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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 20, 2022
Accepted:
December 15,
2022
Received in revised form:
November 30,
2022
Received:
August 8,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
