Open access peer-reviewed chapter
Abstract
Cardiac natriuretic peptides (NPs) play critical roles in body systems, besides essentially maintaining cardiovascular homeostasis. White adipose tissue exerts functions such as energy storage, hormone secretion, thermal insulation, regulation of insulin sensitization, and prevention of traumatic injuries to vital organs. Brown adipose tissue is a thermogenic tissue that protects the body from cold environments by dissipation of chemical energy derived from fuel substrates as heat. NPs have potent regulatory effects on adipose tissues having high expression of NP receptors. Evidence suggests that the NP system participates in the regulation of adipose tissue metabolism during obesity, insulin resistance, and type 2 diabetes. Reduced NP synthesis and changed clearance receptor expression may adversely affect NPs’ target organ metabolism during obesity, insulin resistance, and type 2 diabetes. Defective NP system might lead to adipose tissue dysfunction during obesity, type 2 diabetes, insulin resistance, and cardiovascular disease. Improved NP levels have been associated with positive metabolic outcomes. The positive association between increased NP levels and lower incidence of insulin resistance, obesity, and type 2 diabetes holds promise for future applications of NPs system in clinical settings. This chapter provides an overview of the impact of the NP system on adipose tissue metabolism in cardiometabolic diseases.
Keywords
- natriuretic peptide system
- adipose tissue
- obesity
- insulin resistance
- type 2 diabetes
- thermogenesis
1. Introduction
Natriuretic peptides are hormones that exert cardiovascular and renal effects. Their congenital absence or genetic ablation leads to serious consequences, especially in the cardiovascular system. Thus, cardiovascular health could be improved through genetic and pharmacological manipulation of these natriuretic peptides [1]. Although natriuretic peptides are key players in the regulation of cardiovascular and renal systems, accumulating evidence shows that they could play pivotal roles in counteracting metabolic diseases and conditions such as obesity, type 2 diabetes, and insulin resistance that adversely affect human population across the world. One of the most attractive therapeutic approaches to combat obesity and type 2 diabetes is the activation of brown adipose tissue that has been rediscovered in adult humans in the late 2000s. Stimuli that activate this tissue have been explored in many animal models and in humans [2]. Since the discovery of their potent lipolytic effects on human adipose tissue in the early 2000s [3, 4], many studies have been focused on the effect of natriuretic peptides on glucose and lipid metabolism pathways that are altered in obesity and type 2 diabetes [5]. In addition, promising results came from the studies on activation of brown adipose tissue. These studies reveal that natriuretic peptides might serve as a pathophysiological link between brown adipose tissue activation and metabolic diseases. In fact, obesity, type 2 diabetes, and insulin resistance may commonly manifest in the same patient, all of which are associated with heart failure and development of multiple organ failure due to impaired oxidative metabolism [6]. Therefore, better understanding of the metabolic effects of natriuretic peptides on lipid metabolism during obesity and type 2 diabetes would pave the way for treatment and prevention of those maladies that are blamed for both deaths and impaired quality of life. This chapter provides a general overview of natriuretic peptide system and adipose tissue and discusses genetic, physiological, and pharmacological evidence of natriuretic peptide system linking adipose tissue to obesity and type 2 diabetes.
