title: Increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion improves control of blood pressure in obesity.
abstract: Obesity is a major risk factor for hypertension. The copresentation of hypertension and insulin resistance (IR) suggests a role for IR in blood pressure (BP) dysregulation. To test this hypothesis, peripheral IR has been genetically subtracted in a model of obesity by crossing leptin receptor mutant mice (K(db)H(PTP)) with mice lacking protein tyrosine phosphatase 1B (insulin desensitizer, H(db)K(PTP)) to generate obese insulin-sensitive mice (K(db)K(PTP)). BP was recorded in lean (H(db)H(PTP), H(db)K(PTP)) and obese (K(db)H(PTP), K(db)K(PTP)) mice via telemetry, and a frequency analysis of the recording was performed to determine BP variability. Correction of IR in obese mice normalized BP values to baseline levels (H(db)H(PTP): 116 ± 2 mm Hg; K(db)H(PTP): 129 ± 4 mm Hg; K(db)K(PTP): 114 ± 5 mm Hg) and restored BP variability by decreasing its standard deviation and the frequency of BP values over the upper autoregulatory limit of the kidneys. However, although IR-induced increases in proteinuria (versus 53 ± 13 μg/d, H(db)H(PTP)) were corrected in K(db)K(PTP) (112 ± 39 versus 422 ± 159 μg/d, K(db)H(PTP)), glomerular hypertrophy was not. IR reduced plasma aldosterone levels ruling out a role for mineralocorticoids in the development of hypertension. Taken together, these data indicate that correction of IR prevents hypertension, BP variability, and microalbuminuria in obese mice. Although the mechanism remains to be fully determined, increases in aldosterone or sympathoactivation of the cardiovascular system seem to be less likely contributors.
authors.affiliation: Vascular Biology Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
authors.forename: Mohammed Irfan
authors.initials: MI
authors.lastname: Ali
authors.forename: James D
authors.initials: JD
authors.lastname: Mintz
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: David J
authors.initials: DJ
authors.lastname: Fulton
authors.forename: David W
authors.initials: DW
authors.lastname: Stepp
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000419:Albuminuria / Q000235:genetics / Q000503:physiopathology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D006984:Hypertrophy; D066298:In Vitro Techniques; D007333:Insulin Resistance / Q000235:genetics*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000172:deficiency / Q000235:genetics*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D005730:Ganglionic Blockers; D054411:Receptors, Leptin; D010656:Phenylephrine; D000450:Aldosterone; D008464:Mecamylamine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1