Abstract
A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.
Highlights
Obesity affects more than one-third of individuals in the world, creating an enormous health and economic burden, yet effective non-invasive treatments are limited[1,2]
Our meal pattern analyses revealed that the combined administration of native amylin and GLP-1 was effective in reducing the size of the first meal to a significantly greater degree than vehicle, amylin alone or GLP-1 alone, suggesting that these hormones act in concert to reduce meal size (P < 0.05, One-way ANOVA; Fig. 1A)
The collective results demonstrate that combined therapy of salmon calcitonin (sCT) and liraglutide significantly reduced food intake and body weight compared to vehicle and to a greater degree than the magnitude of food intake and body weight suppression observed after treatment with either mono-therapy alone (Fig. 1B,C)
Summary
Obesity affects more than one-third of individuals in the world, creating an enormous health and economic burden, yet effective non-invasive treatments are limited[1,2]. Once-daily administration of liraglutide produces a clinically-meaningful degree of body weight loss by reducing energy intake, and as such, liraglutide is an approved monotherapy for treating obesity[37,38] Both amylin- and GLP-1-based pharmacotherapies have been separately examined preclinically in the context of combinatorial therapies for obesity treatment with other hormonal systems (e.g; leptin, glucagon, glucose dependent insulinotropic peptide)[6,39,40,41,42]; there is a surprising paucity of reports systematically examining the hypothesis that combined amylin and GLP-1 therapies may provide enhanced suppression in food intake and body weight[43,44]. Here we aim to uncover the behavioral and potential neuroanatomical mechanisms governing the interaction between amylin and GLP-1 signaling in control of energy balance
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