The role of the P2X7 receptor on bone loss in a mouse model of inflammation-mediated osteoporosis

In inflammatory autoimmune diseases, bone loss is frequent. In most cases, secondary osteoporosis is caused by treatment with systemic glucocorticoid. However, the pathogenesis behind the bone loss is presumed multifactorial. We aimed to elucidate the role of the P2X7 receptor on bone mineral density (BMD), microarchitecture, and bone strength in a standardized mouse model of inflammation-mediated osteoporosis (IMO). In total 146 mice completed our protocol, 70 wild type (WT) mice and 76 P2X7−/− (knockout, KO). BMD at the femur and spine decreased significantly from baseline to day 20 in the WT IMO mice (p < 0.01). In the WT vehicle, KO vehicle and KO IMO, no significant BMD changes were found. Bone strength showed a lower mid-shaft max strength (p = 0.038) and also a non-significant trend towards lower strength at the femoral neck of the WT IMO group. Trabecular bone volume fraction (BV/TV) and connectivity density (CD) after 20 days were significantly decreased in the WT IMO group (p = 0.001). In contrast, the WT vehicle and KO vehicle, BV/TV and CD did no change at 20 days. Cortical bone revealed no significant microarchitectural changes after 20 days in the WT IMO group, whereas the total cortical area increased significantly in WT vehicle and KO IMO after 20 days (5.2% and 8.8%, respectively). In conclusion, the P2X7 receptor KO mice did not respond to inflammation with loss of BMD whereas the WT mice had a significant loss of BMD, bone strength and trabecular microarchitecture, demonstrating a role for the P2X7 receptor in inflammatory bone loss

Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.

AIM: To investigate the mechanism of action for body weight loss with semaglutide. MATERIALS AND METHODS: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed. RESULTS: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (-1255 kJ; P < 0.0001), and during the subsequent evening meal (P = 0.0401) and snacks (P = 0.0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (-3036 kJ; P < 0.0001). Fasting overall appetite suppression scores were improved with semaglutide versus placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass. CONCLUSION: After 12 weeks' treatment, ad libitum energy intake was substantially lower with semaglutide versus placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods