Leptin Responsivity Restored in Leptin-Resistant Diet-Induced Obese
(DIO) Rats: Synergistic Actions of Amylin and Leptin for Reduction in
Body Weight (BW) and Fat
Year: 2006
Abstract Number: 52-LB
Authors:
JONATHAN ROTH, CHRISTIAN WEYER, CHRISTEN ANDERSON, DAVID PARKES, ALAIN
BARON
Institutions:
San Diego, CA
Results:
BW is regulated by a complex interaction between signals of long-term
adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety
(e.g., amylin, a hindbrain signal). We hypothesized that amylin and
leptin, in combination, would exert additive/synergistic effects on BW
in DIO. DIO rats received 14d subcutaneous pumps delivering vehicle,
rat amylin (100 mg/kg/d), murine leptin (500 mg/kg/d) or amylin (100
mg/kg/d)+leptin (500 mg/kg/d). BW changes were: leptin: +0.6%, amylin:
–3.4%* and amylin+leptin: –7.1%*⊃# (* p<0.05 vs. vehicle,
⊃#p<0.05 vs. amylin). Cumulative food intake (FI; grams) was:
vehicle: 222, leptin: 221, amylin: 189* and amylin+leptin: 160*⊃#(*
p<0.05 vs. vehicle, ⊃#p<0.05 vs. amylin). Amylin+leptin increased
light cycle fat oxidation and dark cycle energy expenditure (EE; p<0.05
vs. vehicle controls), effects not evident with either treatment alone.
BW, FI and EE changes in the combination group were consistent with
amylin restoring leptin responsivity in DIO. We then tested whether the
amylin+leptin BW synergy was merely attributable to caloric
restriction, or unique to amylin signaling. Changes in BW and
composition were compared in rats pair-fed to an amylin-treated group
that received leptin (PF+leptin), to a group that received
amylin+leptin. BW changes were: leptin: -2.7%, amylin: -6.7%*,
PF+leptin: -6.9%* and amylin+leptin: -12.0%*⊃# (* p<0.05 vs. vehicle,
⊃#p<0.05 vs. amylin and PF+leptin). BW loss with amylin+leptin was
attributable to reduced % body fat (p<0.05 vs. vehicle controls), with
relative increase in % lean tissue. In sum, amylin+leptin co-treatment:
(1) reproducibly induced synergistic, sustained BW loss (2)
specifically decreased adiposity while sparing lean mass, and, (3)
exerted effects through mutiple mechanisms partially dissociable from
amylin's anorexigenic properties. These studies provided pre-clinical
proof of concept for amylin restoring leptin responsivity in obesity, a
finding to be further substantiated in preclinical and clinical studies.