2. The natriuretic peptide system
2.1 Natriuretic peptides
Natriuretic peptides (NPs) are peptide hormones responsible for maintaining cardiovascular homeostasis. Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) constitute the main mammalian natriuretic peptide (NP) system [7, 8]. Emerging evidence shows that these peptides play critical roles in different systems of the body [9]. ANP, the first member of the NP system, is mostly produced and stored in the atrial myocytes, and it is released in response to various stimuli such as heart wall stretch and atrial distension [10]. The discovery of ANP led to the assumption that the heart was formerly an endocrine organ. ANP is first generated as a 152-amino-acid precursor, which is subsequently cleaved into its biologically active form by corin, a transmembrane serine protease that works as a pro-atrial natriuretic peptide-converting enzyme [11]. Initially identified in porcine brain, BNP is the second member of the NP system and is also known as a ventricular natriuretic peptide. It is produced as a 134-amino-acid precursor before being processed into its biologically active form [12, 13]. ProBNP-108 and BNP-32 are the two most physiologically active variants of BNP. BNP-32 is mostly expressed in the atria, but proBNP-108 is primarily expressed in the ventricular myocardium. ProBNP-108 is cleaved by furin, a proprotein convertase, to produce BNP-32 and NT (N-Terminal)-BNP-76 [14]. ANP levels rise in response to increased atrial pressures, whereas BNP levels rise in response to ventricular overload [15]. During congestive heart failure and cardiac hypertrophy, both ANP and BNP are substantially expressed by the atrium and ventricle, with BNP expression levels being reported to be excessively higher than ANP levels [16, 17]. Patients affected by hypertension and obesity, on the other hand, were found to have low plasma ANP levels [18] due to reduced natriuretic peptide release and increased natriuretic peptide clearance (depending on natriuretic peptide receptor C overexpression) [19, 20] and/or due to the activation of the renin-angiotensin-aldosterone system [21]. CNP, the third member of the NP system, is derived from a 126-amino-acid precursor, which is subsequently cleaved by furin into two endogenous forms, CNP-53 and CNP-22 [22, 23]. CNP has been found in a variety of organs, including the heart, kidney, lung, endothelial cells, bone, and the central nervous system, despite its low circulating concentration [24, 25]. CNP is primarily involved in vascular homeostasis and has anti-hypertrophic and anti-fibrotic actions on cardiac myocytes and fibroblasts, respectively, due to its endothelial origin [26, 27]. Later on, two new members of the NP system have been discovered. Of those, D-type natriuretic peptide (DNP, also known as Dendroaspis natriuretic peptide) is a physiologically active peptide molecule of 38 amino acids that was first discovered in the venom of the green mamba snake (
2.2 Natriuretic peptide receptors
The NP signals are conveyed by its transmembrane receptors. A transmembrane natriuretic peptide receptor A (NPRA) is encoded by the
3. Adipose tissue
3.1 Cell type diversity, morphology, and function
Adipose tissue (AT) is a specialized connective tissue that carries out a diverse set of tasks such as energy storage, hormone production, thermal insulation, and thermogenesis [46]. AT, corresponding to roughly 5–50% of human body weight [47], consists of two basic components: cells and extracellular matrix [48]. AT has abundantly adipocytes (also called adipose cells or fat cells), among which other cell types are mesenchymal stem cells, preadipocytes, macrophages, fibroblasts, endothelial cells, and smooth muscle cells [46]. AT is a key player in energy storage and consumption. The excess energy is efficiently stored in the form of neutral triglycerides (TGs) in the AT via lipogenesis, an anabolic pathway encompassing fatty acid synthesis and triglyceride synthesis [49]. On the other hand, when energy consumption is greater than its production, the stored energy is rapidly mobilized to bring into use [50]. This highlights the fact that AT is a dynamically remodelable tissue responsible for storage and reallocation of lipids in response to cellular energy excess or depletion [51]. Furthermore, AT fulfills other physiological tasks and is now regarded as a significant endocrine organ.
AT has been divided into two major subclasses: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is responsible for the production of some pro-inflammatory cytokines and chemokines, including interleukin 6 (IL-6), IL-18 and tumor necrosis factor-alpha (TNF-α), that modulate inflammation [48, 52]. In addition, adipocytes in WAT (white adipocytes) secrete many adipocyte-derived paracrine and endocrine molecules (collectively called “adipokines”), including leptin and adiponectin that regulate energy metabolism [47, 48]. Leptin is regarded as a master regulator of energy balance. It controls glucose metabolism and energy expenditure and suppresses food intake through binding to the long form of the leptin receptor (LEPR) that is highly expressed in brain areas responsible for the control of feeding and energy expenditure [53]. However, the leptin’s ability to lower food consumption is dependent on the melanocortin-3 receptor (MC3R) in the brain, which regulates energy homeostasis [54]. Adiponectin, a well-known homeostatic factor, yields insulin sensitivity-promoting effects by inhibiting hepatic glucose production and stimulating fatty acid oxidation in skeletal muscles [55]. By turning our focus to WAT and BAT below, we give further information about these different types of adipose tissue.
3.2 White adipose tissue
In healthy individuals, WAT makes up at least 10% of the total body weight. Energy storage, hormone secretion, thermal insulation, regulation of insulin sensitivity, and prevention of traumatic injuries to vital organs are among its basic tasks [49]. Adipocytes in the WAT (white adipocytes) have low mitochondrial abundance and store TGs as large intracellular lipid droplets [56]. WAT is mainly subdivided into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) [57]. In humans, SAT is mostly found in the gluteal and femoral regions. It may be divided into two types: deep SAT and superficial SAT, which differ morphologically and metabolically [58]. Deep SAT has been linked to the pathophysiology of obesity-related metabolic complications, whereas superficial SAT is more associated with protective roles against metabolic derangements [59, 60, 61]. Located around the internal organs, VAT exists in pericardial, gonadal, omental, mesenteric, and retroperitoneal storages, and protects them from mechanical damage and friction [62]. SAT and VAT show marked differences in adipocyte phenotype, gene expression signature, and lipolytic and endocrine activities [63].
