Is Conjugated Linoleic Acid (CLA) Supplement Safe?

flustri

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It seems that different isomers have quite different health effects.

Antiobesity Mechanisms of Action of Conjugated Linoleic Acid

doi: 10.1016/j.jnutbio.2009.08.003

Commercial preparations of CLA are made from the linoleic acid of safflower or sunflower oils under alkaline conditions. This type of processing yields a CLA mixture containing approximately 40% of the 9,11 isomer and 44% of the 10,12 isomer [reviewed in 1].

The 9,11 isomer, also known as rumenic acid, is the predominant form of CLA found in naturally occurring foods. 9,11 CLA comprises approximately 90% of CLA found in ruminant meats and dairy products and the 10,12 isomer comprises the remaining 10%.

Supplementation with a CLA mixture (i.e., equal concentrations of the 10,12 and 9,11 isomers) or the 10,12 isomer alone decreases body fat mass (BFM) in many animal and some human studies [reviewed in 11 and 13].

CLA increases inflammation

Although the primary function of WAT is energy storage, it also has the ability to produce a number of pro-inflammatory cytokines. These adipokines (i.e., cytokines produced by adipose tissue) can cause insulin resistance (Fig. 4), thereby suppressing lipid synthesis and increasing lipolysis in adipocytes (Fig. 5). Induction of these inflammatory genes is dependent on various cellular kinases including MAPK, and is driven by transcription factors like NFκB, which have been reported to directly antagonize PPARγ (Fig. 1–Fig. 3). Tumor necrosis factor (TNF)α in particular exerts potent antiadipogenic effects [88, 89], and interleukin (IL)-1β and interferon (IFN)γ have been observed to induce delipidation of human adipocytes [90]. Treatment with 10,12 CLA has also been shown to increase the expression or secretion of IL-6 and IL-8 from murine [24, 50] and human [73, 77, 86] adipocyte cultures, as well as TNFα and IL-1β suppressing PPARγ activity and insulin sensitivity [32, 76, 77, 91].

In human subjects, 10,12 CLA supplementation also increases the levels of inflammatory prostaglandins (PG)s [58, 92]. For example, women supplemented with mixed CLA isomers (5.5 g/day for 16 weeks) exhibited higher levels of C-reactive protein in serum and the prostaglandin 8-iso-PGF2α in urine [93]. Accordingly, the expression of cyclooxygenase 2 (COX-2), an enzyme involved in the synthesis of PGs, was elevated in cultures of newly differentiated human adipocytes treated with 10,12 CLA [71]. Furthermore, 10,12 CLA increased PGF2α secretion from human adipocytes [87].

Inflammatory PGs like PGF2α have been reported to inhibit adipogenesis via phosphorylation of PPARγ by MAPKs [94], and via induction of the normoxic activation of the hypoxia inducible factor-1 (HIF-1). HIF-1 decreases PPARγ and C/EBPα expression by upregulating transcriptional repressor DEC1 [95, 96]. In addition, PGF2α may inhibit adipogenesis by inducing pro-inflammatory transcription factors that antagonize PPARγ.

Notably, data from our laboratory show that ERK and NFκB activation play a critical role in 10,12 CLA’s suppression of adipogenic genes and insulin-stimulated glucose uptake [73, 86]. The molecular mechanisms by which NFκB and other inflammatory transcription factors inhibit PPARγ activity are not completely understood, but results from a study in the bone marrow stromal cell line ST2 suggest that NFκB interacts directly with PPARγ, preventing it from binding DNA [97, 98]. In a different study using chromatin immunoprecipitation, the DNA binding activity of PPARγ did not appear to be affected by TNFα stimulation in 3T3-L1 adipocytes or human embryonic kidney 293 cells. Instead suppression of PPARγ activity involved IKK activation, leading to IκBα degradation and nuclear localization of histone deacetylase (HDAC)3, a component of the PPARγ corepressor complex [99, 100]. NFκB may also repress PPARγ activity via interaction with the DNA-bound retinoid X receptor (RXR)-PPARγ heterodimer, thereby interfering with coactivator recruitment.

Taken together, these data suggest that 10,12 CLA antagonizes PPARγ activity via inflammatory mediators such as MAPKs and NFκB, and/or via induction of the inflammatory PG and adipocytokine production that in turn antagonizes PPARγ activity.

