Dose combinations of exendin-4 and salmon calcitonin produce additive and synergistic reductions in food intake in nonhuman primates

Abstract

Glucagon-like peptide-1 (GLP-1) and amylin mediate the feedback control of eating by seemingly separate, but overlapping mechanisms. This study examined the effects of combined doses of the GLP-1 agonist, exendin-4 (Ex-4), and the amylin analog, salmon calcitonin (sCT), on food intake and meal patterns in adult male rhesus monkeys. Monkeys received intramuscular injections of Ex-4 (0, 0.1, 0.32, or 0.56 microg/kg), sCT (0, 0.1, or 0.32 microg/kg), or combinations thereof before a 6-h daily access to food. Dose combinations produced reductions in food intake that were significantly greater than those produced by the individual doses. Surface plots of the hourly intake indicated a synergistic interaction at lower doses of Ex-4 and sCT during the first 4 h of feeding and additive effects at hours 5 and 6. Meal pattern analysis revealed the combinational doses reduced average meal size and meal frequency by additive interactions, whereas infra-additive effects were apparent at lower doses for first meal size. Combinational doses were further characterized by administration of repeated daily injections of 0.56 microg/kg Ex-4 + 0.32 microg/kg sCT for 5 days. This resulted in sustained reductions in daily food intake (>70% from saline baseline) for 5 days with residual reductions ( approximately 48% from saline baseline) persisting on day 1 following the injections. In contrast, when pair-fed an identical amount of daily food, there was a compensatory food intake increase on day 1 following the pair-feeding ( approximately 132% of saline baseline). Such data suggest Ex-4 and sCT interact in an overall additive fashion to reduce food intake and further the understanding of how GLP-1 and amylin agonist combinations influence feeding behavior.

Amylin: Pharmacology, Physiology, and Clinical Potential

“…Combined amylin and GLP-1 receptor agonism has also been assessed (Bello et al, 2010). This study evaluated the acute anorexigenic effects of coadministering the amylin/calcitonin receptor agonist salmon calcitonin alone and in combination with GLP-1 receptor agonist exenatide in a non-human primate model.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…In all of these studies, the combination of leptin with amylin, FGF21, or exendin-4 improved weight loss synergistically in diet-induced obese rodents when compared with treatment with the respective monotherapies. Other preclinically evaluated GLP-1-based combination therapies include the salmon calcitonin with exendin-4 (Bello et al, 2010), GLP-1 with PYY (Neary et al, 2005), exenatide with CCK (Trevaskis et al, 2015), and liraglutide with an melanocortin 4 receptor agonist (setmelanotide, RM-493) , which has recently been shown to correct obesity in POMC-deficient humans (Kuhnen et al, 2016). In all of these reports, the combination therapy demonstrated metabolic benefits greater than what can be achieved by the respective hormone monotherapies.…”

Cooperative interaction between leptin and amylin signaling in the ventral tegmental area for the control of food intake

“…Amylin acts centrally to promote negative energy balance (24,50), and several reports have demonstrated that amylin can enhance the anorectic effects of other feeding-related signals in an additive if not synergistic manner (6,10,22,35). Of particular interest is that amylin interacts cooperatively with the adipose-derived hormone leptin to produce enhanced suppression of food intake and body weight (13,15).…”