Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus.
Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus (PVN) regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether PVN neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280-420 g) by an infusion of insulin (3.75 mU/kg per min) and 50% dextrose (0.75-2.0 mL/h) for 120 minutes. At 90 minutes, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the PVN with bilateral injection of the GABA(A) receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the PVN did not alter lumbar sympathetic nerve activity, and thereby suggests that insulin activates neurons upstream of the PVN. Interestingly, the sympathetic response to insulin was eliminated by PVN injection of the melanocortin 3/4 receptor antagonist SHU9119, but was unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of PVN neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate that insulin activates a melanocortin-dependent pathway to the PVN that increases glutamatergic drive to the rostral ventrolateral medulla and alters cardiovascular function.
Department of Cellular & Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA.
Kathryn R
KR
Ward
James F
JF
Bardgett
Lawrence
L
Wolfgang
Sean D
SD
Stocker
D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*
D057911:Angiotensin Receptor Antagonists; D058785:GABA-A Receptor Agonists; D007328:Insulin; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D009118:Muscimol; D005947:Glucose; D019808:Losartan
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