Endocrinology · 1994
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 1960s, Douglas Coleman performed parabiosis experiments joining the circulation of ob/ob mice to lean controls and showed that the lean animals produced something the obese mice lacked, a circulating signal that told the brain to stop eating. What that signal was, nobody could determine with the tools then available.
Jeffrey Friedman's laboratory at Rockefeller University spent eight years tracking the ob gene by positional cloning, a laborious chromosome-walking 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. Friedman named it leptin, from the Greek for thin. The protein acted on receptors in the hypothalamus to suppress food intake and increase energy expenditure, and it was entirely absent in ob/ob mice.
The finding recast adipose tissue as an endocrine organ, not merely a passive energy depot. When investigators found rare humans with inactivating mutations in the ob gene, the clinical picture was similar to the mouse: severe early-onset obesity, hyperphagia, and impaired reproductive function. Treatment with recombinant leptin in those patients restored near-normal body weight and corrected the metabolic abnormalities, confirming the pathway was preserved across mammals.
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 pharmaceutical development pivoted toward understanding central resistance mechanisms.
Despite the therapeutic setback, the discovery reorganized the entire field. 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 remain active targets for anti-obesity drugs, including agents approved in subsequent decades that work on pathways leptin's discovery first illuminated.
Key People
- Jeffrey Friedman — Rockefeller University molecular geneticist who cloned the ob gene
- Douglas Coleman — Jackson Laboratory researcher whose parabiosis work predicted leptin's existence
- Rudolph Leibel — Columbia University obesity researcher, collaborator in ob gene mapping
- Stephen O'Rahilly — Cambridge clinician who identified ob gene mutations in severely obese humans
Nature, 1994
Related landmarks
- 1993 · DCCT (Diabetes Control and Complications Trial) (Endocrinology)
- 1998 · UK Prospective Diabetes Study (UKPDS 33) (Endocrinology)
- 1982 · Recombinant Human Insulin (Humulin) Approval (Endocrinology)
- 2008 · ACCORD (Endocrinology)