538-540 Obesity

news feature Whatever happened to leptin?

Just five years ago, it seemed that a single protein PRESS ASSOCIATED might reverse the rising tide of obesity. What worked for mice has not yet translated to people. But watch this space, says Marina Chicurel.

y any reckoning, US$20 million is a lot Leptin is significant because it plays to spend on a protein. But in May an important role in energy homeo- B1995, Amgen of Thousand Oaks, Cali- stasis — the physiological balancing fornia, paid just that for the commercial act that regulates our food intake and rights to leptin, a hormone that made fat our storage and expenditure of ener- mice slim. Identified only six months earlier, gy. It also seems to affect other physi- leptin could be injected into grotesquely ological systems, including carbo- obese, leptin-deficient mice where it curbed hydrate metabolism, reproduction their voracious appetites and boosted their and bone formation. “As a hor- metabolic rates. Within a month, and with mone, leptin is probably as impor- no apparent side-effects, these mice lost tant as insulin,” says Joel Elmquist of almost half of their excess weight. the Beth Israel Deaconess Medical Center Leptin was hailed as the wonder drug to and Harvard Medical School in Boston. defeat a burgeoning epidemic of obesity. But five years down the line, this simple script has Exercising control had to be rewritten. First, data from studies Leptin’s fundamental power stems from its on rodents and humans hinted at leptin’s ability to keep the brain informed about the therapeutic shortcomings. Then, last Oct- status of the body’s energy stores. The ober, came the news that the protein had amount of leptin secreted by fat cells performed poorly in its first clinical trial1. depends on their size. When food is scarce, Although Amgen may not have its hands the cells shrink and secrete less leptin into on a pharmaceutical blockbuster, obesity the bloodstream. This reduces the activity researchers are enthused by the wealth of of nerve cells that have leptin receptors and advances that have followed leptin’s discov- are found in a region of the brain called the ery. And some of these advances may, in the hypothalamus. In turn, this decrease in long term, fulfil the therapeutic hopes once neural activity has two effects on other neu- pinned on leptin. “It transformed the world rons in the hypothalamus: it boosts the of obesity from a backwater of totally release of neuropeptide Y, a neuro- ignored, rather dodgy research into one of transmitter that increases appetite, and it the primary areas of biomedical research,” suppresses Ȋ-melanocyte-stimulating hor- says Stephen O’Rahilly of the University of mone (Ȋ-MSH), which blocks feelings of espite its Cambridge. hunger. Through these pathways, and per- disappointing haps through direct effects on organs such D as the pancreas and liver, leptin ensures performance so far, energy homeostasis. But the balance sometimes breaks down, leptin is still the focus of probably because leptin and its associated neural circuits evolved to maintain adequate interest from drug fat reserves, rather than to avoid excess fat developers. storage — our distant ancestors routinely REMI BANALI/LIAISON AGENCY REMI BANALI/LIAISON had to cope with food scarcity. This view of leptin is different from the versity in New York sequenced the ob gene, protein’s initial characterization as an ‘anti- identified its human counterpart, Ob, and obesity’ hormone. But given the circum- characterized the protein they produce2,3. stances of leptin’s discovery, it is easy to see The team called the protein leptin, from the why the early view prevailed. Since 1950, Greek word leptos, or thin. researchers had realized that the bizarre Within months, several teams, including plight of the ob/ob mouse was the result of a Friedman’s, had injected leptin into ob/ob genetic abnormality. This inbred strain eats mice and transformed them into healthy almost continuously, weighs three-times as animals with normal body weights3–5. Leptin much as normal mice, and suffers from dia- specifically reduced fat mass, sparing other betes. But it was not until 1994 that Jeffrey tissues. “Never had there been any clear Weight watcher: Friedman’s discovery Friedman and his colleagues at the Howard circulating factor that was involved in body kick-started a vibrant field of research. Hughes Medical Institute at Rockefeller Uni- weight regulation,” says Steven Heymsfield

