Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 43, Pages 12298-12303Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1607464113
Keywords
melanocortin-4 receptors; developmental programming; maternal obesity; hypertension; sympathetic nerve activity
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Funding
- BBSRC [BB/H008845/1] Funding Source: UKRI
- MRC [G0802796] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H008845/1] Funding Source: researchfish
- British Heart Foundation [FS/09/057/27957, FS/10/003/28163] Funding Source: researchfish
- Medical Research Council [G0802796] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/H008845/1, BBD5231861] Funding Source: Medline
- British Heart Foundation [FS/09/057/27957, FS/10/003/28163] Funding Source: Medline
- Medical Research Council [G0802796] Funding Source: Medline
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Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control. Mc4r-deficient (Mc4rKO) mice are severely obese but lack obesity-related hypertension; they also show a reduced pressor response to salt loading. We have previously reported that lean juvenile offspring born to diet-induced obese rats (OffOb) exhibit sympathetic-mediated hypertension, and we proposed a role for postnatally raised leptin in its etiology. Here, we test the hypothesis that neonatal hyperleptinemia due to maternal obesity induces persistent changes in the central melanocortin system, thereby contributing to offspring hypertension. Working on the OffOb paradigm in both sexes and using transgenic technology to restore Mc4r in the PVH of Mc4rKO (Mc4rPVH) mice, we have now shown that these mice develop higher BP than Mc4rKO or WT mice. We have also found that experimental hyperleptinemia induced in the neonatal period in Mc4rPVH and WT mice, but not in the Mc4rKO mice, leads to heightened BP and severe renal dysfunction. Thus, Mc4r in the PVH appears to be required for earlylife programming of hypertension arising from either maternal obesity or neonatal hyperleptinemia. Early-life exposure of the PVH to maternal obesity through postnatal elevation of leptin may have long-term consequences for cardiovascular health.
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