3.3 Brown adipose tissue
BAT, as a thermogenic tissue, protects the body from cold environments by dissipating chemical energy derived from fuel substrates as heat [64]. Brown adipocytes contain many small-sized lipid droplets and copious amounts of mitochondria. They express uncoupling protein 1 (UCP1), also called thermogenin, that uncouples the electron transfer chain from the ATP synthesis to generate heat [65]. Two types of brown adipocytes have been identified. The traditional brown adipocytes are myogenic factor 5-positive (
It has long been considered that BAT merely exists in some mammalian species, including human newborns, hibernating animals, and rodents [68, 69, 70]. However, recent studies have shown that BAT is metabolically activated in adult humans upon cold exposure [71, 72, 73]. Mounting lines of evidence have uncovered the possible mechanisms of action of BAT in counteracting obesity and its coexisting diseases in humans [74]. Some studies have demonstrated that exposure to different cold regimes (e.g., 15–16°C for 6 hours/day for 10 days or 17°C for 2 hours/day for 6 weeks) may stimulate human BAT, enhance non-shivering thermogenesis and reduce body fat mass [75, 76, 77, 78, 79, 80, 81]. However, whether these effects might continue in the long-term period (months to years) remain obscure. On the other hand, several studies have revealed that subcutaneously placed embryonic BAT could reverse type 1 diabetes-related parameters in streptozotocin-treated mice, thus improving glucose homeostasis and weight gain and reversing type 1 diabetes independently from insulin [82, 83, 84, 85]. The extent to which BAT thermogenesis would influence obesity and diabetes relies on the quantity of actively recruited BAT [62, 86]. Another study reported that some central neural modulators would decrease fat mass and body weight by activating BAT thermogenesis and triggering the switch from white adipocytes to brown adipocytes in order to burn off excess energy [64].
3.4 Adipose tissue as a cardiovascular system modulator
Considering their anatomical localization, cardiac adipose tissue stores can be described as pericardial adipose tissue (PAT) and perivascular adipose tissue (PVAT) [86, 87]. The pericardial adipose tissue consists of paracardial adipose tissue and epicardial adipose tissue (EAT). EAT is a metabolically active tissue, which provides energy supply to myocardium in case of augmented energy demand [88]. Given all the adipose tissue reservoirs, EAT utilizes the lipogenesis and lipolysis pathways at the highest rate. EAT exerts modulatory effects on the vascular tone and coronary artery functions through secretion of molecules such as adipokines and nitric oxide (NO) [86]. EAT has been reported to possess brown/beige adipocyte-specific phenotypes in hibernators and human adults due to its thermogenic capacity [70, 89].
PVAT, which is located around veins, arteries, and small vessels [90], plays an active role in fine-tuning endothelial function, vascular tone, and vascular remodeling, and represents a dual endocrine-paracrine organ that produces various immunomodulatory and vasoactive molecules, in addition to cytokines and adipokines like leptin and adiponectin [91, 92]. PVAT makes up just 0.3% of total adipose tissue mass and can contain various numbers of brown, white, and beige adipocytes based on its location in the body and despite differences in the predominant cell type. Moreover, it has been shown that periaortic adipose tissue at the thoracic region in human adults has beige-like characteristics, whilst coronary PVAT exhibits WAT-like characteristics [90].
3.5 Dysregulation of adipose tissue in obesity and insulin resistance
Obesity is closely related to impaired insulin sensitivity in the liver, skeletal muscles, and white adipose tissue. Obesity-related insulin resistance is one of the most prevalent causes of type 2 diabetes mellitus and is directly linked to diverse cardiometabolic abnormalities including coronary heart disease, atherosclerosis, and hypertension [46, 49, 93]. In response to chronic excessive calorie intake, expansion of adipose tissue through adipocyte hyperplasia (cell number increase) and/or hypertrophy (cell size increase) is a major determinant of metabolic dysfunction and cardiovascular diseases [49, 94]. Hyperplasia might be regarded as a healthy mechanism of AT expansion. However, hypertrophy could lead to adipocyte dysfunction as adipocytes outreach their expansion limits as a result of development of hypoxic conditions, oxidative stress, and pro-inflammatory cytokine release [95]. Thus, the body region where excessive adiposity occurs is one of the most crucial factors identifying the obesity-related cardiometabolic complications [5].