538 NATURE | VOL 404 | 6 APRIL 2000 | www.nature.com

Predictions of potency Friedman believes it was the powerful images of the transformed obese mice that AGENCY REMI BANALI/LIAISON ignited enthusiasm for leptin. Given the extreme competitiveness of the pharmaceutical industry, Amgen was quick to buy the rights from Rockefeller University. Almost immediately, however, studies on rodents and people began to reveal that there was much more to leptin than first met the eye. The hormone’s precise physiological role seems to vary from species to species. O’Rahilly’s group in Cambridge, for instance, identified two obese, leptin-deficient children — the human equivalent of ob/ob mice6. But, unlike the mice, the twins did not suffer from other conditions such as hypothermia and severe diabetes. Neverthe- less, when O’Rahilly’s group injected one child with leptin, she lost weight rapidly7. Researchers also soon realized that most obese people are not deficient in leptin. In Before and after: dramatic images such as this one fired pharmaceutical enthusiasm for leptin. fact, the majority have higher than normal levels of the hormone8,9. Many obese people at later stages in the process, after leptin has into rats’ brains, the animals immediately seem to be, at least to some extent, resistant to done its work. Millennium Pharmaceuticals start eating excessively13. leptin. In addition, leptin levels vary greatly in Cambridge, Massachusetts, for example, is Peering into the neurons that sport leptin between people with identical percentages of working with drugs giant Hoffmann-La receptors, other groups are looking for intra- body fat, indicating that a variety of factors, Roche to seek ways of heightening the effects cellular drug targets. Louis Tartaglia at genetic and environmental, might contribute of the appetite-suppressing Ȋ-MSH. This Millennium believes the most promising to people’s sensitivity to the hormone8,10. neurotransmitter acts on melanocortin-4 approach is boosting the responsiveness of Despite this evidence, Amgen remained (MC-4) receptors, found on cells in the hypo- the signalling pathway activated by leptin. hopeful. After all, diabetics with high circu- thalamus that are connected to leptin- One component of this pathway, called sup- lating levels of insulin can sometimes benefit responsive neurons. Mice lacking MC-4 pressor of cytokine signalling-3 (SOCS-3), from receiving even more of the hormone. receptors or pro-opiomelanocortin, the pre- was recently identified in Jeffrey Flier’s lab at But the limits to leptin’s therapeutic poten- cursor of Ȋ-MSH, are obese11. Data from two Beth Israel Deaconess and Harvard14. Leptin tial became clear last year with the publica- unpublished studies, including one from seems to boost production of SOCS-3, tion of results from an Amgen trial in which O’Rahilly’s group, suggest that up to five per which in turn seems to stifle further leptin 73 obese volunteers injected themselves with cent of obese children carry mutations in the signalling. It is possible, therefore, that the leptin or a placebo1. melanocortin system, making these muta- resistance of obese people to leptin is the Of the 47 patients who completed the tions the most common genetic defects to be result of SOCS-3 overactivity. study — many withdrew because of problems associated with human obesity to date. with the injections — the eight receiving the But boosting a protein’s function is diffi- Copycat molecules highest dose lost an average of 7.1 kg, while the cult, says Eleftheria Maratos-Flier of the Dissection of leptin’s signalling path has twelve taking a placebo lost 1.3 kg. The effects Joslin Diabetes Center and Harvard Medical also helped reveal the weight-regulating varied widely among patients — from a loss of School. So other companies are focusing on properties of another molecule — ciliary about 15 kg to a gain of 5 kg within the group targets that have weight-reducing effects neurotrophic factor (CNTF). This is one of treated with the highest dose. These doses also when their function is blocked. Some a range of nerve growth factors being induced skin irritation and swelling at the researchers are trying to block melanin-con- explored as treatments for neurodegenera- injection site. “The data reported were fairly centrating hormone (MCH). Although tive diseases. One trial using CNTF to treat moderate,” concedes Carl LeBel, associate there is disagreement about MCH’s exact amyotrophic lateral sclerosis revealed its director of product development at Amgen. position in the circuitry controlled by leptin, leptin-like behaviour in humans. The But these setbacks are not the end of the mice that lack the hormone are much leaner patients did not show much neurological road for leptin. The protein’s discovery has than normal12, and if the hormone is injected improvement, but they lost lots of weight15. provided countless new leads for drug devel- The cell-surface receptor for CNTF closely opment. Within the past five years, research- resembles the leptin receptor, it activates sim- ers have identified more than a dozen key Turn to page 631 ilar intracellular signalling pathways, and it is components in the neurocircuitry under- for the first in a found in related areas of the hypothalamus. lying appetite control. They have also begun regular series of Extending work on mice, in which Ralph to tease out the intracellular signalling path- insight topical reviews. Laufer’s team at IRBM, the Institute for ways activated by leptin. Research in Molecular Biology in Rome, Several companies are exploring the showed that CNTF made obese mice lose fat16, Obesity ▲ therapeutic possibilities of molecules that act George Yancopoulos and colleagues at Regen-

