Adipose tissue natriuretic peptide receptor expression is related to insulin sensitivity in obesity and diabetes

Zuzana Kovacova, William G Tharp, Dianxin Liu, Wan Wei, Hui Xie, Sheila Collins, Richard E Pratley, Zuzana Kovacova, William G Tharp, Dianxin Liu, Wan Wei, Hui Xie, Sheila Collins, Richard E Pratley

Abstract

Objective: Cardiac natriuretic peptides (NPs) bind to two receptors (NPRA-mediator of signaling; NPRC-clearance receptor) whose ratio, NPRR (NPRA/NPRC), determines the NP bioactivity. This study investigated the relationship of NP receptor gene expression in adipose tissue and muscle with obesity and glucose intolerance. Prospectively, the study also assessed whether changes in NP receptor expression and thermogenic gene markers accompanied improvements of insulin sensitivity.

Methods: A cross-sectional study of subjects with a wide range of BMI and glucose tolerance (n = 50) was conducted, as well as a randomized 12-week trial of subjects with type 2 diabetes mellitus (T2DM) treated with pioglitazone (n = 9) or placebo (n = 10).

Results: NPRR mRNA was significantly lower in adipose tissue of subjects with obesity when compared with lean subjects (P ≤ 0.001). NPRR decreased with progression from normal glucose tolerance to T2DM (P < 0.01) independently of obesity. Treatment of subjects with T2DM with pioglitazone increased NPRR in adipose tissue (P ≤ 0.01) in conjunction with improvements in insulin sensitivity and increases of the thermogenic markers PPARγ coactivator-1α and uncoupling protein 1 (P ≤ 0.01).

Conclusions: Decreased adipose tissue NPRR was associated with obesity, glucose intolerance, and insulin resistance. This relationship was not observed for skeletal muscle NPRR. Pharmacological improvement of insulin sensitivity in subjects with T2DM was tied to improvement in NPRR and increased expression of genes involved in thermogenic processes.

Trial registration: ClinicalTrials.gov NCT00656864.

Keywords: adipose tissue; natriuretic peptide receptors; obesity; type 2 diabetes mellitus.

© 2016 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

Figures

Figure 1
Figure 1
Gene expression levels (mRNA) of NPRA and NPRC and the ratio of NPRA and NPRC (NPRR) in subcutaneous adipose tissue between (A) BMI groups (LEAN and OBESE) and (B) glucose tolerance groups (NGT, IGM, and T2DM). (C) Lysates of human subcutaneous adipose from four LEAN subjects, four OBESE subjects with NGT, and six subjects with T2DM were subjected to Western blotting as described in Methods. Samples were processed to assess membrane receptors NPRA and NPRC. β‐actin is measured as the control for total protein applied to the gel. (D) Bar graphs show quantification of NPRA or NPRC normalized to β‐actin. *Significant difference between groups at the level of *P < 0.05; **P < 0.01; and ***P < 0.001. AU, arbitrary units.
Figure 2
Figure 2
Graphical correlations between adipose tissue mRNA levels of (A) NPRA, (B) NPRC, (C) NPRR, and (D) PGC‐1α with insulin Si assessed by IVGTT. r represents Pearson's (parametric) correlation coefficient. NPRR data are log transformed. Squares (□) represent subjects with NGT; triangles (Δ) represent subjects with IGM; and circles (○) represent subjects with T2DM.
Figure 3
Figure 3
Circulating variables of the NP system. Plasma concentrations of BNP and NT‐proBNP were measured in fasting plasma samples and compared between (A) BMI groups (LEAN and OBESE) in the cross‐sectional study and (B) at baseline (PRE) and after 12 weeks of treatment (POST) with PLACEBO or PIOGLITAZONE in the interventional study.
Figure 4
Figure 4
Effect of PIOGLITAZONE versus PLACEBO on mRNA levels of (A) NPRA, (B) NPRC, (C) NPRR, (D) PGC‐1α, and (E) UCP‐1. *Significant difference between groups at the level of *P < 0.05 and **P < 0.01. AU, arbitrary units. UCP‐1 data were not normally distributed and were log transformed for the statistical test.

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