A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.
This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups,P≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P< 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P= 0.02) but not CON or RUN groups (P≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P< 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHYThe new and noteworthy findings are that1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri; olvert@missouri.edu.
T Dylan
TD
Olver
Department of Kinesiology, University of Western Ontario, London, Ontario, Canada.
Matthew W
MW
McDonald
Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri; and.
Diana
D
Klakotskaia
Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri; and.
Rachel A
RA
Richardson
Natural Science Division, Pepperdine University, Malibu, California.
Jeffrey L
JL
Jasperse
Department of Kinesiology, University of Western Ontario, London, Ontario, Canada.
C W James
CWJ
Melling
Department of Psychological Sciences, University of Missouri-Columbia, Columbia, Missouri; and.
Todd R
TR
Schachtman
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri.
Hsiao T
HT
Yang
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri.
Craig A
CA
Emter
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri.
M Harold
MH
Laughlin
D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000628:therapy; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D020769:Posterior Cerebral Artery / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D020334:Rats, Inbred OLETF; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D007328:Insulin; D009569:Nitric Oxide
NO; cerebrovascular; endothelin; insulin; obesity; physical activity