CLA causes insulin resistance

Insulin-stimulated glucose uptake in WAT is mediated via GLUT4 (Fig. 4). Defects in insulin signaling or suppression of GLUT4 translocation to the plasma membrane are primary causes of insulin resistance in adipocytes (Fig. 4,5).

Insulin resistance has been reported in overweight or obese mice [50] or humans [92, 106–108] and in cultures of 3T3-L1 [71] or human adipocytes [72, 86, 87] following supplementation with a CLA mixture or 10,12 CLA alone. Moreover, supplementation with a CLA mixture or 10,12 CLA has been shown to induce hyperinsulinemia, associated with insulin resistance in animals and humans [reviewed in 13]. CLA may inhibit insulin signaling by 1) activating inflammatory pathways and stress kinases, and 2) downregulating expression of genes involved in the insulin signaling and glucose uptake pathways.

In addition, some studies in 3T3-L1 cells [24] and cultures of newly differentiated human adipocytes [71] have suggested that CLA inhibits insulin signaling via increased expression of suppressor of cytokine signaling (SOCS)-3. SOCS-3 impairs insulin signaling and glucose uptake by promoting the phosphorylation of the inhibitory serine 307 on insulin receptor substrate (IRS-1), leading to its ubiquination and proteasome degradation [109]. CLA appears to induce SOCS-3 indirectly via inflammatory cytokines such as TNFα and IL-6 [73, 110]. 10,12 CLA treatment has also been demonstrated to decrease the protein levels of insulin receptor (IR)β [24] and IRS-1 [24, 86], signaling proteins critical for insulin sensitivity. In addition, 10,12 CLA treatment reduced tyrosine phosphorylation (i.e., activation) of insulin receptor (IR)β and IRS-1 in 3T3-L1 adipocytes [24].

10,12 CLA may also directly impair the uptake of glucose and fructose by suppressing the expression of their transporters. 10,12 CLA decreased GLUT4 gene and protein expression [71, 73, 86] in cultures of newly differentiated human adipocytes. In addition, CLA reduced the gene expression of GLUT4 and the glucose/fructose transporter SLC2A5 in WAT and 3T3-L1 adipocytes supplemented with 10,12 CLA [50].

CLA may also cause insulin resistance via its effects on the insulin-sensitizing hormone adiponectin. Adiponectin mRNA levels were decreased following supplementation with 10,12 CLA in mice [24] and in cultures of human adipocytes [73]. Consistent with these data, 10,12 CLA or a CLA mixture decreased adiponectin assembly or secretion in cultures of murine adipocytes, respectively [18, 112]. Because adiponectin is a target gene of PPARγ [113], its suppression may be due, in part, to 10,12 CLA antagonizing PPARγ activity. Accordingly, the PPARγ agonist rosiglitazone was able to prevent CLA-induced suppression of adiponectin serum levels and insulin resistance in mice [95]. However, another PPARγ agonist, troglitazone, did not prevent the 10,12 CLA suppression of adiponectin expression, although it prevented 10,12 CLA suppression of TG levels and adiponectin oligomer assembly in 3T3-L1 adipocytes [18]. These results indicate that CLA may also suppress adiponectin expression by a PPARγ-independent mechanism.

Potential mechanisms responsible for these antiobesity properties of 10,12 CLA include 1) decreasing energy intake by suppressing appetite 2) increasing energy expenditure in WAT, muscle, and liver tissue, or LBM, 3) decreasing lipogenesis or adipogenesis, 4) increasing lipolysis or delipidation, and 5) apoptosis via adipocyte stress, inflammation, and/or insulin resistance.

Based on these data, we propose the following working model (Fig. 7) depicting the mechanisms by which 10,12 CLA decreases WAT mass. We speculate that 10,12 CLA binds to a cell surface FA receptor, or diffuses or flip-flops into adipocytes, thereby activating upstream signals. These upstream signals induce an ISR, FFA release, and activation of NFκB and MAPKs that may directly antagonize PPARγ activity. Increased release of PGs and cytokines may further antagonize PPARγ activity, leading to insulin resistance and delipidation. The resulting FFA accumulation in blood, liver, and muscle increases FFA oxidation and FFA-induced insulin resistance in these tissues. If energy expenditure is not sufficient to completely oxidize these elevated levels of FFAs, hyperlipidemia, hyperglycemia, and lipodystrophy can result.
 
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