Measurement of leptin and leptin binding in the human circulation.

Abstract

Obesity is an extremely common condition in the Western world, affecting approximately one-third of the population. The cost of treatment of the medical consequences of obesity accounts for a large proportion of the health care budget. It is not surprising, therefore, that the discovery of the `fat busting’ hormone leptin has aroused extensive scienti®c interest and media coverage over the last few years. Since the discovery of leptin in 1994, no fewer than 3000 scienti®c papers, many newspaper articles, much television coverage and a deluge of information on the Internet have appeared. Despite this there is surprisingly little detailed information available to clinical biochemists on leptin measurements and their clinical utility in health and disease. It has been known since the 1970s that single gene mutations in obese (ob/ob) and diabetic (db/db) mice led to gross obesity. It was not until 1994, however, that the pioneering work of Friedman et al. showed that the ob gene product, a 16 kDa protein named leptin (from the Greek leptos, meaning thin), was produced by the adipocyte. Mutations in the ob gene led to an absence of circulating leptin in the ob mouse, and resulting hyperphagia and gross obesity in such animals could be completely reversed by administrationof leptin. A few years later it was discovered that the abnormality in db/db mice was severe leptin resistance caused by a leptin receptor mutation. From these studies it is clear (in mice at least) that leptin is intimately involved in controlling adiposity, and further work has led to the hypothesis that leptin carries information about the size of the body’s energy store to the brain. The hypothalamus then responds via neuropeptide-Y to adjust food intake and metabolic rate accordingly (see Fig. 1a). The idea that leptin administration might reduce adiposity resulted in a multi-million dollar investment by the Amgen Corporation in the USA to ®nd a `cure’ for human obesity. Unfortunately, in the majority of cases of human obesity there is no evidence of a monogenic defect in leptin homeostasis. Rather than low circulating leptin concentrations, as found in the obese ob/ob mouse, obese humans have leptin concentrations which are increased in proportion to their fat mass. Given the obvious failure of these high leptin concentrations to produce changes in energy intake or expenditure to restore fat mass to normal, it has been proposed that human obesity is a leptin `resistant’ state (see Fig. 1b). This explanation, however, has been criticized by some, since the only evidence for leptin resistance is that obese humans generally have higher circulating leptin concentrations than do lean subjects. In 1996, the human equivalent of the ob/ob mouse gene was discovered, providing direct evidence that leptin was important in the control of fat mass in the human. Montague and co-workers identi®ed a mutation in two children in the same consanguineous pedigree. Both sisters were grossly obese and serum leptin concentrations were extremely low. Interestingly, administration of human recombinant leptin to the older sister increased satiety and rapid weight decrease occurred. The human equivalent of the db/db mouse gene has also been discovered, but it appears that genetic mutations are an extremely rare cause of obesity in humans. It is now recognized that leptin is involved in a wide range of functions. As well as inhibiting food intake, leptin stimulates and maintains energy expenditure, is a signal to the reproductive system, is involved in haemopoiesis and the immune response and acts as a `metabolic’ hormone in a wide range of processes. The aim of this short article is to familiarize the reader with the rapidly expanding information on leptin, describe the measurement of circulating concentrations of leptin and the leptin binding component and brie y review the value, or potential value, of such measurements in human disease. A deeper coverage of leptin may be found in a number of excellent recent reviews. Personal View Ann Clin Biochem 2000; 37: 244±252