Differential effects of insulin on sympathetic nerve activity in agouti obese mice

Abstract

Objective: Hyperinsulinemia, which often coexists with obesity and type 2 diabetes, is a major risk factor for cardiovascular disease and thought to promote hypertension through the sympathetic effects of insulin. Here, we examined the effect of insulin on regional sympathetic nerve activity (SNA) in obesity.

Methods: Glucose and insulin tolerance tests were performed to examine insulin sensitivity in agouti obese mice. We used also multifiber recording to compare the regional SNA response to intracerebroventricular (ICV) insulin between lean and agouti obese mice.

Results: Agouti obese mice have significantly elevated levels of blood glucose and plasma insulin associated with glucose intolerance and insulin resistance. In lean mice, ICV administration of insulin (20 and 100 microU) caused a dose-dependent increase in SNA subserving hindlimb, kidney and brown adipose tissue (BAT). Of note, the regional SNA responses to insulin were differentially altered in agouti obese mice. Whereas lumbar SNA response to insulin was intact in the obese mice, renal and BAT sympathetic activation to insulin were significantly attenuated in these agouti obese mice. Finally, we assessed the role of phosphoinositol-3 kinase (PI3K) signaling pathway in mediating sympathetic activation to insulin in obesity. Notably, ICV pretreatment with a PI3K inhibitor (LY294002) blocked the increase in lumbar SNA induced by ICV insulin in lean and agouti obese mice.

Conclusions: Our data suggest a differential regulation by insulin of sympathetic outflow to peripheral tissues in obesity. Our findings also demonstrate the importance of PI3K in lumbar sympathetic activation to insulin in obesity.

Fig. 1

Insulin resistance in agouti obese mice. (A–B) Comparison of blood glucose (A) and plasma insulin (B) between lean controls and agouti obese mice. (C–D) Glucose (C) and insulin (D) tolerance tests in lean controls and agouti obese mice. Data represent means±SEM; n=4–10 mice per group. There was a significant difference (P<0.05) between lean and obese mice in the effects of glucose and insulin on blood glucose. * P<0.05 vs. lean control mice.

Fig. 2

Lumbar sympathetic nerve activity (SNA) responses to ICV insulin in lean controls and agouti obese mice. (A–B) Time-course of lumbar SNA response to ICV insulin (100 μU) vs. vehicle in lean controls (A) and agouti obese mice (B). (C) Comparison of the 4^th h of lumbar SNA responses to ICV insulin (0 [vehicle], 20 and 100 μU) and vehicle between controls and agouti obese mice. Data represent means±SEM; n=10–12 mice per group. There was no significant difference between lean and obese mice in the effect of insulin on lumbar SNA (P=0.69). * P<0.05 vs. vehicle.

Fig. 3

Renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) responses to ICV insulin in lean controls and agouti obese mice. Renal (A) and BAT (B) SNA responses, 4 h after ICV injection of insulin (0 [vehicle], 20 and 100 μU) was compared between controls and agouti obese mice. Data represent means±SEM; n=9–12 mice per group. There was a significant difference between lean and obese mice in the effects of insulin on renal (P=0.029) and BAT SNA (P=0.045). * P < 0.05 vs. vehicle; † P < 0.05 vs. lean control mice.

Fig. 4

Effects of PI3K blockade on the lumbar sympathetic nerve activity (SNA) responses to ICV insulin in lean controls (A) and agouti obese mice (B). PI3K inhibitor LY294002 (0.01 and 0.1 μg) or vehicle were given ICV, 10 min before ICV insulin or vehicle. Data represent means±SEM; n=6–9 mice per group. * P<0.05 vs. vehicle; † P<0.05 vs. vehicle-insulin group.