Angiotensin 1-7 as Means to Prevent the Metabolic Syndrome
Lessons From the Fructose-Fed Rat Model
- Yonit Marcus1,2,
- Gabi Shefer2,3,
- Keren Sasson1,
- Fortune Kohen4,
- Rona Limor2,
- Orit Pappo5,
- Nava Nevo4,
- Inbal Biton6,
- Michal Bach2,
- Tamara Berkutzki6,
- Matityahu Fridkin7,
- Dafna Benayahu3,
- Yoram Shechter1 and
- Naftali Stern2,3⇑
- 1Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
- 2Institute of Endocrinology, Metabolism, and Hypertension, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
- 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- 4Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
- 5Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
- 6Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel
- 7Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel
- Corresponding author: Naftali Stern, .
Y.M., Y.S., and N.S. contributed equally to this study.
We studied the effects of chronic angiotensin 1-7 (Ang 1-7) treatment in an experimental model of the metabolic syndrome, i.e., rats given high-fructose/low-magnesium diet (HFrD). Rats were fed on HFrD for 24 weeks with and without Ang 1-7 (576 µg/kg/day, s.c., Alzet pumps). After 6 months, Ang 1-7–treated animals had lower body weight (−9.5%), total fat mass (detected by magnetic resonance imaging), and serum triglycerides (−51%), improved glucose tolerance, and better insulin sensitivity. Similar metabolic effects were also evident, albeit in the absence of weight loss, in rats first exposed to HFrD for 5 months and then subjected to short-term (4 weeks) treatment with Ang 1-7. Six months of Ang 1-7 treatment were associated with lower plasma renin activity (−40%) and serum aldosterone (−48%), less hepatosteatatitis, and a reduction in epididymal adipocyte volume. The marked attenuation of macrophage infiltration in white adipose tissue (WAT) was associated with reduced levels of the pP65 protein in the epididymal fat tissue, suggesting less activation of the nuclear factor-κB (NFκB) pathway in Ang 1-7–treated rats. WAT from Ang 1-7–treated rats showed reduced NADPH-stimulated superoxide production. In single muscle fibers (myofibers) harvested and grown ex vivo for 10 days, myofibers from HFrD rats gave rise to 20% less myogenic cells than the Ang 1-7–treated rats. Fully developed adipocytes were present in most HFrD myofiber cultures but entirely absent in cultures from Ang 1-7–treated rats. In summary, Ang 1-7 had an ameliorating effect on insulin resistance, hypertriglyceridemia, fatty liver, obesity, adipositis, and myogenic and adipogenic differentiation in muscle tissue in the HFrD rats.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0792/-/DC1.
- Received June 13, 2012.
- Accepted October 23, 2012.
- © 2013 by the American Diabetes Association.
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