Conjugated linoleic acid was discovered in 1978 when Michael Pariza, PhD and other researchers at the University of Wisconsin were seeking possible cancer-causing compounds in meat. Instead, they found an anti-cancer compound. Preliminary animal and test tube studies have shown that it might reduce the risk of cancer at several sites, including breast, prostate, colorectal, lung, skin and stomach. Researchers are optimistic that it will produce a similar protective effect in humans.
Conjugated linoleic acid (CLA) is a fatty acid and is naturally present in ruminant milk, ruminant meat and in human breast milk.
1.
CLA refers to a class of isomers of the essential fatty acid linoleic acid, of which two of the CLA isomers [cis-9, trans-11 (c-9,t-11) and trans-10, cis-12 (t-10,c-12) CLA] have shown most physiological effects.
The concentrations of CLA in ruminant derived products range from 3 to 7 mg CLA/g fat depending on source and processing of products (1). Estimated average daily intake of CLA from these dietary sources ranges from 0.10 up to 1 gram of CLA and varies for different countries.
2.
CLA also naturally occurs in vegetable oils in which the two active CLA isomers are present in equal amounts.
3.
Physiological effects of CLA have been observed in several animal and human studies. The studies are performed with mixtures of the CLA isomers that contain mostly c-9,t-11 CLA and t-10,c-12 CLA in roughly equal amounts or as enriched forms of each CLA isomer. Several studies showed positive health effects for CLA, such as an improvement of the immune response, anti-diabetic and anti-atherogenic effects. However, most animal and human studies have demonstrated that CLA reduces body fat mass and increases lean body mass. The type of fat or fatty acid is a determinant of the efficiency of energy storage. Unsaturated fatty acids have in general a lower efficiency of energy storage than saturated fatty acids and result in a lower proportion of body fat. For example fish oil which contains the very long chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and α- and γ-linoleic acids have been documented to lower body fat in animals (4,5). More recently, CLA, which can be made from linoleic acid by isomerisation, has also been found to reduce significantly body fat in animals and humans. This lower efficiency of energy storage is mediated by enhanced energy expenditure. The enhanced energy expenditure may be the result of the following events:
• Long chain unsaturated fatty acids are preferentially oxidized in the peroxisomes instead of the mitochondria and oxidation of fatty acids in the peroxisomes results in the formation of less ATP and as a consequence a higher energy expenditure.
• The incorporation of more unsaturated fatty acids, especially n-3 fatty acids into the phospholipids of the inner membranes of the mitochondria may result in membranes that are more permeable for protons which lead to proton leakage across the inner mitochondrial membrane. As a result, the proton motive force will generate less ATP, less energy will be stored in the form of ATP, and more energy is lost as heat.
4.
Unsaturated fatty acids may act as ligands for transcription factors (e.g. PPARs) and subsequently affect the enzymes for oxidation or synthesis of fatty acids and the uncoupling proteins (UCP). By means of this mechanism, unsaturated fatty acids may e.g. enhance the oxidation of fatty acids and up regulate the UCPs to dissipate the extra energy generated by the increased oxidation. Thus, the body fat lowering properties of unsaturated fatty acids is mediated by a lower efficiency of energy storage and an increased energy expenditure or heat production. Further, it appears that these effects on body fat are more pronounced when the metabolic rate of the species studied is higher. For instance, mice have a 7 times higher metabolic rate than humans, and various studies have shown that the body fat lowering effect of CLA in mice is also considerably higher than in humans.
Mechanism of Action Several mechanisms of action of CLA have been proposed. The effects of CLA may not be explained by one single mechanism, since the two active isomers of CLA induce different effects. One of the mechanisms proposed to explain the effects of CLA on body composition is via the peroxisome proliferator-activated receptor (PPAR). PPAR is a member of the nuclear receptor super family and is a ligand activated transcription factor that affects gene expression in a tissue, sex and species-specific manner. Specific PPAR responsive elements have been identified in the regulatory regions of genes encoding lipid metabolizing enzymes. PPAR is forming a complex with another nuclear receptor family, the retinoid X receptor (RXR). This complex binds to the peroxisome proliferator response element (PPRE) of a target gene, and modifies it's expression. Various types of PPAR (α, γ1, γ2, and δ) have been identified in rodents and humans.
