Amylin-mediated restoration of leptin responsiveness in diet-induced obesity: magnitude and mechanisms.
Previously, we reported that combination treatment with rat amylin (100 microg/kg.d) and murine leptin (500 microg/kg.d) elicited greater inhibition of food intake and greater body weight loss in diet-induced obese rats than predicted by the sum of the monotherapy conditions, a finding consistent with amylin-induced restoration of leptin responsiveness. In the present study, a 3 x 4 factorial design was used to formally test for a synergistic interaction, using lower dose ranges of amylin (0, 10, and 50 microg/kg.d) and leptin (0, 5, 25, and 125 microg/kg.d), on food intake and body weight after 4 wk continuous infusion. Response surface methodology analysis revealed significant synergistic anorexigenic (P < 0.05) and body weight-lowering (P < 0.05) effects of amylin/leptin combination treatment, with up to 15% weight loss at doses considerably lower than previously reported. Pair-feeding (PF) experiments demonstrated that reduction of food intake was the predominant mechanism for amylin/leptin-mediated weight loss. However, fat loss was 2-fold greater in amylin/leptin-treated rats than PF controls. Furthermore, amylin/leptin-mediated weight loss was not accompanied by the counterregulatory decrease in energy expenditure and chronic shift toward carbohydrate (rather than fat) utilization observed with PF. Hepatic gene expression analyses revealed that 28 d treatment with amylin/leptin (but not PF) was associated with reduced expression of genes involved in hepatic lipogenesis (Scd1 and Fasn mRNA) and increased expression of genes involved in lipid utilization (Pck1 mRNA). We conclude that amylin/leptin interact synergistically to reduce body weight and adiposity in diet-induced obese rodents through a number of anorexigenic and metabolic effects.
Trevaskis
James L
JL
Amylin Pharmaceuticals, Inc., San Diego, California 92121, USA.
Coffey
Todd
T
Cole
Rebecca
R
Lei
Chunli
C
Wittmer
Carrie
C
Walsh
Brandon
B
Weyer
Christian
C
Koda
Joy
J
Baron
Alain D
AD
Parkes
David G
DG
Roth
Jonathan D
JD
D000682:Amyloid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D004032:Diet / Q000009:adverse effects; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000187:drug effects*; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects; D058228:Islet Amyloid Polypeptide; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*
D000682:Amyloid; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D008055:Lipids