Dual
amylin and
calcitonin receptor agonists (DACRAs) are novel candidates for treatment of
type 2 diabetes and
obesity because of their beneficial effects on
body weight,
blood glucose,
insulin sensitivity, and food preference, at least short-term. DACRAs activate the receptors for a prolonged time period, resulting in metabolic effects superior to those of
amylin. Because of the prolonged receptor activation, different dosing intervals and, hence, less frequent receptor activation might change the efficacy of DACRA treatment in terms of
weight loss and food preference. In this study, we compared daily dosing to dosing every other day with the aim of understanding the optimal balance between efficacy and tolerability. Obese and lean male Sprague-Dawley rats were treated with the DACRA
KBP-088, applying two different dosing intervals (1.5 nmol/kg once daily and 3 nmol/kg every other day) to assess the effect on
body weight, food intake,
glucose tolerance, and food preference when given the choice between chow (13% fat) and a high-fat diet (60% fat). Treatment with
KBP-088 induced significant
weight loss, reduction in adiposity, improvement in
glucose control, and altered food preference toward food that is less calorie-dense.
KBP-088 dosed every other day (3 nmol/kg) was superior to
KBP-088 once daily (1.5 nmol/kg) in terms of
weight loss and improvement of food preference. The beneficial effects were evident in both lean and obese rats. Hence, dosing
KBP-088 every other day positively affects overall efficacy on metabolic parameters regardless of the lean/obese state, suggesting that less-frequent dosing with
KBP-088 could be feasible. SIGNIFICANCE STATEMENT: Here, we show that food preference can be altered chronically toward choices that are less calorie-dense by pharmacological treatment. Further, pharmacological dosing regimens affect the efficacy differently, as dosing every other day improved
body weight loss and alterations in food preference compared with daily dosing. This suggest that alterations of the dosing regimens could be feasible in the treatment of
obesity.