Natriuretic peptides and fat metabolism Cedric Moro a,b

Purpose of review Cardiac natriuretic peptides have emerged as potent metabolic hormones during the past decade. We here discuss recent work highlighting the potential importance of these hormones in metabolic physiology and diseases. Recent findings Natriuretic peptides signal through a cyclic guanosine monophosphate pathway to convey their biological effects at the cell level. Similarly to cyclic adenosine monophosphate, activation of cyclic guanosine monophosphate signaling induces a browning of white fat and thermogenesis. Natriuretic peptides also enhance oxidative capacity and fat oxidation in skeletal muscle of mice and humans. The molecular mechanism involves an upregulation of mitochondrial fat oxidative capacity and respiration. This may be particularly relevant to relay the physiological adaptations of chronic exercise. Population-based studies indicate that circulating natriuretic peptides are lowered in obesity and predict type 2 diabetes. Recent work also directly link natriuretic peptides with type 2 diabetes through a gut–heart axis. Summary Natriuretic peptides exhibit a wide range of biological actions to control metabolic homeostasis. Natriuretic peptides deficiency in obesity may trigger metabolic dysfunction and lead to type 2 diabetes. Increasing circulating natriuretic peptides level and tissue signaling may help to fight against metabolic complications of obesity. Keywords cGMP signaling, fat oxidation, lipolysis, type 2 diabetes

INTRODUCTION Cardiac natriuretic peptides were initially discovered as critical regulators of blood volume and pressure [1]. A potent metabolic role of natriuretic peptides has also been unraveled about a decade ago through their lipolytic action in white fat as recently reviewed in detail [2]. Recent literature suggests that natriuretic peptides control metabolic homeostasis by targeting multiple organs such as brain, liver, brown fat, skeletal muscle, and pancreas. Circulating natriuretic peptides are markedly reduced in obese individuals and predict obesity-related morbidities such as hypertension and type 2 diabetes (T2D) [3,4 ]. Several polymorphisms of brain natriuretic peptide (BNP), natriuretic peptides receptor-A (NPRA) and natriuretic peptides clearance receptor (NPRC) are associated with abdominal obesity, arterial hypertension and T2D [5,6]. Studies in mice also demonstrated that an upregulation in the biological action of natriuretic peptides exert a protective effect against high fat feeding, whereas natriuretic peptides deficiency and/or defective signaling reproduce an obese and type 2 diabetic phenotype [7]. Combined, the accumulating &

evidences that natriuretic peptides play a key role in the regulation of energy balance led to the concept that obesity-induced natriuretic peptides deficiency could be a determinant for the development of T2D [8]. This review summarizes recently discovered metabolic actions of cardiac natriuretic peptides and pathophysiological relevance in obesity and T2D.

Lipolysis and fat mobilization A potent lipolytic action of natriuretic peptides in human-isolated adipocytes has been reported by our laboratory in early 2000 [9]. The mechanism a Inserm, UMR1048, Obesity Research Laboratory, Institute of Metabolic and Cardiovascular Diseases (I2MC) and bUMR1048, Paul Sabatier University, Toulouse, France

Corresponding to Cedric Moro, Ph.D, Inserm UMR 1048, Institut des Maladies Me´taboliques et Cardiovasculaires, CHU Rangueil, BP 84225, 1 Avenue Jean Poulhe`s, 31432 Toulouse Cedex 4, France. Tel: +33 561 32 5626; fax: +33 561 32 5623; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2013, 16:645–649 DOI:10.1097/MCO.0b013e32836510ed

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KEY POINTS  Natriuretic peptides are now recognized as key metabolic hormones.  Natriuretic peptides promote fat mobilization and oxidation.  Natriuretic peptides predict obesity-related morbidity and T2D.  The antidiabetic action of glucagon-like peptide-1 (GLP-1) agonists and exercise may be partly conveyed by natriuretic peptides.

