Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats |
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| Affiliation: | 1. Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Madrid, Spain;2. Instituto Pluridisciplinar and Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain;3. Unidad de Hipertensión, imas12, Hospital 12 de Octubre, 28041 Madrid, Spain;4. Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain;5. Servicio de Endocrinología y Nutrición, Hospital Clínico San Carlos, IdISSC, 28040 Madrid, Spain;1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO;2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA;1. Institute of Metabolic Sciences and MRC-Metabolic Diseases Unit, University of Cambridge, Cambridge, CB0 0QQ, UK;2. MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH, UK;3. Lilly Research Laboratories, Indianapolis, IN, USA |
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| Abstract: | Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n = 8) or 80% of AL (CR, n = 8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10− 9 to 10− 4 M) was reduced in fa/fa AL compared to control lean AL rats (p < 0.001), and restored by CR. The AMPK activator AICAR (10− 5 to 8·10− 3 M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p < 0.001). Inhibition of PI3K (wortmannin, 10− 7 M), Akt (triciribine, 10− 5 M), or eNOS (L-NAME, 10− 4 M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK–PI3K–Akt–eNOS pathway. |
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