Discovery of Leptin and Its Role in Obesity

In 1950, mutant obese mice with a voracious appetite were discovered by chance in a mouse colony at Jackson Laboratory in Bar Harbor, Maine. These mice exhibited an (ob) genetic mutation. In the 1960s, Douglas Coleman identified mice with both diabetic (db) and obese (ob) genetic mutations. After extensive genetic inbreeding and testing, Coleman, in collaboration with Rudolph Leibel, proposed that the obese (ob) mice lacked a protein hormone regulating food intake and body weight, while the diabetic (db) mice could produce the hormone but lacked the receptor to detect its signal.

In 1994, working at Rockefeller University, Leibel and Jeffrey Friedman identified the gene and hormone responsible for regulating food intake and body weight, naming the hormone leptin (from the Greek word "leptos," meaning "thin"). The genetically mutated obese mice lacked the ability to produce functional leptin, a protein composed of 167 amino acids, primarily synthesized in fat cells. Leptin functions in the hypothalamus to block neuropeptide Y (NPY), a feeding stimulant, and promotes the synthesis of alpha-melanocyte-stimulating hormone (MSH), which plays a role in appetite suppression and skin pigmentation.

Leptin is believed to be involved in the body's adaptation to starvation. When body fat decreases, plasma leptin levels drop, triggering an increase in feeding and a decrease in energy expenditure until normal fat mass is restored. Initially, leptin was hoped to offer a solution for weight reduction in obese individuals. However, human trials revealed that despite frequent and high doses, leptin produced only modest weight loss. As a protein, leptin must be injected since it is inactivated by stomach enzymes if taken orally. The search for effective leptin-based treatments continues.

One of a series of sumo wrestlers drawn by Utagawa Kuniyoshi (1797–1861), a master of Japanese woodblock prints and painting. Competitors in sumo wrestling have no maximum weight limits and have been known to weigh in excess of 500 pounds (225 kilograms).