Close Linkage Between Natriuretic Peptides and Obesity　― Impact of Sex on the Interorgan Metabolic Crosstalk ―

A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are hormones produced in the heart,¹ and serve as critical biomarkers of the severity of heart failure.² BNP production and secretion are stimulated by cardiac overload, so in general, plasma BNP levels correlate well with disease severity. Recently, increasing evidence has indicated that some patients with heart failure show unexpectedly low BNP levels; these findings are particularly salient in obese subjects.^3,4 However, the precise regulatory mechanisms underlying the low reactivity of BNP, as well as its pathophysiological significance, remain unclear.

Article p 647

In this issue of the Journal, Choi et al⁵ report on the effects of age, sex, and obesity-related parameters on circulating levels of N-terminal proBNP (NT-proBNP), a precursor of BNP, in their large-scale study of individuals from a general, healthy population. They found that younger age, male sex, and increases in obesity-related parameters (waist circumference [WC], body mass index [BMI], and body weight [BW]) were related to reduced NT-proBNP levels. Furthermore, after adjusting for the effect of WC and BMI on each other (adjusted multivariable analysis), a higher WC (indicating abdominal obesity) was associated with lower NT-proBNP levels in females but not males (P interaction <0.001). Moreover, BMI was the only parameter inversely associated with NT-proBNP in both sexes in the adjusted multivariable analysis. The study population consisted of a large number of patients (n=39,937) based on a comprehensive health screening program cohort from the Kangbuk Samsung Health Study, presenting convincing evidence.

This study significantly increases our understanding of the complex interrelationships between the cardiac and sex endocrine systems, as has been shown in other recent studies.^6,7 However, the mechanism underlying the sex-specific differences in the linkage between various obesity-associated parameters and NT-proBNP levels remains speculative. Males and females have different anthropometric characteristics and fat distributions (namely, a difference in the distributions of visceral and subcutaneous fat), which may account for the data discrepancy between the WC (possible surrogate marker of visceral adipose tissue) and BMI (possible surrogate marker of general total fat distribution). Likewise, it has also been proposed that sex hormones, particularly testosterone, play a significant role in the regulation of NP production/secretion: testosterone reduces NT-proBNP levels in both sexes, and visceral fat has been recognized as increasing the circulating testosterone levels, particularly in females,^6,7 which may contribute to the consistent finding that the inverse relationship of obesity with NT-proBNP is stronger in females than in males.

In the present study,⁵ subjects with major obesity-related diseases, such as hypertension, coronary artery disease, and diabetes, were excluded, thus investigating the inverse association between BNP and obesity under relatively physiological conditions. Intriguingly, the present findings of a stronger inverse relationship in females than in males are consistent with those from another study⁶ that included subjects with obesity-related diseases. There are likely various confounding biases involved in the regulation of the production/secretion as well as the degradation of NPs (ANP and BNP), in addition to obesity-related parameters (Figure). Furthermore, the confounding biases differ between sexes (namely, sex-associated factors). To eliminate these confounding biases and more directly clarify the possible correlations between BNP and obesity-related parameters by sex, a path analysis based on a covariance structure analysis would be useful.^8,9 In fact, using a path model, we recently published several studies on the regulation and effects of BNP levels in association with various clinical parameters related to energy metabolism.^8,9

Figure.

Natriuretic peptides (NPs) closely coordinate interorgan metabolic crosstalk, largely with adipose tissues. BAT, brown adipose tissue; WAT, white adipose tissue.

In addition to the classical actions of hemodynamic regulation, growing evidence suggests that NPs also regulate energy balance and glucose homeostasis as well as thermogenesis through interorgan metabolic crosstalk with adipose tissue, in which NP receptors are expressed (Figure).^8–13 Recent studies have shown that NPs stimulate triglyceride lipolysis and promote the uncoupling of mitochondrial respiration through induction of adipose tissue browning, which results in improved insulin resistance as well as activation of the thermogenic program.^10–12,14 In fact, we recently reported that an increase in BNP level improves insulin resistance and promotes glucose utilization, particularly in patients with acute coronary syndrome, in which glucose is the preferred substrate for energy metabolism.^8,15 Another study showed that impaired cardiac function is associated with a decrease in body temperature, whereas plasma BNP elevation is associated with an increase in body temperature, suggesting the adaptive heat-retaining property of NPs when body temperature falls due to unfavorable hemodynamic conditions.⁹ These results are supported by an earlier in vitro finding that NPs increase the intracellular temperature in cultured brown adipocytes in a low-temperature-sensitive manner through the uncoupling protein 1 pathway.¹² Conversely, it has also been reported in both experimental^10,11 and clinical studies¹³ that cold exposure induces the elevation of NP levels. A series of these recent studies indicated that NP and obesity are closely linked through interorgan metabolic crosstalk (Figure).

