Structure-effect relation of C18 long-chain fatty acids in the reduction of body weight in rats.

OBJECTIVE

To investigate the relationship between chemical structure and physiological effect, the efficacy and the molecular mechanisms involved in the reduction of body weight by C18 fatty acids (stearic, elaidic, oleic, linoleic and 2-hydroxyoleic acids (2-OHOA)).

DESIGN

Ad libitum fed, lean Wistar Kyoto rats treated orally with up to 600 mg kg(-1) of the fatty acids or vehicle every 12 h for 7 days. Besides, starved rats and rats pairfed to the 2-OHOA-treated group served as additional controls under restricted feeding conditions.

MEASUREMENTS

Body weight, food intake, weight of various fat depots, plasma leptin, hypothalamic neuropeptides, uncoupling proteins (UCP) in white (WAT) and brown adipose tissue (BAT) and phosphorylation level of cyclic AMP (cAMP) response element-binding protein (CREB) in WAT.

RESULTS

Only treatment with oleic acid and 2-OHOA induced body weight loss (3.3 and 11.4%, respectively) through reduction of adipose fat mass. Food intake in these rats was lower, although hypothalamic neuropeptide and plasma leptin levels indicated a rise in orexigenic status. Rats pairfed to the 2-hydroxyoleic group only lost 6.3% body weight. UCP1 expression and phosphorylation of CREB was drastically increased in WAT, but not BAT of 2-OHOA-treated rats, whereas no UCP1 expression could be detected in WAT of rats treated with oleic acid.

CONCLUSION

Both cis-configured monounsaturated C18 fatty acids (oleic acid and 2-OHOA) reduce body weight, but the introduction of a hydroxyl group in position 2 drastically increases loss of adipose tissue mass. The novel molecular mechanism unique to 2-hydroxyoleic, but not oleic acid, implies induction of UCP1 expression in WAT by the cAMP/PKA pathway-dependent transcription factor CREB, most probably as part of a transdifferentiation process accompanied by enhanced energy expenditure.