title: Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity.
abstract: 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 early-life 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.
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom; anne-maj.samuelsson@kcl.ac.uk.
authors: Anne-Maj S
authors: AS
authors: Samuelsson
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Amandine
authors: A
authors: Mullier
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Nuria
authors: N
authors: Maicas
authors: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors: Nynke R
authors: NR
authors: Oosterhuis
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Sung
authors: S
authors: Eun Bae
authors: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M, United Kingdom.
authors: Tatiana V
authors: TV
authors: Novoselova
authors: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M, United Kingdom.
authors: Li F
authors: LF
authors: Chan
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Joaquim M
authors: JM
authors: Pombo
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Paul D
authors: PD
authors: Taylor
authors: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors: Jaap A
authors: JA
authors: Joles
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Clive W
authors: CW
authors: Coen
authors: School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TH, United Kingdom.
authors: Nina
authors: N
authors: Balthasar
authors: Division of Women's Health, King's College London, Women's Health Academic Centre King's Health Partners, London SE1 7EH, United Kingdom.
authors: Lucilla
authors: L
authors: Poston
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D033261:Maternal-Fetal Relations / Q000502:physiology; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000503:physiopathology; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000473:pathology
chemical_list: D020738:Leptin; D044105:Receptor, Melanocortin, Type 4
keywords: developmental programming; hypertension; maternal obesity; melanocortin-4 receptors; sympathetic nerve activity