Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin.

Abstract

Accumulating evidence suggests that insulin acts within the hypothalamus to alter sympathetic nerve activity (SNA) and baroreflex function. Although insulin receptors are widely expressed across the hypothalamus, recent evidence suggests that neurons of the arcuate nucleus (ARC) play an important role in the sympathoexcitatory response to insulin. The purpose of the present study was to determine whether circulating insulin acts directly in the ARC to elevate SNA. In anesthetized male Sprague-Dawley rats (275-425 g), the action of insulin was neutralized by microinjection of an anti-insulin affibody (1 ng/40 nl). To verify the efficacy of the affibody, ARC pretreatment with injection of the anti-insulin affibody completely prevented the increase in lumbar SNA produced by ARC injection of insulin. Next, ARC pretreatment with the anti-insulin affibody attenuated the lumbar sympathoexcitatory response to intracerebroventricular injection of insulin. Third, a hyperinsulinemic-euglycemic clamp increased lumbar, but not renal, SNA in animals that received ARC injection of a control affibody. However, this sympathoexcitatory response was absent in animals pretreated with the anti-insulin affibody in the ARC. Injection of the anti-insulin affibody in the adjacent ventromedial hypothalamus did not alter the sympathoexcitatory response to insulin. The ability of the anti-insulin affibody to prevent the sympathetic effects of insulin cannot be attributed to a general inactivation or nonspecific effect on ARC neurons as the affibody did not alter the sympathoexcitatory response to ARC disinhibition by gabazine. Collectively, these findings suggest that circulating insulin acts within the ARC to increase SNA.

• Authors: Brittany S Luckett, Jennifer L Frielle, Lawrence Wolfgang, Sean D Stocker
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 304 Issue 11 Pg. H1538-46 (Jun 01 2013) ISSN: 1522-1539 [Electronic] United States
• PMID: 23542919 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• GABA Antagonists
• Insulin
• Insulin Antagonists
• Pyridazines
• gabazine
• Oncogene Protein v-akt

Topics

• Adipocytes (metabolism)
• Animals
• Antibodies, Blocking (administration & dosage, pharmacology)
• Arcuate Nucleus of Hypothalamus (physiology)
• Data Interpretation, Statistical
• GABA Antagonists (pharmacology)
• Glucose Clamp Technique
• Hyperinsulinism (physiopathology)
• Injections, Intraventricular
• Insulin (blood, physiology)
• Insulin Antagonists (administration & dosage, pharmacology)
• Male
• Microinjections
• Oncogene Protein v-akt (physiology)
• Phosphorylation
• Pyridazines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sympathetic Nervous System (drug effects)
• Ventromedial Hypothalamic Nucleus (metabolism)