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

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...

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Published in	Obesity (Silver Spring, Md.) Vol. 24; no. 4; pp. 820 - 828
Main Authors	Kovacova, Zuzana, Tharp, William G., Liu, Dianxin, Wei, Wan, Xie, Hui, Collins, Sheila, Pratley, Richard E.
Format	Journal Article
Language	English
Published	United States Blackwell Publishing Ltd 01.04.2016 John Wiley and Sons Inc
Subjects	adipose tissue Adult Body fat Cross-Sectional Studies Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - physiopathology Female Glucose Humans Hypoglycemic Agents - therapeutic use Insulin resistance Insulin Resistance - physiology Kinases Male Metabolic disorders Middle Aged natriuretic peptide receptors Obesity Obesity - metabolism Obesity - physiopathology Original Receptors, Atrial Natriuretic Factor - analysis Receptors, Atrial Natriuretic Factor - metabolism Rodents Thiazolidinediones - therapeutic use type 2 diabetes mellitus adipose tissue type 2 diabetes mellitus natriuretic peptide receptors obesity
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ISSN	1930-7381 1930-739X 1930-739X
DOI	10.1002/oby.21418

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Summary:	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.
Bibliography:	Z.K. performed experiments, researched and analyzed the data, and wrote the manuscript. W.G.T. assisted in the conduct of the clinical study 2 and data analysis. H.X. performed the statistical data analysis. W.W. and D.L. performed experiments. S.C. contributed to study design and discussions and reviewed and edited the manuscript. R.E.P. designed and conducted the clinical studies, reviewed/edited the manuscript, and contributed to discussion. R.E.P. and S.C. are the guarantors of this work, have full access to the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. ClinicalTrials.gov Clinical trial registration identifier NCT00656864 R.E.P. has received research funding from Takeda Pharmaceuticals USA, Inc. S.C. has received research funding from Novo Nordisk and AstraZeneca. The other authors declared no conflict of interest. This work was supported by institutional funds from Florida Hospital Translational Research Institute for Metabolism and Diabetes; institutional funds from Sanford Burnham Prebys Medical Discovery Institute; and an investigator initiated grant from Takeda Pharmaceuticals USA, Inc. : Disclosure Funding agencies Author contributions SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 Funding agencies: This work was supported by institutional funds from Florida Hospital Translational Research Institute for Metabolism and Diabetes; institutional funds from Sanford Burnham Prebys Medical Discovery Institute; and an investigator initiated grant from Takeda Pharmaceuticals USA, Inc. Author contributions: Z.K. performed experiments, researched and analyzed the data, and wrote the manuscript. W.G.T. assisted in the conduct of the clinical study 2 and data analysis. H.X. performed the statistical data analysis. W.W. and D.L. performed experiments. S.C. contributed to study design and discussions and reviewed and edited the manuscript. R.E.P. designed and conducted the clinical studies, reviewed/edited the manuscript, and contributed to discussion. R.E.P. and S.C. are the guarantors of this work, have full access to the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis. Clinical trial registration: ClinicalTrials.gov identifier NCT00656864 Disclosure: R.E.P. has received research funding from Takeda Pharmaceuticals USA, Inc. S.C. has received research funding from Novo Nordisk and AstraZeneca. The other authors declared no conflict of interest.
ISSN:	1930-7381 1930-739X 1930-739X
DOI:	10.1002/oby.21418