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Obesity Falls

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A growing epidemic is sweeping through the developed world, threatening millions with disability and death: obesity. 'Epidemic' may sound exaggerated, but the facts speak for themselves: 154 million people worldwide are obese--or more than 20% are over their ideal body weight--including more than 50% of all Americans. More disturbing is the prevalence of childhood obesity, which has jumped dramatically over the past 20 years and now accounts for a doubling in the incidence of diabetes, a 5-fold increase in sleep apnoea and a 3-fold increase in gall bladder disease. The World Health Organization and the US Surgeon General have already warned that obesity is a serious, life-threatening disease. Indeed, as a major risk factor for hypertension, stroke, heart disease, diabetes and possibly certain forms of cancer, obesity exacts a greater toll on health and healthcare costs than either smoking or drinking. In the USA alone, the direct medical costs of obesity-related diseases account for 6% of the nation's entire healthcare budget. Obesity is, in short, a great deal more than a 'lifestyle' or cosmetic problem.

This has not been lost on the pharmaceutical industry. Companies know that the worldwide market for an effective treatment for obesity is gargantuan: analysts estimate that an effective and safe drug could generate as much as US$26 billion per year in the USA alone. 'It is probably the largest pharmaceutical market ever, and carries with it 27-30 dangerous co-morbidities,' said Louis Tartaglia, Vice President of metabolic diseases at Millennium Pharmaceuticals (Cambridge, MA), who estimates the current annual worldwide market conservatively at US$10-15 billion. If one adds the patients who are obese and diabetic, the number soars even higher, as obesity and diabetes are linked diseases.

The sudden rise in obesity is mainly a result of lifestyle changes, particularly the ready availability of calorie-laden, refined food and a decrease in physical activity. 'Genes have not changed in the past 50 years, but our eating and exercising habits have,' said George Yancopoulos, Chief Scientific Officer and President of Regeneron Pharmaceuticals (Tarrytown, NY), one of many companies working on drugs to treat obesity. But it cannot be lifestyle alone. Certain ethnic groups have a higher prevalence of obesity, and the discovery of a number of genes that regulate fat storage point to an interaction between genetic and environmental factors.

Indeed, research on fat metabolism has made large strides forward over the last decade and has challenged some established views. 'One of the most important advances in obesity research is the realisation that fat is an endocrine tissue,' said Barbara Kahn, Professor of Endocrinology at Harvard University's School of Medicine. Another step forward was the discovery of a number of peptides that function as central regulators of food intake and energy homeostasis. These findings point to a complex involvement of the neuroendocrine system, where the central nervous system and fat interact through hormones and neurotransmitters, and affect other organs, most notably the liver and the pancreas.

Given the complexity of this system, it is no surprise that most treatments have been relatively ineffective or fraught with serious health risks, such as addiction to amphetamine diet pills, heart valve damage and hypertension. Furthermore, only a few drugs have reached the market recently. Xenical (Orlistat), a pancreatic lipase inhibitor developed by Hoffmann-LaRoche (Geneva, Switzerland), works by blocking the absorption of fat in the intestine, but can cause uncomfortable side-effects and has been linked to an increased incidence of cancer. Meridia (known as Reductil in the UK), originally developed by Knoll AG (Ludwidgshafen, Germany), is a serotonin and norepinephrine reuptake inhibitor that is thought to act on the appetite centre of the hypothalamus. However, it often causes elevated blood pressure, and its producer, Abbott Labs (Abbott Park, IL) admitted in March that 34 patients in the USA have died after taking the drug. Italy suspended sales of the drug after receiving 50 reports of adverse reactions, including two deaths. The anti-depressant Wellbutrin (GlaxoWellcome, Research Triangle Park, NC) acts in the same way as Meridia but has only a very mild weight-reduction effect.

But recent findings on fat metabolism open new avenues for developing effective drugs. 'Body weight is regulated through a series of feedback systems that provide targets for effective drug treatment and strategies for drug development,' Peter Kopelman from Queen Mary's School of Medicine & Dentistry at the University of London (UK) said. Food intake can be reduced either by amplifying anorexigenic (anti-appetite) signals or blocking orexigenic (pro-appetite) factors. Other strategies aim at increasing energy expenditure by uncoupling fuel metabolism from the generation of ATP. It is also possible to modulate fat metabolism by regulating fat synthesis or lipolysis or by moderating the fixed 'internal reference point' maintained by the central controller of body weight. An effective anti-obesity treatment must target a number of these regulatory points. 'New drugs must ultimately affect both energy intake and energy expenditure, to have a significant and long-lasting impact on body weight,' according to Kopelman. 'Drugs that work purely on one side of the energy balance--that is, energy intake or expenditure--are unlikely to achieve long-term efficacy because of compensatory adjustments ensuring the maintenance of body fat homeostasis.'

Thus, the major leap in the development of more effective drugs has come through a better understanding of fat metabolism. In particular, the discovery and cloning of the adipocyte-derived hormone leptin and its receptor proved to be major breakthroughs. Leptin is essential for normal body weight regulation and scientists had thought that the obese need leptin in a similar way to diabetic patients who need insulin to process glucose. However, they soon discovered that like most diabetics who are actually insulin-resistant, most obese patients produce plenty of endogenous leptin, but are, in fact, leptin-resistant. Recent research has also begun to uncover the mechanisms of insulin- and leptin-resistance, and the link between obesity and diabetes.

And the pipeline for new drugs is bulging. The most promising, now in phase III clinical trials, is Regeneron's Axokine, an engineered version of ciliary neurotrophic factor, originally developed to treat amyotrophic lateral sclerosis (ALS). Serendipitously, Regeneron discovered that it led to unexpected and substantial weight loss in patients. 'The ALS patients



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