Introduction & Objective: Obese individuals may experience a relative deficiency of natriuretic peptides (NP); this “NP handicap” may contribute to increased risks of hypertension, glucose intolerance, and fat accumulation in obesity. The pathogenesis of the NP handicap is not entirely known; elevated expression of the NP clearance receptor (NPRC) may contribute. We employ a comprehensive evaluation of the mechanisms underlying the NP handicap by measuring adipose gene expression of all 3 NP receptors, the peptidase neprilysin, and all cGMP degrading phosphodiesterases (PDE).
Methods: In a prospective study, we recruited 199 lean and obese adults (n = 55 lean, 144 obese; 56% female). We conducted biopsies of subcutaneous adipose tissue to measure gene expression and also measured circulating NP levels.
Results: Higher BMI was associated with lower circulating pro-Atrial NP and adipocyte gene expression of NPRA. Higher BMI was associated with higher adipose gene expression of proteins that degrade circulating NPs (NPRC, neprilysin) and blunt intracellular NP-evoked cGMP signaling (PDE 1A, 1C, 2A, 5A, 9A, 10A).
Conclusion: The obesity-related NP handicap is not only caused by upregulation of NPRC but appears to be a coordinated regulation of multiple genes in adipose tissue that work in concert to reduce NP signaling events.
R.P. Ceddia: None. E. Brittain: None. M. Mashayekhi: None. S. Huang: None. R. Jones: None. J. Palacios: None. C.F. Reynolds: None. C. Mambungu: None. T. Ikizler: None. T. Wang: None. S. Collins: None. D. Gupta: None. K.N. Bachmann: Employee; Amgen Inc. Stock/Shareholder; Medtronic, Pfizer Inc.
National Institutes of Health (HL145293, T32DK007061, UL1TR002243, KL2TR002245, DK020593, P30AI110527), U.S. Department of Veterans Affairs Clinical Sciences Research and Development (CSR&D) Program (IK2 CX001678), American Heart Association (17SFRN33520017), Vanderbilt Faculty Research Scholars, Vanderbilt Edge for Scholars Research Recovery fund
