Combination Therapy with Amylin and Peptide YY[3–36] in Obese Rodents: Anorexigenic Synergy and Weight Loss Additivity

Abstract

Circulating levels of the pancreatic beta-cell peptide hormone amylin and the gut peptide PYY[3-36] increase after nutrient ingestion. Both have been implicated as short-term signals of meal termination with anorexigenic and weight-reducing effects. However, their combined effects are unknown. We report that the combination of amylin and PYY[3-36] elicited greater anorexigenic and weight-reducing effects than either peptide alone. In high-fat-fed rats, a single ip injection of amylin (10 microg/kg) plus PYY[3-36] (1000 microg/kg) reduced food intake for 24 h (P < 0.05 vs. vehicle), whereas the anorexigenic effects of either PYY[3-36] or amylin alone began to diminish 6 h after injection. These anorexigenic effects were dissociable from changes in locomotor activity. Subcutaneous infusion of amylin plus PYY[3-36] for 14 d suppressed food intake and body weight to a greater extent than either agent alone in both rat and mouse diet-induced obesity (DIO) models (P < 0.05). In DIO-prone rats, 24-h metabolic rate was maintained despite weight loss, and amylin plus PYY[3-36] (but not monotherapy) increased 24-h fat oxidation (P < 0.05 vs. vehicle). Finally, a 4 x 3 factorial design was used to formally describe the interaction between amylin and PYY[3-36]. DIO-prone rats were treated with amylin (0, 4, 20, and 100 microg/kg.d) and PYY[3-36] (0, 200, 400 microg/kg.d) alone and in combination for 14 d. Statistical analyses revealed that food intake suppression with amylin plus PYY[3-36] treatment was synergistic, whereas body weight reduction was additive. Collectively, these observations highlight the importance of studying peptide hormones in combination and suggest that integrated neurohormonal approaches may hold promise as treatments for obesity.

Antiobesity effects of the β-cell hormone amylin in combination with phentermine or sibutramine in diet-induced obese rats

“…The present studies extend emerging literature, where additive or synergistic interactions are reported for amylin in 32 and leptin), 40,41 to include small molecule agents that act via classic neurotransmitters. Consistent with the results reported here, co-administration of the amylin agonist pramlintide with sibutramine or phentermine in a clinical trial has recently been reported to result in increased weight loss in obese subjects.…”

“…[28][29][30] Intermeal interval is governed by a complex cascade of post-ingestive, neural, endocrine and metabolic signals. In rodents, amylin has also been shown to synergize with at least two signals (CCK 31 and PYY ) 32 Co-administration of amylin and phentermine JD Roth et al neurohormonal signals is unknown, but could contribute to amylin þ phentermine protraction of the intermeal interval. The generation of plasma hormonal profiles in amylin þ phentermine-treated rats before and after the consumption of a meal, and/or the assessment of food intake in the context of a sham feeding preparation may aid in our understanding of these potential mechanisms.…”

“…Body composition analyses indicated that weight loss with amylin, or amylin and phentermine combination, was fat-specific, and not accompanied by loss of lean tissue. Although a formal pharmacological demonstration of additivity or synergy would require more sophisticated experimental designs such as isobolographic or response surface methodology, 32,37 these findings provide preclinical proof-of-concept for a mathematically additive interaction between phentermine and amylin for anorexigenic effects and weight loss within certain dose ranges.…”

Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight

“…11 Furthermore, the combination of amylin with other anorexigenic agents elicits additive (peptide YY , glucagon-like peptide 1 receptor agonism, phentermine and sibutramine) and even synergistic actions (leptin, cholecystokinin) to reduce food intake and body weight, illustrating the advantage of targeting multiple metabolic pathways to modulate body weight. [22][23][24][25] Importantly, clinical studies confirm the potential of amylin receptor agonism to promote weight loss. For example, pramlintide significantly reduced body weight in patients with diabetes on insulin therapy, an intervention associated with weight gain.…”

CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

“…Because the analysis of the feeding microstructure is essential to assess the mechanisms regulating feeding behavior (18), we investigated the feeding pattern using a newly developed automated episodic food intake-monitoring device, which allows the undisturbed continuous monitoring during the dark phase with minimal human interference. This has been used in rats before (15,31,39,49) and was established recently for the use in mice (21,52). To investigate the specificity of the observed effects on feeding behavior, other behavioral parameters, such as grooming and locomotor activity, were assessed as established originally by Antin et al (1) and in our previous studies (50,53).…”