Enhanced Amylin-Mediated Body Weight Loss in Estradiol-Deficient Diet-Induced Obese Rats

• Published in: Endocrinology (Philadelphia) 2010-12, Vol.151 (12), p.5657-5668
• Main Authors: Trevaskis, James L, Turek, Victoria F, Wittmer, Carrie, Griffin, Peter S, Wilson, Julie K, Reynolds, James M, Zhao, Yu, Mack, Christine M, Parkes, David G, Roth, Jonathan D
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Amylin; Animals; Area postrema; Biological and medical sciences; Body weight; Body weight gain; Body weight loss; Diabetes; Diabetes mellitus; Diet; Eating - drug effects; Energy Metabolism - drug effects; Estradiol - deficiency; Female; Food; Food intake; Fundamental and applied biological sciences. Psychology; Hippocampus; Islet Amyloid Polypeptide - pharmacology; Leptin; Leptin - metabolism; Medical sciences; Metabolic diseases; Metabolic rate; Metabolism; Neurogenesis; Nutrient deficiency; Obesity; Obesity - metabolism; Ovariectomy; Oxygen Consumption - drug effects; Post-menopause; Rats; Rats, Zucker; Respiration; Sex hormones; Signal Transduction; Swimming; Vertebrates: endocrinology; Weight loss; Weight Loss - drug effects
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0590

In rodents, ovariectomy (OVX) elicits weight gain and diminished responsiveness to homeostatic signals. Here we characterized the response of obese OVX rats to peripheral amylin. Rats received sham surgery (SHAM), OVX, or OVX with hormonal replacement (17β-estradiol, 2 μg per 4 d; OVX+E) and were infused with vehicle or amylin (50 μg/kg · d) for 28 d. Amylin reduced body weight (5.1 ± 1.1%) and food intake (10.9 ± 3.4%) in SHAM rats but was twice as efficacious in OVX rats in reducing weight (11.2 ± 1.9%) and food intake (23.0 ± 2.0%). There were no differences between amylin-treated SHAM and OVX+E rats. OVX decreased metabolic rate (∼24%) and increased respiratory exchange ratio relative to SHAM. Amylin partially normalized metabolic rate (13% increase) in OVX rats and decreased respiratory exchange ratio in OVX and SHAM rats. Regarding central mechanisms, amylin infusion corrected the OVX-induced decrease in hippocampal neurogenesis and increased immobility in the forced swim test. Additionally, amylin increased neurogenesis (∼2-fold) within the area postrema of OVX rats. To assess the contribution of endogenous leptin to amylin-mediated weight loss in OVX rats, amylin was administered to SHAM or OVX Zucker diabetic fatty rats. In SHAM rats, amylin infusion reduced food intake but not body weight, whereas in OVX Zucker diabetic fatty rats, food intake, body weight, and insulin were reduced. Overall, amylin induced greater body weight loss in the absence of estradiol via central and peripheral actions that did not require leptin. These findings support the clinical investigation of amylin in low estradiol (e.g. postmenopausal) states. Amylin induces greater weight loss in obese estradiol-deficient rats and is associated with enhanced metabolic effects and induction of neurogenesis in the area postrema.