EDITORIAL COMMENT
A New Role for the Natriuretic PeptidesMetabolic Regulators of the Adipocyte*
Lisa C. Costello-Boerrigter, MD, PhD* and
John C. Burnett, Jr, MD
Cardiorenal Research Laboratory, Mayo Clinic and Foundation, Rochester, Minnesota
* Reprint requests and correspondence: Dr. Lisa C. Costello-Boerrigter, Cardiorenal Research Laboratory, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905 (Email: costello.lisa{at}mayo.edu).
Key Words: adiponectin • natriuretic peptides • heart failure
The heart and adipose tissue are both endocrine organs, and there is increasing evidence for cross talk between them, although precise mechanisms remain poorly defined. Of particular importance is the role that such cross talk could play in both total body metabolism and cardiac metabolism. The timely and thought-provoking article by Tsukamoto et al. (1) in this issue of the Journal adds to this body of knowledge by examining both in vitro and in vivo the biological actions of cardiac natriuretic peptides on adiponectin production and secretion.
By now the cardiovascular community is well aware that atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) promote vasodilation and natriuresis, improve diastolic function, suppress aldosterone, and inhibit cardiac hypertrophy and fibrosis (2,3). Less well known is that ANP and BNP have metabolic roles; specifically, ANP and BNP are lipolytic and slow gastric emptying and absorption (4,5). Indeed, the binding of ANP or BNP to the natriuretic peptide receptor-A (NPR-A) receptor, which is present in adipocytes, results in the production of the second messenger cGMP. The cGMP in turn activates protein kinase G, leading to phosphorylation of hormone sensitive lipase (HSL). The HSL is thus activated, and hydrolysis of fatty acids ultimately occurs (4,6). In addition, ANP has been shown to induce postprandial lipid oxidation in humans (7). These lipolytic actions of ANP and BNP, which generally are assumed to be primate-specific, underscore an emerging role for the heart in human metabolism (8).
This role has caused speculation as to the potential role of chronic, pathological BNP elevation in cardiac cachexia (9). Conversely, plasma BNP and N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels are depressed in obese patients as compared with lean patients, despite the obese patients having greater left ventricular end-diastolic pressures. This finding has led to the conjecture that decreased natriuretic peptide concentrations in the obese are secondary to a relatively decreased myocardial synthesis or impaired release from the cardiomyocytes (10). Indeed, this suppression of ANP and BNP in obese patients could, based upon the cardiorenal and metabolic properties of ANP and BNP, contribute to clinical phenotypes associated with the metabolic syndrome. Furthermore, the newly appreciated metabolic properties of these 2 cardiac hormones may suggest a novel therapeutic target in metabolic diseases such as obesity.
Adiponectin, a 244-amino acid peptide that is known to self-associate to form multimers, was first described in 1995 and is also emerging as an important regulator of metabolism (11–14). Adiponectin is primarily, if not exclusively, thought to be produced by adipocytes, although the authors of some studies have shown that cardiomyocytes produce low levels of adiponectin and that there is a significant step-up of adiponectin levels in the coronary sinus compared with the aortic root in heart failure (HF) patients, suggesting that there may be cardiac release of adiponectin in patients with HF (15,16). Despite the fact that adiponectin is primarily produced by adipose tissue, there seems to be an almost-paradoxical relationship between adiponectin plasma concentrations and body mass index. Indeed, it is well established that, in humans, plasma adiponectin levels are inversely related to body mass index and percent body fat (17). Plasma adiponectin concentrations are low in the obese, in patients with diabetes and in those with insulin resistance, and in patients with coronary atherosclerotic disease (18–20). In contrast, plasma adiponectin levels are high in individuals with anorexia nervosa and in HF patients with cachexia (21–23). Furthermore, the administration of exogenous adiponectin to animals resulted in weight loss (24).
The authors of previous studies have found a positive correlation between adiponectin and NT-proBNP or BNP levels in HF patients and in normal individuals (23,25,26). Weight loss after bariatric surgery has been shown to result in increased adiponectin as well as BNP and NT-proBNP levels (27,28). It has also been shown in a small clinical study that decompensated HF patients who received ANP infusions had increased plasma levels of total and high molecular weight (multimeric) adiponectin (29).
With all of this background, the work of Tsukamoto et al. (1) adds mechanistic insights. Importantly, the authors demonstrated that ANP and BNP via the cGMP pathway increase adiponectin messenger ribonucleic acid expression and increase adiponectin secretion from cultured adipocytes. How this functionally impacts HF is still unclear, although these authors and others have speculated that, in the setting of HF, adiponectin secretion may occur to attenuate the chronic energy deprivation the heart faces as it switches from predominantly fatty acid oxidation to glucose oxidation (1,15,23). Also, the natriuretic peptide-induced lipolysis and adiponectin secretion could aid in weight loss, which in the setting of HF could be considered a cardiac unloading action. An extreme form of this could be cardiac cachexia. Clearly, there is a need for further work in this fascinating area.
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Footnotes
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Supported by National Institutes of Health grants HL36634 and HL76611. The Mayo Clinic and Foundation has licensed novel natriuretic peptides to Nile Therapeutics and Anexon. Dr. Burnett has received a grant from Scios, and is chair of the Nile Scientific Advisory Board.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures Am Heart J 2006;152:1071-1076.[CrossRef][Web of Science][Medline] 11. Wang Y, Xu LY, Lam KS, et al. Proteomic characterization of human serum proteins associated with the fat-derived hormone adiponectin Proteomics 2006;6:3862-3870.[CrossRef][Web of Science][Medline] 12. Scherer PE, Williams S, Fogliano M, et al. A novel serum protein similar to C1q, produced exclusively in adipocytes J Biol Chem 1995;270:26746-26749.[Abstract/Free Full Text] 13. Sattar N, Wannamethee G, Sarwar N, et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis Circulation 2006;114:623-629.[Abstract/Free Full Text] 14. Lara-Castro C, Luo N, Wallace P, et al. Adiponectin multimeric complexes and the metabolic syndrome trait cluster Diabetes 2006;55:249-259.[Abstract/Free Full Text] 15. Fujioka D, Kawabata K, Saito Y, et al. 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