Bsx molecule could be new target for obesity drugs

By Pete Mansell

- Last updated on GMT

Related tags Obesity

A molecule that links spontaneous physical activity such as
fidgeting and food intake could be a promising new target for drugs
to control diet-induced obesity, researchers from Europe and the US
suggest.

The scientists from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, the German Institute of Nutrition (DIFE) in Nuthetal and the University of Cincinnati in Ohio, US describe the identification of the brain-specific homeobox transcription factor Bsx and its effect on the locomotor activity, response to hunger and body weight of experimental mice in the 6 June issue of the journal Cell Metabolism​ (Vol 5, 450-463). The researchers found that mice engineered to lack the Bsx molecule displayed less spontaneous activity than normal mice used as controls, perceived hunger signals differently and expressed significantly lower levels of the hypothalamic neuropeptides NPY and AgRP (neropeptide Y/agouti-related peptide) - which regulate feeding behaviour and body weight - in the neural control centre at the base of the brain. The scientists started from the premise that, while food intake and activity-induced thermogenesis (the production of heat by metabolic processes) are important factors in regulating energy balance - and therefore preventing obesity - the molecular mechanism underlying the co-ordination of food intake with locomotive behaviour to obtain energy equilibrium or homeostasis is unclear. They found that Bsx was a requirement for adaptive increases in NPY and AgRP expression, food intake prompted by ghrelin - a gut-derived peptide hormone whose circulating levels increase during fasting and which directly stimulates NPY and AgRP neurons - and for a normal hyperphagic (increased appetite) response to fasting. Since a lack of Bsx also restored the hyperphagia of mice deficient in leptin - a protein hormone key to regulating energy intake and expenditure, and which directly inhibits NPY and AgRP neurons - the researchers concluded that Bsx may also be required for non-physiological types of hyperphagia. Despite the "massive" downregulation of NPY and AgRP expression in Bsx-deficient mice, however, these animals had a significant increase in fat mass, although their body weight did not differ from that of normal mice and there was no obvious change in energy expenditure, the scientists noted. The answer to this paradox, they suggested, was the reduced locomotive activity in Bsx-deficient mice, resulting in less food-seeking behaviour but also less spontaneous activity that would burn off calories. Downregulation of NPY and AgRP expression "should reduce food consumption and increase energy expenditure leading to a lean phenotype"​, whereas reduced locomotion "should decrease energy expenditure and promote body weight gain,"​ the researchers wrote. "The observed increase in fat mass suggests therefore that reduced motor activity-induced thermogenesis is the prevailing of the two metabolic defects on normal chow." ​ As Bsx is conserved across species, these observations provide some clues as to why body weight varies in humans on the same diet. "Differences in Bsx activity between individuals could help explain why some people are intrinsically more active than others and less susceptible to diet-induced obesity,"​ commented Maria Sakkou from the EMBL's Developmental Biology Unit. "Bsx might be the key to why the same diet makes one person fat while leaving another unaffected." ​ Future studies on the regulation of Bsx activity and the transcription network underlying NPY/AgRP physiology "may provide new insight into mechanisms that are responsible both for adaptive hyperphagia as well as spontaneous physical activity and might open new avenues to control obesity",​ wrote Sakkou et al​. Currently the only drugs available to treat obesity are Sanofi-Aventis' Acomplia (rimonabant), an oral appetite suppressant that works by blocking cannabinoid binding to the CB-1 receptors found on the surface of cells; Abbott Laboratories' centrally acting Reductil/Meridia (sibutramine); and Roche's Xenical (orlistat), a lipase inhibitor that prevents absorption of dietary fat in the gastrointestinal tract. GlaxoSmithKline's (GSK) low-dose, over-the-counter version of Xenical, Alli, was approved by the US Food and Drug Administration in February. GSK has just ended a collaboration with Swedish biotech Biovitrum, under which the two companies were developing selective agonists of 5-HT2c, one of the serotonin receptors in the brain, for obesity and related diseases. As Biovitrum explained, in the early stages of the programme it completed Phase II clinical trials with the 5-HT agonist BVT.993, which was found significantly to reduce body weight without any serious side-effects. However, the compound was not considered to be selective enough and in 2003 the project was brought back to the preclinical phase, with GSK taking over responsibility for finding compounds more selective for the target receptor. With GSK pulling out of the collaboration, all rights to these compounds have returned to Biovitrum. The Swedish company has decided nonetheless not to develop them any further for the obesity indication. It has seven projects in clinical development, one of which focuses on treating obesity by suppressing appetite through a different 5-HT receptor, Biovitrum noted. Another anti-obesity project at the preclinical stage aims to develop an oral mimetic of leptin.

Related topics Preclinical Research

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