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Pharmacologic blockade of the natriuretic peptide clearance receptor promotes weight loss and enhances insulin sensitivity in type 2 diabetes

Published:December 20, 2022DOI:https://doi.org/10.1016/j.trsl.2022.12.005

      Abstract

      While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. To determine if pharmacologic blockade of NPRC enhanced the beneficial metabolic actions of NPs in type 2 diabetes, we blocked NP clearance in a mouse model of type 2 diabetes using the specific NPRC ligand ANP(4-23). We found that treatment with ANP(4-23) caused a significant decrease in body weight by increasing energy expenditure and reducing fat mass without a change in lean body mass. The decrease in fat mass was associated with a significant improvement in insulin sensitivity and reduced serum insulin levels. These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.

      Abbreviations:

      ANCOVA (analysis of covariance), ANP (atrial NP), BAT (brown adipose tissue), BNP (brain NP), CKD (chronic kidney diseases), CLAMS (Comprehensive LAb Monitoring System), CNP (C-type natriuretic peptide), HbA1c (hemoglobin A1c), HSL (hormone sensitive lipase), ITT (insulin tolerance test), KO (knockout), MCP1 (monocyte chemotactic protein-1), MRI (magnetic resonance imaging), NPRC (NP clearance receptor), NPRs (NP receptors), NPs (natriuretic peptides), PBS (phosphate buffered saline), PDEs (phosphodiesterases), RER (respiratory exchange ratio), UCP1 (uncoupling protein 1), US (United States), VCO2 (carbon dioxide release), VO2 (oxygen consumption), WAT (white adipose tissue), 1-α (peroxisome proliferator-activated receptor gamma coactivator)
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