title: Central proopiomelanocortin but not neuropeptide Y mediates sympathoexcitation and hypertension in fat fed conscious rabbits.
abstract: OBJECTIVE
  High-fat diet (HFD)-induced hypertension in rabbits is neurogenic because of the central sympathoexcitatory actions of leptin. Hypothalamic melanocortin and neuropeptide Y (NPY) neurons are recognized as the major signalling pathways through which leptin exerts its central effects. In this study, we assessed the effects of specific antagonists and agonists to melanocortin and NPY receptors on HFD-induced sympathoexcitation and hypertension.
  
  
  METHODS
  Rabbits were instrumented with intracerebroventricular cannula, renal sympathetic nerve activity (RSNA) electrode, and blood pressure telemetry transmitter.
  
  
  RESULTS
  After 3 weeks HFD (13.5% fat, n = 12) conscious rabbits had higher RSNA (+3.8  nu, P = 0.02), blood pressure (+8.6  mmHg, P < 0.001) and heart rate (+15  b/min, P = 0.01), and brain-derived neurotrophic factor levels in the hypothalamus compared with rabbits fed a control diet (4.2% fat, n = 11). Intracerebroventricular administration of the melanocortin receptor antagonist SHU9119 reduced RSNA (-2.7  nu) and blood pressure (-8.5  mmHg) in HFD but not control rabbits, thus reversing 100% of the hypertension and 70% of the sympathoexcitation induced by a HFD. By contrast, blocking central NPY Y1 receptors with BVD10 increased RSNA only in HFD rabbits. Intracerebroventricular α-melanocortin stimulating hormone increased RSNA and heart rate (P < 0.001) in HFD rabbits but had no effect in control rabbits.
  
  
  CONCLUSIONS
  These findings suggest that obesity-induced hypertension and increased RSNA are dependent on the balance between greater activation of melanocortin signalling through melanocortin receptors and lesser activation of NPY sympathoinhibitory signalling. The amplification of the sympathoexcitatory effects of α-melanocortin stimulating hormone also indicates that the underlying mechanism is related to facilitation of leptin-melanocortin signalling, possibly involving chronic activation of brain-derived neurotrophic factor.
authors.affiliation: aBaker IDI Heart and Diabetes Institute, MelbournebDepartment of Anatomy and Developmental Biology, Monash University, ClaytoncSchool of Medicine (Optometry), Deakin University, GeelongdDepartment of Pharmacology, Monash University, Clayton, Victoria, Australia*Benjamin Barzel and Kyungjoon Lim are joint first authors.†James A. Armitage and Geoffrey A. Head are joint senior authors.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Barzel
authors.forename: Kyungjoon
authors.initials: K
authors.lastname: Lim
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Burke
authors.forename: James A
authors.initials: JA
authors.lastname: Armitage
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D059305:Diet, High-Fat; D006339:Heart Rate / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism*; D007668:Kidney / Q000294:innervation; D020738:Leptin / Q000378:metabolism*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011817:Rabbits; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors; D044101:Receptors, Melanocortin / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000521:alpha-MSH / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006728:Hormones; D020738:Leptin; D009478:Neuropeptide Y; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C103272:SHU 9119; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D009074:Melanocyte-Stimulating Hormones