Enhanced amylin-mediated body weight loss in estradiol-deficient diet-induced obese rats.
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.
Trevaskis
James L
JL
Amylin Pharmaceuticals, Inc., San Diego, California 92121, USA.
Turek
Victoria F
VF
Wittmer
Carrie
C
Griffin
Peter S
PS
Wilson
Julie K
JK
Reynolds
James M
JM
Zhao
Yu
Y
Mack
Christine M
CM
Parkes
David G
DG
Roth
Jonathan D
JD
D000818:Animals; D004032:Diet; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004958:Estradiol / Q000172:deficiency*; D005260:Female; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D020738:Leptin / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010052:Ovariectomy; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction; D013550:Swimming; D015431:Weight Loss / Q000187:drug effects*
D058228:Islet Amyloid Polypeptide; D020738:Leptin; D004958:Estradiol