Origin of Aberrant Blood Pressure and Sympathetic Regulation in Diet-Induced Obesity.
High fat diet (HFD)-induced hypertension in rabbits is neurogenic and caused by the central action of leptin, which is thought to be dependent on activation of α-melanocortin-stimulating hormone (α-MSH) and neuropeptide Y-positive neurons projecting to the dorsomedial hypothalamus (DMH) and ventromedial hypothalamus (VMH). However, leptin may act directly in these nuclei. Here, we assessed the contribution of leptin, α-MSH, and neuropeptide Y signaling in the DMH and VMH to diet-induced hypertension. Male New Zealand white rabbits were instrumented with a cannula for drug injections into the DMH or VMH and a renal sympathetic nerve activity (RSNA) electrode. After 3 weeks of an HFD (13.3% fat; n=19), rabbits exhibited higher RSNA, mean arterial pressure (MAP), and heart rate compared with control diet-fed animals (4.2% fat; n=15). Intra-VMH injections of a leptin receptor antagonist or SHU9119, a melanocortin 3/4 receptor antagonist, decreased MAP, heart rate, and RSNA compared with vehicle in HFD rabbits (P<0.05) but not in control diet-fed animals. By contrast, α-MSH or neuropeptide Y injected into the VMH had no effect on MAP but produced sympathoexcitation in HFD rabbits (P<0.05) but not in control diet-fed rabbits. The effects of the leptin antagonist, α-MSH, or neuropeptide Y injections into the DMH on MAP or RSNA of HFD rabbits were not different from those after vehicle injection. α-MSH into the DMH of control diet-fed animals did increase MAP, heart rate, and RSNA. We conclude that the VMH is the likely origin of leptin-mediated sympathoexcitation and α-MSH hypersensitivity that contribute to obesity-related hypertension.
From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (K.L., B.B., S.L.B., J.A.A., G.A.H.); Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia (B.B., J.A.A.); School of Medicine (Optometry), Deakin University, Waurn Ponds, Victoria, Australia (J.A.A.); and Department of Pharmacology, Monash University, Clayton, Victoria, Australia (G.A.H.).
Kyungjoon
K
Lim
From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (K.L., B.B., S.L.B., J.A.A., G.A.H.); Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia (B.B., J.A.A.); School of Medicine (Optometry), Deakin University, Waurn Ponds, Victoria, Australia (J.A.A.); and Department of Pharmacology, Monash University, Clayton, Victoria, Australia (G.A.H.).
Benjamin
B
Barzel
From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (K.L., B.B., S.L.B., J.A.A., G.A.H.); Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia (B.B., J.A.A.); School of Medicine (Optometry), Deakin University, Waurn Ponds, Victoria, Australia (J.A.A.); and Department of Pharmacology, Monash University, Clayton, Victoria, Australia (G.A.H.).
Sandra L
SL
Burke
From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (K.L., B.B., S.L.B., J.A.A., G.A.H.); Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia (B.B., J.A.A.); School of Medicine (Optometry), Deakin University, Waurn Ponds, Victoria, Australia (J.A.A.); and Department of Pharmacology, Monash University, Clayton, Victoria, Australia (G.A.H.).
James A
JA
Armitage
From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (K.L., B.B., S.L.B., J.A.A., G.A.H.); Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia (B.B., J.A.A.); School of Medicine (Optometry), Deakin University, Waurn Ponds, Victoria, Australia (J.A.A.); and Department of Pharmacology, Monash University, Clayton, Victoria, Australia (G.A.H.). geoff.head@bakeridi.edu.au.
Geoffrey A
GA
Head
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004302:Dorsomedial Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D020738:Leptin / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D009478:Neuropeptide Y / Q000378:metabolism / Q000494:pharmacology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D011817:Rabbits; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors; D044101:Receptors, Melanocortin / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism* / Q000473:pathology; D000521:alpha-MSH / Q000378:metabolism / Q000494:pharmacology
D020738:Leptin; D009478:Neuropeptide Y; D054411:Receptors, Leptin; D044101:Receptors, Melanocortin; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones
SHU9119; hypertension; leptin; neuropeptide Y; obesity