involves activation of NPRA, cyclic guanosine monophosphate (cGMP) signalling, and translocation of one of the limiting enzyme of lipolysis, hormone-sensitive lipase [10,11]. Both intravenous and in-situ infusions of human atrial natriuretic peptide (hANP) through a microdialysis probe induce lipolysis and promote fat mobilization in healthy volunteers. We have also shown that intravenous infusion of hANP, at doses mimicking physiological changes as observed during moderate exercise, activates whole-body fat mobilization and oxidation either in the fasted or the fed state [12]. Finally, we could also demonstrate that acute physical exercise induces cardiac natriuretic peptides release and fat mobilization in lean healthy volunteers [13]. We accumulated evidence as well that the lipolytic effect of natriuretic peptides may be blunted in obese individuals potentially due to downregulation of NPRA signaling and/or upregulation of natriuretic peptides clearance and enzymatic degradation at the level of the fat cell. This reduced fat cell responsiveness to natriuretic peptides can be partly recovered by aerobic exercise training both in vitro and in vivo in obese women with polycystic ovary syndrome [14].

expression through a p38 mitogen-activated protein kinase/activating transcription factor 2 pathway. UCP1 dissipates energy as heat thus increasing metabolic inefficiency and energy expenditure. This finding may be physiologically relevant considering the presence of functional brown fat in humans [16]. Mice and human studies also suggest that natriuretic peptides favor whole-body fat oxidation [7,12]. For instance, mice overexpressing BNP are protected from high fat diet-induced obesity and insulin resistance compared to control mice [7]. This adaptive phenotype appears largely mediated by an upregulation of whole-body energy expenditure and fat oxidation. Importantly, we have recently uncovered a functional natriuretic peptides signaling in human skeletal muscle [17 ]. We could hence show that 3-day treatment of human primary myotubes with ANP and BNP increases mitochondrial fat oxidative capacity. At the molecular level, this effect requires the transcriptional activation of PGC-1a and subsequent induction of oxidative phosphorylation (OXPHOS) genes and mitochondrial respiration. Of interest, we observed that natriuretic peptides treatment also induced UCP-3 and the ATP/ADP translocase ANT1 which increases basal proton leak and energy uncoupling. This finding may be physiologically relevant as we observed a concomitant upregulation of NPRA, PGC-1a, and OXPHOS genes in the skeletal muscle of obese individuals in response to an 8-week aerobic exercise training program [17 ]. Altogether, these data suggest that some of the physiological and metabolic adaptations of skeletal muscle in response to chronic exercise could be mediated by natriuretic peptides. &


A NOVEL GUT–HEART AXIS IN TYPE 2 DIABETES Recent findings unravel a novel mechanism of control of cardiac ANP secretion by the gut hormone GLP-1 thus revealing an unsuspected gut–heart crosstalk that regulates blood pressure [18 ]. GLP-1 agonists such as liraglutide and exenatide are widely used in the treatment of T2D. These drugs were also incidentally shown to lower blood pressure in T2D individuals [19]. In a recent study, Kim et al. [18 ] have elegantly shown that the GLP-1 agonist liraglutide induces ANP secretion from the cardiac atrium. They also show that the blood pressure lowering effect of liraglutide is abrogated in Nppa (ANP) knockout mice. In summary, this study suggests that ANP mediates the blood pressure-lowering effect of GLP-1 agonists. These findings that have an important clinical implication as T2D and hypertension are frequent comorbidities of obesity. GLP-1 agonists lower blood glucose through &&

ENERGY EXPENDITURE AND FAT OXIDATION Numerous studies demonstrated a role of natriuretic peptides in the regulation of energy balance and energy expenditure. Recent work in mouse models suggests that natriuretic peptides enhance wholebody energy expenditure [7]. This was associated with an upregulation of the uncoupling protein-1 (UCP1) in brown fat. Importantly, it was recently reported that natriuretic peptides activate mitochondrial biogenesis and uncoupling in white fat, thus inducing a so-called ‘browning’ process [15 ]. Natriuretic peptides induce peroxisome proliferator-activated receptor-gamma coactivator 1-a (PGC-1a) and UCP1 &



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Natriuretic peptides and fat metabolism Moro