It has been considered that enlargement of VAT has established a strong link between adverse metabolic alterations and increased cardiovascular risk, while expansion of SAT makes a minor contribution to these adverse outcomes [49]. The “portal hypothesis” may account for one of the possible reasons for this difference. The portal hypothesis propounds that visceral fat tissue in obese patients increasingly releases free fatty acids (FFAs) and cytokines into the portal vein, resulting in their accumulation in the liver. Then, hepatic fat accumulation promotes the development of hepatic insulin resistance and type 2 diabetes [96, 97, 98]. This condition that increases the amount of FFAs transported to the liver via the portal circulation is also linked to atherogenic lipid profile and hepatic steatosis [98]. Another possible reason for this difference is that VAT is more susceptible to the effects of pro-inflammatory molecules than other adipose tissues, since increased adiposity creates a pro-inflammatory milieu. It has been reported that VAT has higher expression and secretion of several pro-inflammatory mediators including TNF-α and IL-6, as compared to SAT [99, 100]. Augmented expression of pro-inflammatory cytokines causes phosphorylation of serine/threonine residues of insulin receptor substrate proteins, leading to dissociation of insulin receptor substrate proteins from effector proteins in the insulin signaling cascade pathway and resulting in the development of insulin resistance [101]. In addition, pro-inflammatory cytokines cause local and systemic inflammation by triggering recruitment of macrophages and T-lymphocytes to the relevant sites [102]. Resident macrophages play a crucial role in the promotion and perpetuation of adipocyte dysregulation and insulin resistance. Furthermore, experimental evidence shows that necrotic cell death in adipose tissue over the course of obesity might induce the recruitment of pro-inflammatory M1 macrophages, which produce multiple pro-inflammatory cytokines that exacerbate chronic inflammation and insulin resistance [103]. Additionally, it has been shown that anti-inflammatory adiponectin is expressed at a lower level in VAT than in SAT and its circulating concentrations are reduced in obese people with augmented visceral fat accumulation [104].
SAT has a restricted potential to expand owing to its poor adipogenesis capability. This limited capacity results in adipocyte hypertrophy, promoting the formation of fat storages in non-adipose tissues such as in the heart, liver, and skeletal muscles [105]. This deleterious mechanism of adipogenesis is also regarded as “lipotoxicity” and is linked to the development of systemic insulin resistance and enhanced risk of type 2 diabetes. It has been put forward that intrahepatic content of TGs represents a more acceptable marker of insulin resistance than VAT [106]. On the other hand, PVAT exhibits hyperplastic and hypertrophic characteristics in obesity [107]. It has been propounded that “obesity triad” encompassing oxidative stress, inflammation, and hypoxia might be the major mechanism responsible for PVAT dysfunction in obesity. Adipocyte dysfunction during obesity arises from the “whitening” of PVAT, which creates a hypoxic and pro-inflammatory milieu affecting the vasculature [86]. Moreover, reduced adiponectin production by PVAT in obesity promotes endothelial dysfunction [108]. In this respect, studies using genetically-modified and diet-induced animal models of obesity revealed that anticontractile properties of PVAT are totally lost [49].
Adequate insulin signaling in AT is a crucial factor in the maintenance of systemic blood glucose homeostasis, as evidenced by a number of mice models, even though skeletal muscle is responsible for the bulk of insulin-stimulated glucose uptake [109]. Adipocyte-specific glucose transporter type 4 (GLUT4) knockout in mice affects skeletal muscle and liver insulin signaling, which results in glucose intolerance, insulin resistance, and hyperinsulinemia [110]. Adipocyte-specific insulin receptor-knockout mice exhibited basal glucose uptake in a similar fashion, but insulin-stimulated glucose uptake by adipocytes was considerably lower than in controls. These mice had improved systemic glucose tolerance [111]. It is worthy to note that this difference might arise from the activation of alternative signaling pathways to compensate for the innate lack of adipocyte insulin signaling pathway. A recent study on adipocyte-specific insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) knockout (one of these receptors: IRKO, IGF-1RKO or both of them: double KO, DKO) mice found that while all KO groups had equivalent or lower fat mass than controls, IRKO and DKO mice showed systemic insulin resistance and hepatic steatosis in comparison with the controls and IGF-1RKO groups. The combined ablation of these receptors led to serious glucose homeostasis disturbances [112]. Together, these findings indicate that when there are deficiencies in insulin receptor signaling in the innate AT, a compensatory mechanism may be triggered possibly through insulin-independent signaling pathways in other insulin-responsive tissues in order to counteract systemic glucose intolerance. However, this evidence suggests that adequate insulin signaling inside the AT is critical for overall health.
