Safety issues 1241 In animals

The first adverse effects of feeding CLA, and especially the 10t,12c-18:2 isomers, were reported for animals and described for mice by Tsuboyama-Kasaoka et al. (2000). In C57BL/6J mice, supplementation with a 1% equi-molar mixture of the 9c,11t and 10t,12c isomers reduced fat mass but the liver was massively enlarged. Histological analysis revealed a macrovesicu-lar steatosis. Further studies (Clement et al., 2002) showed that mice fed with 10t,12c-enriched CLA developed lipoatrophy, hyperinsulinaemia and fatty liver while the 9c,11t isomer had little or no effect (Clement et al., 2002; Degrace et al., 2003). While adipose tissue mass was shown to decrease after feeding CLA for 6 days, plasma levels of leptin and adiponectin decreased after 2 days of feeding, and hyperinsulinaemia developed on day 6 (Poirier et al., 2005). CLA was shown to alter the capacity of pancreatic islets to secrete insulin and the increase in insulin secretion was correlated to an increase in beta cell mass and number, leading to liver steatosis (Poirier et al., 2005). Degrace et al. (2003) demonstrated using C57BL/6J mice that the steatosis was not due to an alteration of the liver lipoprotein production. A three-fold decrease in plasma triacylglycerol and induction of mRNA expression of low-density lipoprotein receptors suggest an increase in the lipoprotein clearance at the level of liver. Further work also indicated that the steatosis was not due to impaired fatty acid oxidation as in fact in the liver, fatty acid oxidation capacities were increased when mice were fed the 10t,12c isomer, which increased both liver carnitine palmitoyl-transferase I and acyl-CoA oxidase gene expression for example (Degrace et al., 2004).

12.4.2 In humans

Earlier human studies carried out by B erven et al. (2000) on overweight and obese subjects, using gel capsules, only reported small adverse events as a result of feeding CLA isomers for 12 weeks. In this study, blood lipids, haematological parameters, blood electrolytes, and liver safety parameters did not change significantly within the groups during the study. However, three subjects in each treatment reported adverse events such as diarrhoea or gastritis heartburn. No adverse events were also reported in the study of Malpuech-Brugere et al. (2004) when feeding pure isomers of CLA in a food matrix. In the study of Gaullier et al. (2005), who fed CLA isomers as free fatty acids (CLA-FFA) or triacylglycerols (CLA-TG) to healthy overweight subjects for 1 year, followed by a dose of 3.4 g CLA/day as TG for 1 year, similar adverse events such as gastrointestinal pains were reported. However, serum high-density lipoprotein (HDL) cholesterol decreased in the group previously fed CLA-TG. Serum lipoprotein a, Lp(a) also tended to increase in both CLA groups after 24 months. In addition to Lp(a) an increase in the leukocyte and thrombocyte counts was also observed; the authors indicated that these changes were within the normal ranges but may indicate the presence of an inflammatory or immunological response to CLA supplementation. Serum insulin level increased in the CLA-TG group while no modifications were found in the CLA-FFA group.

In a study on subjects with type 2 diabetes, Moloney et al. (2004) showed that a supplementation of 3.0 g/day of CLA for 8 weeks resulted in an increase in fasting glucose concentration and reduction of insulin sensitivity. CLA also reduced fibrinogen concentrations but had no effect on C-reac-tive protein and interleukin-6. In another study (Belury et al., 2003), also with subjects having type 2 diabetes, the quantity of 10t,12c isomer in plasma was inversely correlated with changes in body weight and in serum leptin. Unfortunately no information was available on body composition and insulin sensitivity. Concerns were raised by the findings of the group of Smedman, who carried out studies on a high-risk group of abdominally obese men. None of the studies carried out by this group showed any effects of CLA on body weight or BMI even if CLA resulted in a slight decrease in body fat, particularly of abdominal fat in obese men. On the contrary, CLA isomer induced lipid peroxidation, as reported in Fig. 12.6. Administration of a CLA mixture to obese men at 4.2 g/day for 1 month resulted in an increase of both 8-isoprostaglandin F2a (PGF2a) and of 15-oxo dihydro-PGF2a as indicators of non-enzymic and enzymatic arachidonic acid oxidation, respectively, (Basu et al., 2000) as compared with the control group. However, these peroxidation parameters went back to their original values 2 weeks after cessation of the treatment (Fig. 12.6). In another feeding trial on 60 men with metabolic syndrome, the same team observed the same effect on lipid peroxidation parameters when pure 10t, 12c-18:2 was administered (Fig. 12.7) indicating that the effect observed during the first study could be due to the 10t,12c isomer (Riserus et al., 2002b). Furthermore, feeding this pure isomer also resulted in an increase of C-reactive protein by 110% compared with placebo. The increase in 8-iso-PGF2a was also independently related to insulin resistance and oxidative stress seems closely related to insulin resistance. The 10t,12c-18:2 isomer was also found to induce hyperproinsulinaemia which as reported by the

Fig. 12.6 Effect of feeding and of withdrawing CLA to humans on the excretion of 8-isoprostaglandin F2a (PGF2a) and of 15-oxodihydro-PGF2a in urine.

0.35

0.35

8-iso-PGF2a

15-oxodihydro-PGF2a

Fig. 12.7 Effect of feeding pure 10t,12c and a CLA mixture on plasma C-reactive protein (CRP) and on the excretion of 8-iso-PGF2a and of 15-oxodihydro-PGF2a

ƍTTTTT

8-iso-PGF2a

15-oxodihydro-PGF2a

Plasma CRP

Fig. 12.7 Effect of feeding pure 10t,12c and a CLA mixture on plasma C-reactive protein (CRP) and on the excretion of 8-iso-PGF2a and of 15-oxodihydro-PGF2a authors may predict diabetes and cardiovascular disease (Riserus et al 2004b). Interestingly, a similar effect of an enriched 9c,11t fraction (increased insulin resistance, lipid peroxidation compared with placebo) was observed without affecting serum lipids or glucose concentration (Riserus et al., 2004b) while 10t,12c was shown to increase glycaemia and decrease HDL cholesterol (Riserus et al., 2002a). The authors, however, think that further work with a larger group is needed before any conclusions about the effect of the 9c,11t isomer in obese men can be drawn. In contrast, a study carried out on healthy subjects (Noone et al., 2002) indicated that a mixture of CLA improved plasma triacyglycerol concentrations with no adverse effects on insulin and glucose metabolism.

12.5 Conclusions: conjugated linoleic acid and functional foods

If we consider what has been published on the effects of CLA in animals and humans, the consumption of food containing CLA does not seem to provide enough active component to exert any beneficial activity. As demonstrated for mammary cancer and for atherosclerosis (Sebedio et al., 2003) the active component is the 9c,11t-18:2, and increasing the daily consumption of CLA up to 3 g/day would hardly be possible either by increasing the amount of products containing CLA or/and by enriching products from ruminant origin for example. As previously underlined, a lot of consideration has been given to the second solution and strategies have been proposed not only to enrich milk and meat from ruminants but also pig and chicken tissues. However, methods of enrichment practised for ruminants are different from those used in the latter case. While the fatty acid precursors of CLA are fed to ruminants, ClA mixtures containing both the 9c,11t-and the 10t,12c-18:2 isomers are usually given to pigs and chickens (Watkins and Li, 2003). This latter practice would result in introducing the 10t,12c isomer in the food chain, which may not be a good idea considering the adverse effects observed in some cases with the 10t,12c isomer, as discussed previously.

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