In the 1990s, it was discovered that genetically obese mice have mutations in the leptin gene, or in the gene for the leptin receptor. Leptin is a hormone, produced mainly by adipose tissue, that acts on receptors in the brain to produce a feeling of satiety and reduce appetite. Daily injections of leptin to leptin-deficient mice led to a dramatic reduction in food intake and body weight, leading to hopes that leptin treatment would have similar effects in obese people. Obese individuals, however, often have unusually high circulating leptin levels rather than suffering from a leptin deficiency, leading to the hypothesis that these people are insensitive to the effects of leptin.
Hopes that leptin could be used to treat obesity have now been revived by scientists at the Children’s Hospital in Boston who have found a way to increase leptin sensitivity in mice. They showed that obesity increases endoplasmic reticulum (ER) stress and initiates the unfolded protein response in the hypothalamus, leading to inhibition of leptin receptor signalling. The resulting leptin resistance, which led to increased obesity, was reversed by the known chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA) which improve ER function and decrease the accumulation and aggregation of misfolded proteins. The study is published in the January 7th issue of the journal Cell Metabolism.
Tesofensine is a serotonin-noradrenaline-dopamine re-uptake inhibitor that was originally developed for the treatment of Parkinson’s and Alzheimer’s disease. Although development for these diseases has been discontinued, the discovery that tesofensine caused unintended weight loss in obese patients led to the initiation of new trials for the treatment of obesity. The drug works by suppressing hunger, leading to an energy deficit which burns off excess body fat. Neurosearch, the company that is developing tesofensine, has announced preliminary results from a phase II proof of concept study published online in the Oct 23 edition of the Lancet. The study, which was carried out in five centres in Denmark, involved 203 obese patients with body mass index of 30-40 kg/m2 and weighing just over 100kg at the start of the study. The patients ate a limited-energy diet and were assigned to tesofensine (0.25mg, 0.5mg or 1.0mg once daily) or placebo groups for 24 weeks. A total of 161 patients completed the study; mean weight loss for the placebo group was 2.2kg and for the tesofensine groups was 6.7 kg, 11.3 kg, and 12.8 kg (0.25mg, 0.5mg and 1.0mg respectively). For the 0.5 mg and 1.0 mg dose groups, the weight loss was around twice that achieved using sibutramine or rimonabant. The most common side-effects caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhea and insomnia; blood pressure was also increased in the 1.0 mg group.
The study authors conclude that the 0.5 mg dose of tesofensine is more promising than the 1.0 mg dose since it produces a similar weight loss with fewer side-effects, but say that larger phase III trials are needed to substantiate their findings.
A study carried out in a small group of female students has shown that mental exercise increases food intake. In a ‘within-subjects’ study, each student spent 45 minutes resting, reading a document and writing a summary, or performing a battery of computerised tests. At the end of each 45 minute period, the students were invited to eat as much as they wanted from a buffet.
When the students had been involved in mental activity, they consumed 200 – 250 kilocalories more than when they had been resting. No specific dietary preferences or differences in appetite sensation markers were seen after mental exercise compared with resting. Mean cortisol levels were significantly higher and there was a significant increase in variations in plasma glucose and insulin levels after mental activity. Since the period of mental activity used almost no extra calories compared with resting, this study suggests a new risk factor for positive energy balance with the potential to lead to obesity.
Ore Pharmaceuticals has recently announced that it has acquired from Roche the exclusive development rights for the clinical-stage compound romazarit. Ore Pharmaceuticals specialises in identifying potential new uses for drug candidates that have previously failed clinical development for reasons other than safety.
Romazarit was originally designed by scientists at Roche as a potential disease-modifying anti-rheumatic drug. The compound showed activity in an adjuvant arthritis model although the mechanism of action was not clearly defined. Romazarit was well tolerated in phase II clinical studies for rheumatoid arthritis, but did not make it to market.
Ore Pharmaceuticals has identified novel potential therapeutic uses for romazarit in prevalent metabolic diseases such as obesity, dyslipidemia and hypercholesterolaemia and has recently filed a patent application covering use of the compound for these indications. Romazarit has been shown to modulate a key pathway related to metabolic function, and lowered lipid levels, body weight, and plasma glucose levels in preclinical models. Ore Pharmaceuticals plans to select the most appropriate of the potential indications and prepare for Phase II clinical trials. The Company will engage in out-licensing efforts in parallel with internal development efforts.
A recent report in the journal Cell Metabolism (Cell Metab. 2008,7(5):377-388) identifies the serine/threonine kinase, calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), as a key component of the ghrelin signalling pathway. Ghrelin, which is produced in the stomach, is a polypeptide that promotes food intake by increasing production of the appetite-stimulating neurotransmitter, neuropeptide Y, by the hypothalamus. The authors established the role of CAMKK2 in appetite control and glucose tolerance both by experiments with CAMKK2-null mice and by administering the CAMKK2 inhibitor, STO-609, to normal mice. CAMKK2 is expressed at low levels in peripheral tissue and the effects of inhibition are likely to be brain-specific. The results suggest that blocking CAMKK2 has the potential to promote weight loss and improve glucose tolerance.
Other approaches to the management of obesity targeting the ghrelin pathway are being investigated. A group at the Scripps Institute has developed an anti-obesity vaccine that is directed against ghrelin and a number of groups are investigating small molecule modulators of the ghrelin receptor.