title: Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet.
abstract: 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 (SI) in a nonhypertensive obese canine model. SIwas 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 × 10-4dL ⋅ kg-1⋅ min-1⋅ pmol/L-1at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 × 10-4dL ⋅ kg-1⋅ min-1⋅ pmol/L-1at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic SIin HFD-fed animals (1.8 ± 0.3 × 10-4dL ⋅ kg-1⋅ min-1⋅ pmol/L-1at 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 SIin 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.
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA malini.s.iyer@gmail.com.
authors: Malini S
authors: MS
authors: Iyer
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Richard N
authors: RN
authors: Bergman
authors: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Jeremy E
authors: JE
authors: Korman
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Orison O
authors: OO
authors: Woolcott
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Morvarid
authors: M
authors: Kabir
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.|Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Ronald G
authors: RG
authors: Victor
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Deborah J
authors: DJ
authors: Clegg
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Cathryn
authors: C
authors: Kolka
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004285:Dogs; D005943:Gluconeogenesis / Q000502:physiology; D015309:Glucose Clamp Technique; D007003:Hypoglycemia / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007668:Kidney / Q000294:innervation* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D012083:Renin / Q000097:blood; D013564:Sympathetic Nervous System / Q000378:metabolism
chemical_list: D002395:Catecholamines; D007328:Insulin; D000071518:Liver X Receptors; D012083:Renin