Discovery of Leptin

For decades, the ob/ob mouse sat in Jackson Laboratory cages eating without restraint, growing to three or four times normal weight, and offering no explanation for why. Beginning in the late 1960s, Douglas Coleman joined the circulations of pairs of mice. Normal mice attached to diabetes (db) mutants stopped eating and starved, and obese (ob) mice attached to normal partners ate less, which suggested that ob mice lacked a circulating satiety factor while db mice could not respond to it. What that signal was, nobody could determine with the tools then available.

Jeffrey Friedman, who joined Rockefeller University in 1986 and worked early on with Rudy Leibel, spent eight years tracking the ob gene by positional cloning, a laborious strategy that required mapping the gene's location before its sequence was known. In 1994 they identified the gene and showed it encoded a 167-amino-acid protein secreted by adipose tissue. Because the protein made animals slim down, Friedman named it leptin, from leptos, the Greek word for thin. It acted on the brain to suppress food intake, and ob/ob mice made no functional leptin; a receptor was identified in late 1995.

The finding recast adipose tissue as an endocrine organ, not merely a passive energy depot. In 1997 Sadaf Farooqi and Stephen O'Rahilly in Cambridge identified rare people with mutations in the leptin gene, who had severe early-onset obesity and constant hunger. They proved extremely sensitive to leptin replacement: one boy, morbidly obese at three, was at the 75th percentile for weight by seven after daily injections.

The therapeutic optimism that followed was quickly tempered by an unexpected finding. Most obese individuals have elevated leptin levels, not low ones; their brains had become resistant to the signal, in a manner analogous to insulin resistance in type 2 diabetes. Leptin replacement did not produce meaningful weight loss in common obesity, and researchers turned to the question of why obese people resist their own leptin.

Leptin also proved useful in lipodystrophy, in which patients lack fat tissue and make too little of the hormone. Researchers traced leptin's downstream targets through the hypothalamic arcuate nucleus, identifying the melanocortin system, the MC4 receptor, and a web of appetite-regulating neuropeptides that had been invisible before 1994. Those circuits became targets for anti-obesity drug development.