Of mice and (wo)men: the obesity (ob) gene, its product, leptin, and obesity

Obesity is epidemic in developed nations, including Australia² and the United States,³ and is rapidly becoming so in many developing countries (particularly Pacific Island nations), as a penalty of modernisation,² and in disadvantaged communities in developed countries (e.g., Afro-Americans and Mexican Americans).³ The annual cost of obesity to the United States is close to US$69 billion⁴ and this includes the cost of morbidity and mortality from cardiovascular disease, gallbladder disease, NIDDM, cancer and musculoskeletal disorders. Who can guess the personal cost to millions of obese people who splurge US$33 billion annually on new diet books or new "fad" diet programs?⁵

There has been no lack of effort or interest in obesity research, but the tangible results for clinical practice have been disappointing. This explains the community focus on each new miracle diet. We know about the importance of nutrition, exercise, community lifestyle interventions and pharmacotherapy for obesity, and the role of surgery for morbid obesity. Also, the genetic, sociocultural and behavioural risk determinants of obesity are well understood,⁶ but the basic physiological mechanisms that regulate body weight and adipose tissue have largely remained a mystery.

Then, in late 1994 came the cloning of the mouse ob gene and its human homologue,¹ followed within months by reports that injections of the ob protein/hormone expressed by the ob gene (named leptin, from the Greek root leptos, meaning thin) make obese mice thin.^7-9

Based on research involving parabiosis (joining of the mice by anastomosis of the skin, which allows cross-circulation experiments) of obese (ob/ob) and diabetes mutant (db/db) mice, Coleman suggested over 20 years ago that a satiety factor produced in adipose tissue circulated in plasma and affected appetite through interaction with the hypothalamus.¹⁰ He further suggested that ob/ob mice lacked the satiety factor that could regulate adiposity by modulation of appetite and metabolism. There the suggestion remained until Friedman and his colleagues cloned the ob gene.¹

They and other researchers subsequently prepared the recombinant ob protein, leptin; injecting ob/ob mice with leptin resulted in diminished food intake, increased energy expenditure, and dramatic weight reduction.^7-9 After two weeks of treatment, there was a reduction of body fat from 12.2% to 0.7%!⁸ The ob gene is overexpressed in adipose tissue of obese human subjects,^11,12 and overexpression and hyperleptinaemia have now been demonstrated in the best animal model of human NIDDM, Psammomys obesus.¹³ We are currently exploring the role of leptin in the high frequency of hyperglycaemia, hyperinsulinaemia and obesity which occurs in this rodent model.

Thus, research begun over 20 years ago has culminated in findings that have set the obesity field alight and opened up new possibilities in pharmacotherapy of obesity. A look into the crystal ball reveals a vista to be explored in intermediary metabolism. It could revolutionise our knowledge of appetite control and energy regulation, and the interaction of leptin with other key hormones, such as insulin and glucagon in insulin sensitivity and resistance, remains to be explored. How many other unknown hormones are being produced by adipose tissue? Already we know that leptin administration to mice lowers blood glucose and insulin levels in obese mice.⁷ While assays for leptin are still in the early stages of development, high blood leptin concentrations (four to five times higher than in non-obese persons) have been demonstrated in obese subjects,^14,15 and we have recently confirmed this and demonstrated a highly significant direct correlation between leptin, body mass index and serum insulin (Zimmet et al., unpublished data).

Whether leptin itself is the "magic bullet" to cure obesity remains to be established, as studies in humans suggest that the problem in obese subjects may be decreased sensitivity to leptin (i.e., leptin resistance). The significance of this will become apparent as research moves to the next phase: the search for and study of the hypothalamic leptin receptor, and human clinical trials. The pace at which new developments are emerging is breathtaking, and in the space of a few weeks publications have appeared on the identification and cloning of the leptin receptor in mice,¹⁶ and a mutation has been identified in the leptin receptor of the db/db mouse.¹⁷

There will undoubtedly be concern about misuse of therapeutic agents with so much promise -- either leptin itself or drugs directed at the hypothalamic leptin receptor -- particularly with the possibility of a person gorging and then having an injection or taking a tablet to undo the consequences of the indulgence! While these concerns are important, this discovery provides a quantum leap in our understanding of the pathophysiological mechanisms leading to obesity and has clearly defined an avenue for its prevention. This then leads to exciting possibilities for understanding the aetiology and reducing the morbidity and mortality of a host of chronic conditions associated with obesity, including coronary artery disease, the insulin resistance metabolic syndrome (or syndrome X) and NIDDM.

Coleman's elegant parabiosis experiments and Friedman's relentless search for the ob gene and leptin bring hope to hundreds of millions of obese people around the world. Debate about the appropriateness of animal experimentation will continue forever, but here is one classic example where such research may pay huge human dividends. This discovery may help the community understand how medical research works for society's ultimate benefit, and gives researchers a tangible result to convince politicians that funds applied to long term basic medical research can be an excellent investment!

Paul Zimmet
Chief Executive Officer, International Diabetes Institute
Melbourne, VIC

Greg R Collier
Senior Lecturer, School of Nutrition and Public Health
Deakin University, Geelong, VIC

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Reprints: Professor P Zimmet, Chief Executive Officer, International Diabetes Institute, 260 Kooyong Road, Caulfield, VIC 3162.