant gene or protein expression, (b) attenuating endoplasmic reticulum stress signaling, (c) blocking proinflammatory cytokines or endotoxin-mediated kinases and transcription factors involved in metabolic disease, (d) suppressing inflammatory- or inducing metabolic-gene expression via increasing histone deacetylase activity, or (e) activating transcription factors that antagonize chronic inflammation. Thus, polyphenol-rich grape products may reduce obesity-mediated chronic inflammation by multiple mechanisms, thereby preventing metabolic diseases.

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