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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 ?g/d, H(db)H(PTP)) were corrected in K(db)K(PTP) (112 ± 39 versus 422 ± 159 ?g/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.

SUBMITTER: Belin de Chantemele EJ

PROVIDER: S-EPMC3475734 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion improves control of blood pressure in obesity.

Belin de Chantemèle Eric J EJ Ali Mohammed Irfan MI Mintz James D JD Rainey William E WE Tremblay Michel L ML Fulton David J DJ Stepp David W DW

Hypertension (Dallas, Tex. : 1979) 20121008 5

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), ...[more]

PMID: 23045458

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Project description:A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn2+) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn2+) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing ("anti-diabetic") effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.

Dataset Information

Increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion improves control of blood pressure in obesity.

Publications

Increasing peripheral insulin sensitivity by protein tyrosine phosphatase 1B deletion improves control of blood pressure in obesity.

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