Impacts of AT insulin sensitivity on systemic health may be mediated by the regulation of adipose tissue lipolysis that breaks down triglycerides into FFAs and glycerol. Situations like fasting, exercise, and stress induce lipolysis through adrenergic activation, thus mobilizing energy storage. In case of fed state, insulin inhibits lipolysis in the direction of lipid storage. As a result, defective insulin signaling in AT could lead to an increase in basal lipolysis rate [113]. Since the inflammatory cytokine TNF may stimulate lipolysis independently of insulin signaling, chronic low-grade inflammation caused by obesity may also trigger excessive FFA release by adipocytes and promote lipotoxicity and lipid-induced insulin resistance [114, 115]. Obesity and insulin resistance have extensively been linked to elevated rates of basal lipolysis. The ensuing rise in circulating FFA levels increases metabolic dysfunction by promoting lipid accumulation in the liver and muscle [113]. Disturbances in lipid storage, such as those caused by obesity or lipodystrophy, can impair adipocyte function and lead to insulin resistance. Insulin resistance in the adipose tissue disrupts normal adipocyte signaling and metabolism, leading to an increase in lipolysis. Ectopic lipid accumulation and insulin resistance in other tissues, such as skeletal muscle and liver, can result from chronically increased circulating lipids. Insulin resistance in the liver is deleterious because insulin signaling controls hepatic glucose synthesis. All of these events have the potential to produce a major effect on metabolic health, culminating in a vicious cycle that perpetuates systemic metabolic illness [48, 113]. Type 2 diabetes and hepatic lipid accumulation are common in situations with high basal lipolysis, such as Cushing’s syndrome [116, 117], as well as in cases of lipoatrophy when circulating lipids are excessive [118]. Although the bulk of whole-body glucose uptake could not have been directly taken up by AT, it is obvious that impairment in glucose uptake and lipid accumulation in AT have an impact on other insulin-responsive organs, modulating the overall status of systemic health [48]. Much more remains to be found out how altered adipose tissue metabolism is going to contribute to metabolic conditions such as obesity, insulin resistance, and type 2 diabetes.
4. Natriuretic peptides as key players in adipose tissue dysfunction, obesity, and insulin resistance
4.1 Physiological actions of natriuretic peptides on adipose tissue
Currently, NPs have been well established to be powerful metabolic hormones that are responsible for the fulfillment of key functions in adipose tissue having high expression of NP receptors [119]. Demonstration of ANP mRNA expression by human adipose tissue is a strong indication that ANP exerts autocrine/paracrine effects on this tissue [120]. In 2000, it was evidenced that, in the potency order of ANP > BNP> > CNP, NPs exert potent lipolytic effects on human adipose tissue in both
NPs play additional roles in modulating the release of adipokines and cytokines from adipose tissue. When ANP is added to isolated human adipocytes
The relevant clinical implications of administering NPs as metabolic hormones have been excellently reviewed [22]. Intravenous infusion of ANP in lean and obese human subjects led to a remarkable rise in plasma FFA and glycerol concentrations, indicating lipid mobilization. Microdialysis data in subcutaneous abdominal adipose tissue also revealed that both groups had an increase in the extracellular glycerol concentration during ANP administration [130, 131]. However, this increase was not reversed with the use of propranolol, a β-adrenergic receptor antagonist used to blunt β-adrenergic effect of catecholamines on adipose tissue [130]. This finding supports the fact that ANP is a powerful lipolytic hormone that acts independently of the activation of the sympathetic nervous system [130, 131]. It is generally known that, during exercise, the heart releases ANP and BNP into the bloodstream [132]. The increment in ANP and BNP levels in the bloodstream during exercise is a robust indicator of contribution to enhanced energy supply [123]. Similarly, plasma adiponectin concentrations increased in both healthy volunteers [133] and patients with heart failure [126, 134] after intravenous injection of human ANP.