Exercise GLP-1 agonists

Apart from their well known central role in the regulation of thirst and vasopressin secretion, natriuretic peptides have recently been shown to acutely inhibit the feeling of hunger and suppress food intake in healthy volunteers [23 ]. This effect involves a peripheral suppression of fasting-induced secretion of total and acylated ghrelin. Ghrelin is an orexigenic hormone secreted by the stomach, which promotes food consumption. Together, these data also highlight a heart–gut–brain axis at the basis of the anorectic effect of natriuretic peptides. Natriuretic peptides also induce expression and secretion of the antidiabetic hormone adiponectin in a cGMP-dependent manner in cultured human adipocytes [24]. Importantly, we could show that hANP infusion increased total and high-molecular weight adiponectin levels in healthy individuals [25]. It was also recently suggested that acute BNP infusion (4 h) in human volunteers reduces blood glucose levels in response to an oral glucose challenge [26]. The authors reported no effect on insulin secretion and peripheral insulin sensitivity, and attributed the blood glucose-lowering effect of BNP to an increase in blood glucose distribution volume. Finally, it was reported that genetic inactivation of the cGMP-dependent kinase-I, which mediates the cellular effect of natriuretic peptides, promotes fasting hyperglycemia and reduces insulin tolerance in mice [27]. These metabolic disturbances could reflect an inability of insulin to suppress hepatic glucose production in this model, suggesting that natriuretic peptides signaling may control insulin action and neoglucogenesis in liver. In summary, natriuretic peptides modulate several signals and processes involved in the control of glucose homeostasis, which highlights their potential as antidiabetic hormones. Acute and chronic studies with natriuretic peptides in mice and humans will be needed to confirm the antidiabetic role of natriuretic peptides. &

Cardiac ANP secretion ↑ Adiponectin ↑ Thermogenesis ↑ Lipolysis ↑ Mitochondrial biogenesis ↑ Fat oxidation

↓ Food intake ↓ Gastric emptying

↑ Insulin secretion ↑ β-cell mass

↓ Hepatic glucose production ↓ Postprandial blood glucose

FIGURE 1. Hypothetical model by which atrial natriuretic peptide (ANP) could convey the antidiabetic action of physical exercise and glucagon-like peptide-1 agonists (GLP-1). ANP promotes lipolysis, thermogenesis and adiponectin secretion in white fat, mitochondrial biogenesis and fat oxidation in skeletal muscle, insulin secretion and b-cell mass expansion in pancreas, reduced hepatic glucose production and postprandial blood glucose, as well as inhibition of food intake and gastric emptying. Combined these effects concur to reduce peripheral lipotoxicity and improve blood glucose control.

combined inhibition of gastric emptying, stimulation of insulin secretion, and inhibition of food intake [20]. Natriuretic peptides have also been shown to decrease gastric emptying [21], enhance insulin secretion [22], and inhibit food intake [23 ]. Considering that the blood glucose-lowering effect of GLP-1 agonists also largely overlap with those of ANP, ANP may convey the antidiabetic action of GLP-1 agonists (Fig. 1). &

ANTI-DIABETIC EFFECT OF NATRIURETIC PEPTIDES There are likely multiple mechanisms by which natriuretic peptides could exert an antidiabetic action. It was first shown by Addisu et al. [21] that BNP infusion significantly reduces gastric emptying and absorption in mice. These effects are largely abolished in NPRA knockout mice compared to their wild-type littermates. As previously discussed, reduced gastric emptying has been associated with lower postprandial glucose excursion and better glucose control [20]. Others have shown that ANP enhances insulin secretion in mice islets in an NPRA-dependent manner [22]. ANP also increases b-cell insulin content in freshly isolated islets, whereas both b-cell insulin content and b-cell mass are significantly reduced in NPRA knockout mice. Thus, NPRA knockout mice also exhibit fasting hyperglycemia.

