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

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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.

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Most cited references 26

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Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

S Nambi, K Mather, A. Katz … (2000)

Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.

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Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.

Marica Bordicchia, Dianxin Liu, Ez-Zoubir Amri … (2012)

The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.

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Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

Lincoln R Potter, Sarah Abbey-Hosch, Deborah Dickey (2006)

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.

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Author and article information

Journal

Journal ID (nlm-ta): Obesity (Silver Spring)

Journal ID (iso-abbrev): Obesity (Silver Spring)

Journal ID (doi): 10.1002/(ISSN)1930-739X

Journal ID (publisher-id): OBY

Title: Obesity (Silver Spring, Md.)

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1930-7381

ISSN (Electronic): 1930-739X

Publication date (Electronic): 17 February 2016

Publication date (Print): April 2016

Volume: 24

Issue: 4 ( doiID: 10.1002/oby.v24.4 )

Pages: 820-828

Affiliations

[ ¹ ] Translational Research Institute for Metabolism and DiabetesFlorida Hospital Orlando FloridaUSA

[ ² ] Division of Endocrinology, Diabetes and MetabolismUniversity of Vermont College of Medicine Burlington VermontUSA

[ ³ ] Center for Metabolic Origins of DiseaseSanford Burnham Prebys Medical Discovery Institute Orlando FloridaUSA

Author notes

[*] [* ]Correspondence: Richard E. Pratley ( richard.pratley@ 123456flhosp.org ) or Sheila Collins ( scollins@ 123456sbpdiscovery.org )

Article

Publisher ID: OBY21418

DOI: 10.1002/oby.21418

PMC ID: 5067565

PubMed ID: 26887289

SO-VID: 9e5e3c11-5969-4f64-8099-0359ce2de86b

License:

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 10 June 2015

Date revision received : 22 September 2015

Date accepted : 30 October 2015

Page count

Pages: 9

Funding

Funded by: Florida Hospital Translational Research Institute for Metabolism and Diabetes

Funded by: institutional funds from Sanford Burnham Prebys Medical Discovery Institute

Funded by: Takeda Pharmaceuticals USA, Inc

Custom metadata

source-schema-version-number 2.0

component-id oby21418

cover-date April 2016

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.5 mode:remove_FC converted:18.10.2016

ScienceOpen disciplines: Medicine

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

Data availability:

ScienceOpen disciplines: Medicine

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

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

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Most cited references 26

Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.

Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

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