Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. We therefore hypothesized that inhibiting SNS by using Renal Denervation (RDN) will improve insulin sensitivity (SI) in our non-hypertensive obese canine model. SI was measured using euglycemic hyperinsulinemic clamp (EGC), before (w0) and after six weeks of high-fat diet (w6-HFD) and after either RDN (HFD+RDN) or sham surgery (HFD+Sham). As expected, HFD induced insulin resistance in the liver (2.5±0.6x10-4dl.kg-1min-1pM-1 at w0 vs 0.7±0.6x10-4dl.kg-1min-1pM-1 at w6-HFD (P<0.05) in sham, 1.6±0.3 at w0 vs 0.5±0.3 at w6-HFD (P<0.001) in HFD+RDN). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic SI in fat-fed dogs (1.8±0.3x10-4dl.kg-1min-1pM-1 at HFD+RDN, P<0.001 vs w6-HFD, P=ns vs w0) by reducing hepatic gluconeogenic genes including G6Pase, PEPCK and FOXO1. Our data suggests that RDN down-regulated hepatic gluconeogenesis primarily by up-regulating liver-X-receptor (LXR-α) via the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic SI in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a putative new therapeutic target to counteract insulin resistance.
- Received January 1, 2016.
- Accepted July 26, 2016.
- © 2016 by the American Diabetes Association.