The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 5 No.
5 • October 2002
Isomer of Conjugated Linoleic Acid (CLA) Induces
Hyperinsulinemia and Fatty Liver in the Mouse
Dose determines differential effects of bioactive
substances such as CLA. CLA is widely used for its potential fat-reducing
effects. It is known to have powerful anticarcinogenic effects. The mechanisms
for these effects are still not entirely clear, though much has been published
on this subject.
The anticarcinogenic effects have been reported to appear
in animals when they are fed much lower amounts of CLA than what is needed to
affect weight. Mammary cancer development in rats treated with the carcinogen
DMBA was reduced in a dose-dependent manner, with total mammary tumor yield
reduced by 22, 36, 50, and 58% in the 0.05, 0.1, 0.25, and 0.5% CLA diets,
respectively. The researchers report that intergroup comparison showed that as
little as 0.1% CLA was sufficient to cause a significant reduction in the number
of tumors. Another study noted that there appeared to be a dose-dependent
protection of synthetically prepared CLA against dimethylbenz(a)anthracene-induced
mammary tumors in rats at levels of 1% CLA and below, but no further beneficial
effect was evident at levels above 1%.
Fat reduction may take larger amounts of CLA. One study
reported that, using a mixture of synthetically prepared cis-9,trans-11-CLA
(37%) and trans-10,cis-12-CLA (46%) in mice, there was no significant effect on
weight gain if diets contained 0.5% CLA or less. In another study, it was
reported that the trans-10,cis-12-CLA isomer is responsible for body-composition
changes in mice in vivo, whereas the cis-9,trans-11-CLA isomer was without
activity in this respect.
A recent study reported that mice fed diets enriched in
trans-10,cis-12-CLA at 0.4% w/w for 4 weeks developed lipoatrophy (loss of fat),
hyperinsulinemia (abnormally high insulin levels), and fatty livers, whereas
diets enriched in cis-9,trans-11-CLA had no significant effects. The researchers
suggest that the hyperinsulinemia may have induced fatty liver by increasing
liver fatty acid intake and lipogenesis. They note that a trend toward an
increase in insulin levels in CLA-supplemented humans has been reported.
However, a different paper reporting on a double-blind, 12-week study of 53
healthy men and women, aged 23–63, receiving either 4.2 g/d of CLA or the same
amount of olive oil, observed no major differences in plasma insulin, blood
glucose, serum lipoproteins, nonesterified fatty acids, or plasminogen activator
The authors explain that CLA-induced decrease in adipose
tissue mass is associated with an increase in energy expenditure [which may be
secondary to a stimulation of the sympathetic (adrenergic) nervous system] and
that CLA reduces lipid uptake and storage by inhibiting lipoprotein lipase and
stearoyl-CoA desaturase I. They note that it has been suggested that the
decrease in fat tissue involves an apoptotic mechanism (cell death of fat cells)
linked to an increase in tumor necrosis factor-alpha production. Tumor necrosis
factor-alpha is a cytokine involved in inflammation, among other things.
A study reported in the August 2001 International Journal
of Obesity found that 14 men with significant abdominal fat receiving 4.2 grams
of CLA a day for 4 weeks had an average loss of 1.4 cm in waist circumference,
while there was no decrease in the placebo group. The average person eats about
500 grams of food a day. 4.2 grams of CLA then represents 0.84% of the diet.
This is 8 times the 0.1% CLA that was reported to reduce mammary cancers in
One (for women) or two (for men) glasses of alcohol a day
provides a myriad of health benefits, including reduced risk of cardiovascular
disease, increased HDL, and increased insulin sensitivity, but 16 glasses of
wine a day may very well result in a fatty liver.
Also, the detrimental effects on animals deprived of
essential fatty acids are enhanced by CLA. Hence, those on a low-fat diet who
are also taking CLA may be particularly vulnerable to those adverse effects.
Living a long time means you have to be careful about
risks. Mice and rats are not people and may be more sensitive to the effects of
CLA that result in fatty liver and hyperinsulinemia, but until more studies of
potential adverse effects have been done at the high doses of CLA used in
weight-reducing regimens, you don't know. For several months, Durk was taking
4 grams a day of CLA (and hadn't noticed any effect on either weight or
percent body fat), and Sandy was taking 3 grams a day (she didn't notice any
effects on weight or body fat, either) before we read this paper. (Neither of us
was on a calorie-restricted diet.) We have both reduced our dose to 1 gram a
day, which we expect to provide significant anticarcinogenic effects, until
there are more data available on possible side effects of high-dose CLA.
- Ip, Clement, Scimeca, Thompson. Conjugated linoleic
acid. Cancer 74:1050-4 (1994).
- Ip, Singh, Thompson, Scimeca. Conjugated linoleic acid
suppresses mammary carcinogenesis and proliferative activity of the mammary
gland in the rat. Cancer Res 54:1212-5 (1994).
- Hayman et al. High intake, but not low intake, of CLA
impairs weight gain in growing mice. Lipids 37(7):689-92 (2002).
- Pariza, Park, Cook. Conjugated linoleic acid and the
control of cancer and obesity. Toxicol Sci 52(Suppl):107-10 (1999).
- Clement, Poirier, et al. Dietary trans-10,cis-12
conjugated linoleic acid induces hyperinsulinemia and fatty liver in the mouse.
J Lipid Res 43:1400-9 (2002).
- Smedman, Vessby. Conjugated linoleic acid
supplementation in humans—metabolic effects. Lipids 36(8):773-81 (2001).
- Reaney, Westcott. Conjugated linoleic acid—seven
decades of achievement. Inform 13:802-5 (2002).