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Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (S I ) in a nonhypertensive obese canine model. S I was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 ± 0.6 vs. 0.7 ± 0.6 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L - 1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L -1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic S I in HFD-fed animals (1.8 ± 0.3 × 10 -4 dL ⋅ kg -1 ⋅ min -1 ⋅ pmol/L -1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor α through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic S I 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 new therapeutic target to counteract insulin resistance., (© 2016 by the American Diabetes Association.)