Abstract
Obesity decreases baroreflex gain (BRG); however, the mechanisms are unknown. We tested the hypothesis that impaired BRG is related to the concurrent insulin resistance, and, therefore, BRG would be improved after treatment with the insulin-sensitizing drug rosiglitazone. Male rats fed a high-fat diet diverged into obesity-prone (OP) and obesity-resistant (OR) groups after 2 weeks. Then, OP and OR rats, as well as control (CON) rats fed a standard diet, were treated daily for 2 to 3 weeks with rosiglitazone (3 or 6 mg/kg) or its vehicle by gavage. Compared with OR and CON rats, conscious OP rats exhibited reductions in BRG (OP, 2.9 ± 0.1 bpm/mm Hg; OR, 4.0 ± 0.2 bpm/mm Hg; CON, 3.9 ± 0.2 bpm/mm Hg; P < 0.05) and insulin sensitivity (hyperinsulinemic euglycemic clamp; OP, 6.8 ± 0.9 mg/kg · min; OR, 22.2 ± 1.2 mg/kg · min; CON, 17.7 ± 0.8 mg/kg · min; P < 0.05), which were well correlated (r2 = 0.49; P < 0.01). In OP rats, rosiglitazone dose-dependently improved (P < 0.05) insulin sensitivity (12.8 ± 0.6 mg/kg · min at 3 mg/kg; 16.0 ± 1.5 mg/kg · min at 6 mg/kg) and BRG (3.8 ± 0.4 bpm/mm Hg at 3 mg/kg; 5.3 ± 0.7 bpm/mm Hg at 6 mg/kg). However, 6 mg/kg rosiglitazone also increased BRG in OR rats without increasing insulin sensitivity, disrupted the correlation between BRG and insulin sensitivity (r2 = 0.08), and, in OP and OR rats, elevated BRG relative to insulin sensitivity (analysis of covariance; P < 0.05). Moreover, in OP rats, stimulation of the aortic depressor nerve, to activate central baroreflex pathways, elicited markedly reduced decreases in heart rate and arterial pressure, but these responses were not improved by rosiglitazone. In conclusion, diet-induced obesity impairs BRG via a central mechanism that is related to the concurrent insulin resistance. Rosiglitazone normalizes BRG, but not by improving brain baroreflex processing or insulin sensitivity.
Footnotes
This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL088552]; and the American Heart Association, Pacific Mountain Affiliate [Grant-in-Aid 09GRNT2060630; Postdoctoral Fellowship 7500041].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- BRG
- baroreflex gain
- TZD
- thiazolidinedione
- PPAR-γ
- peroxisome proliferator-activated receptor-γ
- DIO
- diet-induced obesity
- HFD
- high-fat diet
- OP
- obesity prone
- OR
- obesity resistant
- CON
- control
- MAP
- mean arterial pressure
- HR
- heart rate
- ADN
- aortic depressor nerve
- ROS
- reactive oxygen species
- ANOVA
- analysis of variance
- 3-ROSI
- 3 mg/kg rosiglitazone
- 6-ROSI
- 6 mg/kg rosiglitazone.
- Received March 23, 2012.
- Accepted July 17, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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