The present study⁵ raises 2 important points from the pathophysiological perspective. First, care should be taken when interpreting the plasma BNP level as a biomarker of cardiac diseases, particularly in obese patients. The mechanism underlying the unexpectedly low BNP levels generally observed in obese subjects is much more complex than previously suspected, and other factors, including age and sex, should be taken into consideration. Second, given that insulin resistance is a cornerstone of the pathogenesis of heart failure¹⁵ and that NPs play a critical role in energy metabolism regulation in addition to their known role in hemodynamic regulation, subjects with low BNP levels may be predisposed to developing cardiovascular diseases. Understanding the characteristics of patients with low BNP levels (i.e., NP-insufficient individuals) is important, particularly when considering the administration of agents that increase circulatory NP levels.

References

• 1.   Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90: 195–203.
• 2.   Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure: Digest version. Circ J 2019; 83: 2084–2184.
• 3.   Bachmann KN, Gupta DK, Xu M, Brittain E, Farber-Eger E, Arora P, et al. Unexpectedly low natriuretic peptide levels in patients with heart failure. JACC Heart Fail 2021; 9: 192–200.
• 4.   Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004; 109: 594–600.
• 5.   Choi HI, Lee MY, Oh BK, Lee SJ, Kang JG, Lee SH, et al. Effects of age, sex and obesity on N-terminal pro B-type natriuretic peptide concentrations in the general population. Circ J 2021; 85: 647–654.
• 6.   Suthahar N, Meijers WC, Ho JE, Gansevoort RT, Voors AA, van der Meer P, et al. Sex-specific associations of obesity and N-terminal pro-B-type natriuretic peptide levels in the general population. Eur J Heart Fail 2018; 20: 1205–1214.
• 7.   Clerico A, Passino C, Emdin M. The paradox of low B-type natriuretic peptide levels in obesity revisited: Does sex matter? Eur J Heart Fail 2018; 20: 1215–1216.
• 8.   Uno G, Nagoshi T, Yoshii A, Inoue Y, Tanaka Y, Kimura H, et al. Collaborative activities of noradrenaline and natriuretic peptide for glucose utilization in patients with acute coronary syndrome. Sci Rep 2019; 9: 7822.
• 9.   Kang R, Nagoshi T, Kimura H, Tanaka TD, Yoshii A, Inoue Y, et al. Possible association between body temperature and B-type natriuretic peptide in patients with cardiovascular diseases. J Card Fail 2021; 27: 75–82.
• 10.   Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest 2012; 122: 1022–1036.
• 11.   Carper D, Coue M, Nascimento EBM, Barquissau V, Lagarde D, Pestourie C, et al. Atrial natriuretic peptide orchestrates a coordinated physiological response to fuel non-shivering thermogenesis. Cell Rep 2020; 32: 108075.
• 12.   Kimura H, Nagoshi T, Yoshii A, Kashiwagi Y, Tanaka Y, Ito K, et al. The thermogenic actions of natriuretic peptide in brown adipocytes: The direct measurement of the intracellular temperature using a fluorescent thermoprobe. Sci Rep 2017; 7: 12978.
• 13.   Kashiwagi Y, Komukai K, Kimura H, Okuyama T, Maehara T, Fukushima K, et al. Therapeutic hypothermia after cardiac arrest increases the plasma level of B-type natriuretic peptide. Sci Rep 2020; 10: 15545.
• 14.   Miyashita K, Itoh H, Tsujimoto H, Tamura N, Fukunaga Y, Sone M, et al. Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes 2009; 58: 2880–2892.
• 15.   Nagoshi T, Yoshimura M, Rosano GM, Lopaschuk GD, Mochizuki S. Optimization of cardiac metabolism in heart failure. Curr Pharm Des 2011; 17: 3846–3853.