Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice
Introduction
Orexins-A (OXA) and -B (OXB) are C-terminally amidated peptides of 33 and 28 amino acids, respectively, derived from the same precursor peptide [1]. They activate two G-protein-coupled receptors: the orexin-1 (OX1) receptor, which has approximately 10-fold greater affinity for OXA than OXB, and the OX2 receptor, which has similar affinity for the two peptides [2], [3].
Intracerebroventricular (i.c.v.) injection of the orexins, especially of OXA, stimulates feeding, giving rise to their name [1], [4]. However, whether the orexins are physiologically important in the regulation of feeding or in the development of obesity is open to question because in some studies they have had only weak effects on food intake, and obese (fa/fa) Zucker rats have shown no difference in brain OXA or hypothalamic prepro–orexin mRNA levels from lean rats [5], [6], [7]. An alternative role is thought to be in the regulation of sleep and arousal [6], [8]. Other studies, in contrast, have shown reductions in hypothalamic prepro–orexin mRNA levels not only in fa/fa rats, but also in ob/ob and db/db mice [9], [10]. Moreover, there was an elevated level of hypothalamic prepro–orexin mRNA in rats prone to obesity on a high-fat diet that increases further when the rats are administered such a diet [11]. Overall, the evidence for OXA having a role in the regulation of feeding can be compared favourably with that for two other orexigenic peptides, melanin-concentrating hormone and galanin [12], [13]. This does not preclude roles for orexins in the regulation of sleep and other behaviours, or in neurohormonal regulation. Indeed, it seems possible that orexins may mediate a range of responses that support food-seeking behaviour when there is a deficiency of fuel for the brain [13], [14].
A key criterion supporting a role for a neuropeptide in the regulation of feeding is that blockade of its activity should alter natural feeding. This evidence is available for the orexin system since central administration of antibodies to both OXA and the OX1 receptor reduces food intake [15], [16]. In addition, we have shown that SB-334867-A, an OX1 receptor antagonist with 50-fold lower affinity for the OX2 receptor [17], [18], [19], reduces food consumption in male and female rats [20]. The structure of feeding behaviour (the behavioural satiety sequence) is well-preserved: SB-334867-A advanced the transition from feeding to resting in the manner of other satiety agents, and there was no disruption in the behavioural satiety sequence which known sedative agents elicit [21].
We now report that in genetically obese (ob/ob) mice, SB-334867-A not only reduced food intake, but also increased energy expenditure, and on repeated administration, reduced body weight via a reduction in body fat content while preserving lean mass. Furthermore, fasting blood glucose was lowered despite a trend to reduced plasma insulin, indicating increased insulin sensitivity. These findings provide further evidence that orexins play a role in the regulation of energy balance, and suggest that OX1 receptor antagonists have potential in the treatment of obesity and Type 2 diabetes.
Section snippets
Animals
Female ob/ob mice were obtained from Harlan Olac at 6–7 weeks of age. On arrival, they were housed under controlled temperature (24±2 °C) and lighting conditions (12 h light–dark cycle), and were allowed 5 days habituation prior to the study. Food (chow pellets) and water were available ad libitum. All procedures carried out were in accordance with Home Office Guidelines.
Compound preparation and administration
SB-334867-A [17], [18], [19] and the β3-adrenoceptor agonist
Food consumption and body weight
SB-334867-A significantly reduced cumulative 24 h food intakes between days 3 and 14 (last measurement) of the study (Fig. 1). Since SB-334867-A might have a greater effect on food intake in the period immediately following each injection than at later times during each 24 h period, food intake was also measured at 4 h post-dose on three occasions. At 4 h post-dose, SB-334867-A reduced food intake on days 1 (by 33±15%, P=0.06), 6 (by 28±9%, P=0.17) and 13 (by 29±22%, P=0.24); these changes were
Discussion
These findings in ob/ob mice demonstrate an anti-obesity effect with a selective OX1 receptor antagonist for the first time. The inhibitory effects of SB-334867-A on food intake are consistent with our previous work, which was carried out in Sprague Dawley [20] or Lister hooded [21] rats. Cumulative food intake in ob/ob mice was reduced over the entire 14 days of the study, without any signs of desensitisation. SB-334867-A also reduced body weight gain, with the greatest reduction being
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