THERAPEUTIC POTENTIAL IN METABOLIC DISEASES A drop in plasma natriuretic peptides level and/or tissue response is observed in various pathological conditions such as obesity, the metabolic syndrome, and heart failure. Downregulation of natriuretic peptides level and/or NPRA signaling with high fat feeding and obesity could contribute to ectopic lipid deposition and insulin resistance by reducing skeletal muscle mitochondrial biogenesis and fat oxidation. More studies in animal models as well as in humans are required to establish the causal link

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between natriuretic peptides deficiency and the development of obesity and insulin resistance. Both GLP-1 agonists [20] and regular physical exercise [28] exhibit potent blood glucose-lowering effects in individuals with T2D. Considering that natriuretic peptides may convey the antidiabetic action of exercise and GLP-1 agonists (Fig. 1), the development of natriuretic peptide analogs and NPRA agonists may be useful to alleviate the metabolic complications of obesity and perhaps to treat T2D. In the same line, strategies based on chronic inhibition of neutral endopeptidase, which degrades natriuretic peptides, could raise circulating natriuretic peptides level in obesity and preserve the beneficial actions of natriuretic peptides signaling in metabolic tissues [29]. The development of natriuretic peptides analogs potentially resisting to NPRC-mediated clearance and/or NPRC-selective antagonists may also be useful.

CONCLUSION In summary, cardiac natriuretic peptides are increasingly recognized as key regulators of metabolic homeostasis. During the last 3 years, several studies demonstrated an effect of natriuretic peptides in metabolic organs such as skeletal muscle, brown fat, and pancreas. It is also suggested that natriuretic peptides secretion may be controlled by gut hormones such as GLP-1 and physical exercise. These studies clearly illustrate the fascinating interorgan crosstalk involved in metabolic regulation. More importantly, multiple population-based studies have evoked a strong association between low level of circulating natriuretic peptides and T2D, or inversely, a protective role of high circulating natriuretic peptides level against metabolic complications of obesity, particularly T2D and hypertension. Thus raising circulating natriuretic peptides level may prevent the development of metabolic disturbances in obese individuals. Further research is now needed to first establish a causal relationship between natriuretic peptides deficiency in obesity and T2D, and second to investigate the therapeutic potential of natriuretic peptides in preclinical and clinical studies. Acknowledgements C.M. is currently receiving grant support from the National Research Agency ANR-12-JSV1-0010-01, European Federation for the Study of Diabetes/Novo Nordisk and Socie´te´ Francophone du Diabe`te. Conflicts of interest There are no conflicts of interest.


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Natriuretic peptides and fat metabolism Moro 22. Ropero AB, Soriano S, Tuduri E, et al. The atrial natriuretic peptide and guanylyl cyclase-A system modulates pancreatic beta-cell function. Endocrinology 2010; 151:3665–3674. 23. Vila G, Grimm G, Resl M, et al. B-Type natriuretic peptide modulates ghrelin, & hunger, and satiety in healthy men. Diabetes 2012; 61:2592–2596. This is a nice clinical study demonstrating for the first time an appetite-suppressant effect of BNP in humans. 24. Tsukamoto O, Fujita M, Kato M, et al. Natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure. J Am Coll Cardiol 2009; 53:2070–2077. 25. Birkenfeld AL, Boschmann M, Engeli S, et al. Atrial natriuretic peptide and adiponectin interactions in man. PLoS One 2012; 7:e43238.

26. Heinisch BB, Vila G, Resl M, et al. B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled cross-over study in healthy men. Diabetologia 2012; 55:1400–1405. 27. Lutz SZ, Hennige AM, Feil S, et al. Genetic ablation of cGMP-dependent protein kinase type I causes liver inflammation and fasting hyperglycemia. Diabetes 2011; 60:1566–1576. 28. Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA 2010; 304:2253–2262. 29. Birkenfeld AL, Adams F, Schroeder C, et al. Metabolic actions could confound advantageous effects of combined angiotensin II receptor and neprilysin inhibition. Hypertension 2011; 57:e4–5.

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Natriuretic peptides and fat metabolism.

Cardiac natriuretic peptides have emerged as potent metabolic hormones during the past decade. We here discuss recent work highlighting the potential ...
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