PPARα is highly expressed in liver and may play a crucial role in regulating lipid metabolism in the liver. Since most of the target genes of PPAR are involved in the control of lipid and energy metabolism, and since PPAR is activated by lipids such as fatty acids, it is evident that the family of PPAR's plays a crucial role in translating nutritional signals into changes in gene expression. PPRAα is expressed
predominantly in liver, heart, kidney, intestinal mucosa, and brown adipose tissue, thus tissues with high catabolic rates for fatty acids and peroxisomal metabolism. PPARy is predominantly expressed in adiposetissue and has been linked to adipocyte differentiation.
So far, PPRE has been identified as the promotor of genes of various peroxisomal and mitochondrial fatty acid oxidation enzymes, and it has been demonstrated that the expression of these genes is under control of PPAR. Poly-unsaturated fatty acids activate PPAR more than saturated and monounsaturated fatty acids and fatty acids and eicosanoids are ligands of PPAR to induce its DNA binding and expression of target genes. The role of the transcription factor sterol regulatory element binding proteins (SREBPs) in lipid and carbohydrate metabolism is demonstrated in several studies. Roche et.al showed that the c-9.t-11 CLA isomer inhibit the SREBP expression in the liver.
Upon activation by fatty acids and drugs that affect lipid metabolism, PPAR's control the expression of genes implicated in intra and extra cellular lipid metabolism, most notably those involved in peroxisomal β-oxidation. In animals, brown adipose tissue (brown fat) also plays a role in lipid and energy metabolism. This tissue contains, unlike typical (white) adipose tissue numerous mitochondria whose cytochromes cause its brown color. The mechanism of heat generation in brown fat involves the regulated uncoupling of oxidative phosphorylation in their mitochondria. These mitochondria in brown fat contain the uncoupling protein (UCP1) that is absent in the mitochondria of other tissues and which act as a channel to control the permeability of the inner mitochondrial membrane to protons.
Across the inner mitochondrial membrane, a proton gradient is generated (caused by the energy released by oxidation) and the free energy sequestered by the electrochemical gradient powers the synthesis of ATP. Recently, a homologue of the uncoupling protein UCP1 has been cloned , UCP2 and UCP-3 which is present in skeletal muscles. Several studies have been done to examine the role of these uncoupling proteins on metabolic rate and obesity in humans. Also the role of exercise on energy metabolism has been linked to UCP3. It has been hypothesized that UCP3 may function as a fatty acid transporter across the inner mitochondrial membrane. It has been shown that tumour necrosis factor (TNF)-α and UCP2 mRNA levels increased in isolated adipocytes from CLA-fed mice compared to control mice. Because it is known that TNF-α induces apoptosis of adipocytes and up regulates UCP2 mRNA, a marked increase of TNF-α mRNA with an increase of UCP2 mRNA in adipocytes explained the CLA induces apoptosis according to Tsuboyama-Kasoka et al. (14). UCP2 is the predominant uncoupling protein in white adipose tissue, and an increase in UCP2 may contribute to increased energy expenditure by CLA feeding.
In Vitro Effects For investigating the possible effect of an ingredient on fat cells, a cell line of fat cells (for example the 3T3-L1) is used extensively. These cells typically grow in a culture medium and are induced to differentiate by hormonal treatment. Treatment of 3T3-L1 cells with CLA inhibited differentiation of the fat cell in a dose-dependent manner. These findings imply that fat reduction observed in in vivo studies caused by CLA treatment may be attributed to its inhibition of both cell growth (proliferation) and differentiation of preadipocytes in animals. Park et al. (6) found in cultured 3T3-L1 adipocytes, that the t-10,c-12 CLA isomer is responsible for the observed reduction of the lipoprotein lipase activity and the intracellular triacylglycerol and glycerol, and enhanced glycerol release into the medium. The c-9,t-11 CLA isomer did not affect these biochemical activities. The authors therefore suggested that CLA-associated body composition changes result from feeding the t-10,c-12 CLA isomer.
