Scientists are a unique breed whose research may seem to have little
relevance to human health. Often, they are unable to communicate
effectively what they are actually doing (particularly to economic
rationalists intent on slashing research budgets), and especially
when, as with obesity, the research appeared to have "hit the wall",
with little hope of an imminent breakthrough. Then, along comes a
discovery in obese mice1 so stunning that it opens up a
new era in obesity research, with possible spin-offs for management
of obesity and other associated disorders such as
non-insulin-dependent diabetes mellitus (NIDDM).
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
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
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
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!
Chief Executive Officer, International Diabetes Institute
Greg R Collier
Senior Lecturer, School of Nutrition and Public Health
Deakin University, Geelong, VIC
- Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse
obese gene and its human homologue. Nature 1994; 372:
Segal L, Carter R, Zimmet P. The cost of obesity. The Australian
perspective. PharmacoEconom 1994; 5(Suppl 1): 45-52.
VanItallie TB. Worldwide epidemiology of obesity.
PharmacoEconom 1994; 5(Suppl 1): 1-7.
Wolf AM, Colditz GA. The cost of obesity: the US perspective.
PharmacoEconom 1994; 5(Suppl 1): 34-37.
Berg FM. Diet industry hard hit since 1990, hopes for recovery.
Healthy Weight Journal 1994; 8: 67-68.
Lissner L. Causes, diagnosis and risks of obesity.
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Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese
gene product on body weight regulation in ob/ob mice.
Science 1995; 269: 540-543.
Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of
the plasma protein encoded by the obese gene. Science 1995;
Campfield LA, Smith FJ, Guisez Y, et al. Recombinant mouse OB
protein: evidence for a peripheral signal linking adiposity and
central neural networks. Science 1995; 269: 546-549.
Coleman DL. Effects of parabiosis of obese with diabetic and
normal mice. Diabetologia 1973; 9: 294-298.
Masuzaki H, Ogawa Y, Isse N, et al. Human obese gene expression:
adipocyte- specific expression and regional differences in the
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Lnnquist F, Arner P, Nordfors L, et al. Overexpression of the
obese (ob) gene in adipose tissue of human obese subjects.
Nat Med 1995; 1: 950-953.
Walder K, Zimmet P, Collier GR. Expression of the ob (obese) gene in
Psammomys obesus, an animal model of obesity and non-insulin
dependent diabetes mellitus (NIDDM). Proceedings of the 3rd
Scientific Meeting of the Australasian Association for the Study of
Obesity [abstract]. Melbourne: Australasian Association for the
Study of Obesity, 1995: 42.
Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and
rodent: measurement of plasma leptin and ob RNA in obese and
weight-reduced subjects. Nat Med 1995; 1: 1155-1161.
Ionsidine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive
leptin concentrations in normal-weight and obese humans. N Engl J
Med 1996; 334: 292-295.
Tartaglia LA, Dembski M, Weng X, et al. Identification and
expression cloning of a leptin receptor, OB-R. Cell 1995; 83:
Lee G-W, Proenca R, Montez JM, et al. Abnormal splicing of the
leptin receptor in diabetic mice. Nature 1996. In press.
Reprints: Professor P Zimmet, Chief Executive Officer,
International Diabetes Institute, 260 Kooyong Road, Caulfield, VIC