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

Objective: To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. Design: DIO rats were intraperitoneally injected with a single dose of amylin (10 μg kg-1) and/or phentermine (1...

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Published in:International Journal of Obesity 2008-08, Vol.32 (8), p.1201-1210
Main Authors: Roth, J.D, Trevaskis, J.L, Wilson, J, Lei, C, Athanacio, J, Mack, C, Kesty, N.C, Coffey, T, Weyer, C, Parkes, D.G
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Language:English
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Summary:Objective: To characterize the interactive effects of amylin with phentermine or sibutramine on food intake, body weight/composition and gene expression in diet-induced obese (DIO) rats. Design: DIO rats were intraperitoneally injected with a single dose of amylin (10 μg kg-1) and/or phentermine (1 mg kg-1) or chronically infused with amylin (100 μg kg-1 d-1) or vehicle with or without phentermine (0.5-10 mg kg-1 d-1) or sibutramine (3 mg kg-1 d-1) using two surgically implanted subcutaneous osmotic mini-pumps. Measurements: Twenty-four hour food intake, locomotor activity and components of meal microstructure (meal size, latency, duration and intermeal interval) were measured following acute administration (amylin, phentermine or amylin+phentermine). Body weight and composition (for amylin and/or sibutramine or phentermine) and metabolism-related gene mRNA expression in the liver (fatty acid synthase, stearoyl-CoA desaturase-1 and carnitine palmitoyltransferase-1) and brown fat (β-adrenergic receptors and uncoupling protein-1) were measured (for amylin and/or phentermine) after sustained infusion (2 weeks). Results: Acute co-administration of amylin (10 μg kg-1) and phentermine (1 mg kg-1) reduced acute food intake (up to 19 h) more than either monotherapy. In two studies, sustained subcutaneous infusion of amylin for 2 weeks decreased cumulative food intake (22%) and vehicle-corrected body weight gain (approximately 4-8%). Phentermine's anorexigenic (10-17%) and weight-reducing effects (approximately 0-5%) were only evident at the highest dose tested (10 mg kg-1 d-1). Combination of amylin (100 μg kg-1 d-1) and phentermine reduced food intake (30-43%), body weight (8-12%) and adiposity to a greater extent than either monotherapy. Amylin prevented phentermine-induced reductions in UCP-1 mRNA in brown adipose tissue. When amylin+sibutramine were infused, mathematically additive decreases in food intake (up to 45%) and body weight (up to 12%) were evident. Similar to amylin+phentermine treatment, amylin+sibutramine mediated weight loss was attributable to significant reductions in fat mass. Conclusions: Combined treatment of DIO rats with the pancreatic β-cell hormone amylin and phentermine or sibutramine resulted in additive anorexigenic, weight- and fat-reducing effects.
ISSN:0307-0565
1476-5497
DOI:10.1038/ijo.2008.91