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Leptin May Not Cure Obesity After All: Presented at SFN

By Glynn Wilson

NEW ORLEANS, LA -- November 12, 2003 -- The protein hormone leptin may not be the wonder drug to cure the world's rising obesity problem, as some researchers had previously thought, according to a study presented here November 8^th at the Society for Neuroscience 33^rd Annual Meeting.

Leptin does not work in humans, stated lead author, Nina Eikelis, BSc (Hons), an Australian doctoral student at the Baker Heart Research Institute, Melbourne, Australia. Ms. Eikelis' paper was co-authored by Gavin Lambert, PhD, laboratory head, and Murray Esler, MD, head, Cardiovascular Neuroscience Division.

"It was thought that obesity was probably due to the fact that leptin cannot cross to the brain and tell the brain to stop eating," stated Ms. Eikelis. "In fact, leptin may be released by the brain."

The International Obesity Task Force estimates that 300 million people worldwide are obese, making them subject to diabetes, infertility, sleep apnea, cardiovascular problems and premature death.

The causes of obesity have been traced to heredity, metabolic disorders (such as an underactive thyroid), bad social habits due to increased prosperity, psychological factors, and, most recently, an energy imbalance, leading researchers to look at the protein hormone leptin.

Leptin is known to act in the brain at the level of the hypothalamus to reduce the appetite and stimulate thermogenesis. In lab mice, administration of leptin results in significant weight reduction.

"We thought leptin was going to be a great anti-obesity drug. Given to any animal, lean or obese, it reduces their body weight," Ms. Eikelis said. "But it does not work in most humans."

There are a small number of humans who do not produce leptin, Ms. Eikelis noted, so it might work in that small number of cases.

While other researchers have come to believe that human obesity is a state of leptin resistance, evidence from animal and human studies now indicate that leptin is derived from non-adipose stores, such as the pituitary gland, the placenta and the stomach.

This study investigated extra-adipocyte leptin release and whether it is changed in obesity by looking at arteriovenous blood sampling to test for leptin release to plasma from individual organs. Two groups of healthy male volunteers were recruited for the study to avoid the confounding influence of gender.

Using well-established catheter methods, the coronary sinus, renal vein, internal jugular vein and hepatic vein were reached with a fluoroscopic control to look for serotonin turnover in the brain.

A surprising finding was that no leptin overflow was found into the coronary sinus of the heart. Also unexpected was the finding that no net release of leptin was found into the hepatic vein. The proportion of plasma leptin deriving from brain leptin release into the jugular veins was surprisingly large (>40%), and was markedly higher in obese men than lean men.

The authors concluded that the higher leptin levels in obese patients were due to a higher leptin secretion rate, not a reduction in leptin clearance, as had been previously predicted.

By demonstrating brain leptin release, the authors say they have disproved "the notion that leptin resistance exists in human obesity due to failure of leptin to enter the brain and exert its effects in the hypothalamus."

The results of the study suggest that safety signals are not deficient in obese individuals after all, so researchers should look for other causes of obesity, and alternative treatments.


[Study title: Brain Leptin Overflow and Serotonin Turnover in Human Obesity. Abstract 231.6]

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