Leptin as a treatment for obesity? Fat chance

The prospect of treating obese humans with leptin, a natural appetite suppressant secreted by fat cells, is looking increasingly slim after a new study by a Melbourne researcher.

Touted as a potential miracle weight loss when it was first tested in obese rats in the mid-1990s, leptin subsequently failed the pinch test in all but a tiny minority of obese humans.

A new study by a Melbourne University and the Florey Institute has found that leptin, administered intravenously to lab rats on a weight loss diet, fails even to maintain their weight loss when they return to ad libitum feeding.

The project, led by honours student Eleni Velkoska, of the Department of Pharmacology, has provided further evidence of the complexity of the brain-body signalling networks that regulate appetite and energy metabolism.

As adipose cells in the body's fat-storage depots become overcharged with fat, they begin to secrete leptin. The leptin molecules travel through the bloodstream to the brain, where they attach to leptin receptors to the hypothalamus, the brain's appetite centre, suppressing the urge to eat.

The more fat cells, the higher the level of leptin in the bloodstream, and the greater the degree of appetite suppression; leptin levels drop during fasting, increasing appetite.

In theory, the brain-body feedback loop mediated by leptin should prevent obesity by switching off appetite in obese individuals -- and the theory appeared to be confirmed when the hormone produced spectacular weight loss in leptin-deficient, obese laboratory rodents in the mid-1990s.

But only a small minority of obese human volunteers benefited from leptin therapy -- those from families with inherited genetic disorders that prevented them secreting leptin, or deactivated their hypothalamic leptin receptors.

Velkoska, whose project was co-supervised by Assoc Prof Margaret Morris and the Florey's Dr Richard Weisinger, has published her findings in the International Journal of Obesity.

Her study was designed to test a current theory that the brain has a saturation point for leptin, beyond which the hormone produces no further appetite-suppressing effect.

The study tested whether a low dosage of leptin, administered intravenously by drip, would suppress appetite and stabilise bodyweight in non-obese rats that had lost weight on a 12-day diet.

By augmenting depleted serum levels of leptin in the hungry rats, the extra leptin should have suppressed their appetites.

Returned to unrestricted diet of rat chow after the treatment, the test rats ate less than a saline-placebo control group for the first six days, but by 14 days both groups had regained all the weight they had lost.

Velkoska said because the experiment involved only a low dose of leptin, the results should be interpreted with caution.

According to Morris, the hormone was too expensive to run a parallel treatment that have might have produced a weight-stabilising effect at a higher dosage. But she said rats, and probably humans too, appeared to have an inbuilt set-point for bodyweight.

"Following their diet, the rats were probably just trying to return to their set-point, or their normal body weight. A similar thing is observed in humans when we lose weight due to illness," she said.

Morris said many other variables were involved in regulating bodyweight, and she is investigating other nerve-signalling molecules that regulate appetite.

At next week's meeting of the Australian Society for Neuroscience in Adelaide, she will present the results of her recent research into how overfeeding in newborn rats may cause them to become obese adults.