Edited by: Thomas W. Durso
'LEPTINOMANIA': A paper coauthored by Jose Caro, now of Lilly Research Laboratories, was the second to look at leptin.
Comments by Jose F. Caro, Lilly Research Laboratories, Eli Lilly and Co., Indianapolis
This paper, according to investigator Jose F. Caro, helped to usher in "leptinomania." It was the second paper to explore leptin, a protein that helps to control weight by regulating appetite and energy expenditure. In the first (Y.R. Zhang et al., Nature, 372:425-32, 1994), Jeffrey M. Friedman at Rockefeller University in New York cloned a mouse's obese (ob) gene. The ob gene encodes for the production of leptin, and when it is mutated in mice, the result is obesity (K.S. Brown, The Scientist, Sept. 16, 1996, page 12).
In this paper, Caro, then chairman of the department of medicine at Thomas Jefferson University in Philadelphia and now the vice president of endocrine research and clinical investigation at Eli Lilly and Co.'s Lilly Research Laboratories in Indianapolis, cloned and sequenced the ob gene in humans. "This is the second paper [in] the era of leptinomania. I prefer to call it the golden days of obesity research," he says with a laugh.
Caro's team presented some interesting findings: While obese mice had a mutated ob gene, obese people did not. "We found something more important than that: The adipose tissue, the fat cells from obese patients, was overproducing the message for this gene."
Obese people had high levels of the messenger RNA for leptin and thus seemed to be producing enough of the hormone. So the researchers came up with a new concept, which they termed leptin resistance. Caro compares it to a similar situation among Type II diabetics. "Patients have plenty of insulin [yet] have insulin resistance. In this case we developed the concept of leptin resistance. The patients are overproducing this gene that's supposed to keep them thin. Yet they are obese, which must mean the brain is not receiving the message."
Caro believes that this paper has been highly cited because its finding that the gene is not mutated in obese people and its postulation of the leptin resistance concept have "been well-accepted by most people working on obesity. Every obese model in animals or humans that has been reported since the Friedman paper has been proven to overproduce leptin. So leptin resistance is a general phenomenon in every animal or human model of obesity. All these animals with obesity or humans with obesity have high leptin."
Since the publication of this report, Caro has written more than 50 papers on obesity research. Among them were articles showing that leptin was increased in the blood of obese patients (R.V. Considine et al., New England Journal of Medicine, 334:292-5, 1996); that the receptor for leptin in the hypothalamus is normal in human obesity (R.V. Considine et al., Diabetes, 19:992-4, 1996); and that the cause of leptin resistance may be the inability of leptin to cross the blood-brain barrier (J. Caro et al., Lancet, 348:159-61, 1996).