Individuals vary in their ability to control body weight. Obesity is frequently associated with insulin resistance and diabetes, which often leads to heart, kidney and other diseases. Obesity is an important health problem and has reached epidemic proportions in many countries. The discovery by Douglas L Coleman led the way to the work of Jeffrey M Friedman, who uncovered a hormone that increased our understanding of the biological pathways that regulate body weight.

These studies began with the work of Douglas L Coleman at The Jackson Laboratories in Bar Harbor, Maine, USA. Coleman investigated two strains of mice (ob/ob and db/db), both of which exhibit grossly morbid obesity and severe diabetes caused by homozygosity, for two different recessive mutations. Coleman suspected that the ob/ob mice lacked a circulating hormone whereas the db/db mice overproduced it. So, he performed experiments in which the circulations of these 2 different strains of mice were joined together in a technique called parabiosis. When attached to a db/db mouse, the ob/ob mouse stopped eating and lost weight, while the db/db mouse remained obese. Coleman concluded that the ob/ob mice failed to produce a functional hormone that inhibits eating whereas the db/db mice overproduced the hormone, but lacked the receptor necessary to receive and transmit the hormone signal. When the circulations of ob/ob and db/db mice were joined during the parabiosis, the anti-obesity hormone from the db/db mouse crossed into the ob/ob mouse and induced its weight loss. The db/db mouse showed no change in body weight because it lacked the receptor for this hormone and therefore remained obese.

Coleman’s hormone hypothesis was validated dramatically by Jeffrey M Friedman, working at The Rockefeller University in New York, USA. Using the then new techniques of gene mapping associated with conventional matings in mice, Friedman narrowed down the genetic region that contains the ob gene. The task was arduous because the genetic trait is recessive and the heterozygous mice have no manifestations. Thus he had to breed these mice for many generations to locate the chromosome that contained the gene locus. After years of work he found the gene on mouse chromosome 6. The gene encoded a secreted protein that Friedman named leptin. This gene was mutated in the ob/ob mouse resulting in the absence of leptin production. As the function of leptin was to suppress appetite, these mice continued to eat and became obese. Surprisingly, the leptin gene was active in fat cells and secreted leptin. This was a totally unexpected result because fat cells were thought to form a passive tissue for storage and not known before to produce and secrete important hormones. Subsequently, Friedman and others identified the leptin receptor, and showed that the leptin receptor gene is defective in db/db mice, thereby confirming Coleman’s foresight in proposing his hypothesis.

The Coleman/Friedman discoveries foster an explosion in our knowledge of how fat cells signal the brain to control energy intake. Friedman showed that leptin acts in the hypothalamus region of the brain to trigger a cascade of signals that regulate food intake.

A morbidly obese human individual with a mutation in the leptin gene was later found by English scientist Stephen O’Rahilly who demonstrated that leptin is also important for humans. Individuals with leptin mutations have insatiable appetites from birth and in the case of one boy, a staggering weight of 42 kg was reached by 3 years of age. Injection of leptin into this boy led to rapid weight loss and reduced food intake. Subsequently, mutations in the leptin receptor were identified in other obese people – human equivalents of db/db mice. Today we know that all normal humans depend on leptin to control their body weight.

Leptin and leptin receptor mutations are not common in humans and unfortunately, leptin is not effective when administered to obese humans who have normal genes for leptin and its receptor. Ongoing studies are beginning to determine why ordinary obese humans become resistant to their own leptin.

The discoveries of Coleman and Friedman have changed our concept of obesity from a defect in willpower to a misbalance of hormone signalling. Stimulated by their work, scientists identified other hormonal signals for appetite control.

Soon after its discovery, Farid Chehab at the University of California, San Francisco and Jeffrey Flier at Harvard University found that leptin triggers reproductive function. These studies led to promising ongoing clinical trials to treat some types of amenorrhea. Furthermore, Marc Reitman at NIH and Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical School showed that loss of body fat – so called lipodystrophy – in mice results in drastically low leptin levels and onset of diabetes, which could be treated with leptin. Based on these observations, individuals with lipodystrophy and diabetes can now be treated with exogenous leptin to prevent or ameliorate their diabetes. All of these advances would have been inconceivable without the pioneering work of Coleman and Friedman.


Life Science and Medicine Selection Committee
The Shaw Prize

7 October 2009, Hong Kong