Supplemental Solutions The typical North American diet does not deliver enough conjugated linoleic acid to get the weight-loss benefits. To get the level used in research studies (1,000 mg with meals three times daily) you would have to eat about 5.8 pounds of fresh ground beef, 53 ounces of American cheese or 1.7 gallons of vanilla ice cream! Simply stated, you cannot get the amount needed for weight loss from your diet. Fortunately, scientists are able to convert the linoleic acid of pure safflower oil into CLA to make it available as a nutritional supplement.
No side-effects or drug interactions have been reported with conjugated linoleic acid supplementation, but since its effects during pregnancy and lactation have not been sufficiently evaluated, it should not be used then.
Bioavailability CLA has been identified in human adipose tissue, serum, bile and duodenal juices The primary CLA in human serum lipids is the c-9,t-11 isomer. The fatty acid composition of blood lipids and adipose tissue is markedly influenced by the fatty acid composition of dietary fat. In addition, the time required for changes in dietary fat to be reflected in plasma lipids is not exactly known. Huang et al. showed that short-term (4-wk) consumption of a diet supplemented with Cheddar cheese (112 g/day, providing about 180 mg CLA) significantly increased plasma CLA concentrations by 19-27%.
Michael T. Murray is a graduate, faculty member and trustee of Bastyr University in Seattle, Washington. He has written over 20 books, including the best-selling Encyclopedia of Natural Medicine.
Source: alive #224, June 2001
Original Research Communication
Conjugated linoleic acid supplementation for 1-y reduces body fat mass in healthy overweight humans1,2,3
Jean-Michel Gaullier, Johan Halse, Kjetil Høye, Knut Kristiansen, Hans Fagertun, Hogne Vik and Ola Gudmundse
1 From the Scandinavian Clinical Research AS (JMG, KK, and OG) and the Scandinavian Statistical Services AS (HF), Kjeller, Norway; the Betanien Medical Center, Oslo (JH); the Helsetorget Medical Center, Elverum, Norway (KH); and the Matforsk (Norwegian Food Research Institute), Ås, Norway (HV).
Background
Short-term trials showed that conjugated linoleic acid (CLA) may reduce body fat mass (BFM) and increase lean body mass (LBM), but the long-term effect of CLA was not examined.
Objective
The objective of the study was to ascertain the 1-y effect of CLA on body composition and safety in healthy overweight adults consuming an ad libitum diet.
Design
Male and female volunteers (n = 180) with body mass indexes (in kg/m2) of 25–30 were included in a double-blind, placebo-controlled study. Subjects were randomly assigned to 3 groups: CLA-free fatty acid (FFA), CLA-triacylglycerol, or placebo (olive oil). Change in BFM, as measured by dual-energy X-ray absorptiometry, was the primary outcome. Secondary outcomes included the effects of CLA on LBM, adverse events, and safety variables.
Results
Mean (± SD) BFM in the CLA-triacylglycerol and CLA-FFA groups was 8.7 ± 9.1% and 6.9 ± 9.1%, respectively, lower than that in the placebo group (P < 0.001). Subjects receiving CLA-FFA had 1.8 ± 4.3% greater LBM than did subjects receiving placebo (P = 0.002). These changes were not associated with diet or exercise. LDL increased in the CLA-FFA group (P = 0.008), HDL decreased in the CLA-triacylglycerol group (P = 0.003), and lipoprotein(a) increased in both CLA groups (P < 0.001) compared with month 0. Fasting blood glucose concentrations remained unchanged in all 3 groups. Glycated hemoglobin rose in all groups from month 0 concentrations, but there was no significant difference between groups. Adverse events did not differ significantly between groups.
Conclusion
Long-term supplementation with CLA-FFA or CLA-triacylglycerol reduces BFM in healthy overweight adults.
Reference: Gaullier JM, Halse J, Hoye K, Kristiansen K, Fagertun H, Vik H, Gudmundsen O. (2003). Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. American Journal of Clinical Nutrition, 79, 1118-1125