NATURE | VOL 404 | 6 APRIL 2000 | www.nature.com 539

© 2000 Macmillan Magazines Ltd news feature ▲ eron Pharmaceuticals in Tarrytown, New York, started experimenting with axokine, a patented derivative of CNTF. When they Counting the cost of obesity made normal rodents obese by putting them on a high-fat diet, the animals became resis- For the first company to bring a tant to leptin. But when the researchers potent weight-loss drug to the injected these same animals with axokine, the market, the rewards could be huge. Indirect cost Direct cost Across the industrialized world, the rodents shed 30 per cent of their body weight $47.6 $51.6 and maintained their moderate eating habits, prevalence of obesity is rising. Last even several days after their last injection. month, the Worldwatch Institute in Washington DC reported that 1.1 Sights set on success billion people worldwide are now Last September, Regeneron completed a suffering from the health phase I clinical trial of axokine. Although at consequences of overconsumption 14% high doses the drug seemed to cause cold — equal to the number plagued by sores and nausea, patients tolerated low hunger. In the United States alone, 63% 8% doses well. The results have yet to be pub- where more than one in three adults 6% 5% lished, but most patients lost significant is classified as obese, the condition 4% amounts of weight, reducing their energy is estimated to cause 300,000 intake by about 500 calories a day. Yan- premature deaths each year. And, as copoulos calls axokine “the most promising these figures reveal, the associated weight loss agent ever described”, but others burden of disease causes a Diabetes Hypertension are more cautious. Tartaglia at Millennium, significant annual dent in the US Cancer Osteoarthritis for example, worries that tinkering with a economy — both from the direct Gallbladder disease Coronary neuronal growth factor could have delayed cost of treating conditions triggered heart disease effects that are difficult to predict. by obesity, and from lost economic Source: Wolf, A. M. & Colditz, G. A., Obes. Res. 6, 97-106 (1998) Despite its disappointing performance so productivity. far, leptin itself is still the focus of interest from drug developers. Many scientists, including those from Amgen, think leptin might help barrier. This could be important, because the diabetes develops when pancreatic ȋ-cells die people maintain weight loss. For most people, ratio of leptin in cerebrospinal fluid to that in after accumulating excessive fat in their cyto- the hardest part of dieting is not shedding blood is four times lower in obese people plasm. By stimulating receptors on the surface weight, but keeping it off — they tend to than in those of normal weight17,18. of ȋ-cells, Unger thinks leptin can stop this return to their previous weight. The drop in The success or failure of these strategies, from happening. But other researchers cau- the level of circulating leptin is probably partly however, depends on how leptin sensitivity tion that leptin’s interaction with insulin to blame for this because the ensuing shrink- varies from person to person. Because of remains mysterious and controversial. age of fat cells sounds a ‘starvation alarm’ that their resistance to leptin, flushing the cere- While Amgen’s multimillion-dollar bet boosts the appetite. Leptin injections could brospinal fluid of obese people with leptin- on leptin doesn’t look like yielding an help overcome this by fooling the brain into like molecules might make very little differ- immediate bonanza for the company, obesi- thinking that its energy stores are not at risk. ence. So Amgen is searching for biomarkers ty researchers agree that the protein has kick- Amgen is also designing second-genera- that correlate with leptin sensitivity. This started an exciting field — both for basic tion versions of leptin. The goal is to make may allow leptin to be prescribed selectively research and for drug development. “What- leptin mimics that are more soluble — to to those who are likely to respond more ever has happened to leptin as an immediate increase the dose that can be injected into strongly to the hormone. therapeutic tool, as a discovery that sparked patients — and more stable, to last longer in Leptin’s reach may also extend to the treat- an area of biomedical research, it’s phenom- the bloodstream. Other researchers are ment of other, related diseases. Roger Unger at enal,” says O’Rahilly. ■ designing small molecules with leptin-like the University of Texas Southwestern Medical Marina Chicurel is a freelance writer in Santa Cruz. activity that can easily cross the blood–brain Center in Dallas believes that obesity-induced 1. Heymsfield, S. B. et al. J. Am. Med. Assoc. 282, 1568–1575 (1999). 2. Zhang, Y. et al. Nature 372, 425–432 (1994). 3. Halaas, J. L. et al. Science 269, 543–546 (1995). 4. Pelleymounter, M. A. et al. Science 269, 540–543 (1995). 5. Weigle, D. S. et al. J. Clin. Invest. 96, 2065–2070 (1995). 6. Montague, C. T. et al. Nature 387, 903–908 (1997). 7. Farooqi, I. S. et al. N. Engl. J. Med. 341, 879–884 (1999). 8. Maffei, M. et al. Nature Med. 1, 1155–1161 (1995). 9. Considine, R. V. et al. N. Engl. J. Med. 334, 292–295 (1996). 10.Lonnqvist, F., Arner, P., Nordfors, L. & Schalling, M.

ERIC SANDER/LIAISON AGENCY Nature Med. 1, 950–953 (1995). 11.Huszar, D., et al. Cell 88, 131–141 (1997). 12.Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S. & Maratos-Flier, E. Nature 396, 670–674 (1998). 13.Qu, D. et al. Nature 380, 243–247 (1996). 14.Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Mol. Cell. 1, 619–625 (1998). 15.ALS CNTF Treatment Study Group Neurology 46, 1244–1249 (1996). Diet plan: Amgen still 16.Gloaguen, I. et al. Proc. Natl Acad. Sci. USA 94, 6456–6461 believes leptin is the (1997). key to the lucrative 17.Caro, J. et al. Lancet 348, 159–161 (1996). obesity market. 18.Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. Jr Nature Med. 2, 589–591 (1996).

540 NATURE | VOL 404 | 6 APRIL 2000 | www.nature.com