Insulin acts in the arcuate nucleus to increase lumbar sympathetic nerve activity and baroreflex function in rats

Although the central effects of insulin to activate the sympathetic nervous system and enhance baroreflex gain are well known, the specific brain site(s) at which insulin acts has not been identified. We tested the hypotheses that (1) the paraventricular nucleus of the hypothalamus (PVN) and the arcuate nucleus (ArcN) are necessary brain sites and (2) insulin initiates its effects directly in the PVN and/or the ArcN. In α-chloralose anaesthetised female Sprague–Dawley rats, mean arterial pressure (MAP), heart rate (HR) and lumbar sympathetic nerve activity (LSNA) were recorded continuously, and baroreflex gain of HR and LSNA were measured before and during a hyperinsulinaemic–euglycaemic clamp. After 60 min, intravenous infusion of insulin (15 mU kg−1 min−1), but not saline, significantly increased (P < 0.05) basal LSNA (to 228 ± 28% control) and gain of baroreflex control of LSNA (from 3.8 ± 1.1 to 7.4 ± 2.4% control mmHg−1). These effects were reversed (P < 0.05) by local inhibition (bilateral microinjection of musimol) of the PVN (LSNA to 124 ± 8.8% control; LSNA gain to 3.9 ± 1.7% control mmHg−1) or of the ArcN (LSNA in % control: from 100 ± 0 to 198 ± 24 (insulin), then 133 ± 23 (muscimol) LSNA gain in % control mmHg−1: from 3.9 ± 0.3 to 8.9 ± 0.9 (insulin), then 5.1 ± 0.5 (muscimol)). While insulin receptor immunoreactivity was identified in neurons in pre-autonomic PVN subnuclei, microinjection of insulin (0.6, 6 and 60 nU) into the PVN failed to alter LSNA or LSNA gain. However, ArcN insulin increased (P < 0.05) basal LSNA (in % control to 162 ± 19, 0.6 nU; 193 ± 19, 6 nU; and 205 ± 28, 60 nU) and LSNA baroreflex gain (in % control mmHg−1 from 4.3 ± 1.2 to 6.9 ± 1.0, 0.6 nU; 7.7 ± 1.2, 6 nU; and 7.8 ± 1.3, 60 nU). None of the treatments altered MAP, HR, or baroreflex control of HR. Our findings identify the ArcN as the site at which insulin acts to activate the sympathetic nervous system and increase baroreflex gain, via a neural pathway that includes the PVN.