4.2 Dysregulation of natriuretic peptide system in obesity and insulin resistance
Considering the link between NPs and their receptors, cardiometabolic diseases, insulin resistance, type 2 diabetes, and obesity, substantial progress has been made in the knowledge of metabolic effects of NPs during recent decades (Figure 1). For example, NPs are implicated in many processes including improvement in insulin resistance and induction of lipolysis. Multiple lines of evidence suggest that NPs act as key players in the regulation of metabolic pathways and in the pathophysiology of cardiometabolic diseases, obesity, and type 2 diabetes [22]. The lower availability of NPs could be attributable to their decreased production and release as well as to the increased function of their clearance receptor. Animal experiments revealed that diabetic obese db/db mice and obese Zucker fatty rats have lower cardiac ANP and BNP expression at the mRNA level [135, 136]. However, feeding mice with a high-fat diet had no effect on their plasma BNP levels [137]. NPRC mRNA level rose in the heart of db/db mice [125], but NPRA and NPRC expression decreased and increased, respectively, in white and brown adipose tissue of db/db mice [137]. Moreover, obese mice fed a high-fat diet had increased levels of endopeptidase and neprilysin (which are responsible for NP breakdown) in plasma and in mesenteric fat, indicating a higher NP clearance [138].
Figure 1.
Involvement of natriuretic peptides and their receptors in the pathophysiology of obesity, type 2 diabetes, and insulin resistance, with possible implications for cardiometabolic health. Natriuretic peptide signaling evoked through the NPRA and NPRB starts with cGMP signaling, which enhances lipolysis in white adipose tissue, thermogenesis in brown adipose tissue, and oxidative capacity in skeletal muscle under physiological circumstances. These physiological actions protect against obesity, type 2 diabetes, and insulin resistance, thus providing significant cardiometabolic health benefits. In pathological settings, changes in the NPRA/NPRC and NPRB/NPRC ratios in favor of NPRC result in reduced natriuretic peptide production and release, and in increased clearance receptor function. Obesity, type 2 diabetes, and related comorbidities compromise cardiometabolic health and are all partly consequences of the aforementioned alterations in the natriuretic peptide system. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNP, C-type natriuretic peptide; NPRA, natriuretic peptide receptor A; NPRB, natriuretic peptide receptor B; NPRC, natriuretic peptide receptor C; PGC1α, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; PPARδ, peroxisome proliferator-activated receptor-delta; UCP1, uncoupling protein 1.
Insulin resistance, type 2 diabetes, and obesity have all been reported to be inversely associated with human plasma NPs [6]. Obese people showed lower plasma BNP levels than non-obese people, indicating a negative relationship between body mass index (BMI) and BNP levels [139]. A cohort study revealed that plasma NT-proANP and NT-proBNP concentrations were inversely related to obesity and to all other components of the metabolic syndrome, with the exception of hypertension [140]. VAT and hepatic fat mass in patients with heart failure were found to be adversely associated with BNP and NT-proBNP plasma levels. In addition, a link between reduced circulating NP levels and altered AT distribution was also found. Elevated levels of NPs, on the other hand, have been reported to be a stronger indicator of obesity profile [141]. The NPRA to NPRC ratio decreased in the adipose tissue of obese patients with type 2 diabetes, indicating increased NP clearance. Treatment with pioglitazone increased the NPRA to NPRC ratio as well as the insulin sensitivity, indicating that a lower NPRA to NPRC ratio is linked to glucose intolerance and insulin resistance [142]. Obese patients also exhibited high neprilysin expression, indicating that NPs break down rapidly and their effects lessen [138]. Overall, these findings suggest that reduced circulating NP levels are closely associated with the progression of numerous metabolic disorders, including type 2 diabetes and obesity. Currently, the capacity of neprilysin inhibitors, such as sacubitril, to raise NP levels is being considered as one of the major strategies for improving the metabolic profile in type 2 diabetes and obesity through remodeling adipose tissue [143]. Nevertheless, further research and clinical trials are required to obtain the optimal metabolic benefits from those drugs and to maximize their effects.
The relevance of NP receptors and signaling cascade components in metabolic function research has been demonstrated using genetically engineered mouse models. Body weight and fat mass were reduced in NPRC knockout mice (NPRC−/−). Furthermore, adding ANP to adipocyte culture from NPRC knockout mice boosted UCP1 expression, resulting in lipolysis [127]. In comparison to wild-type counterparts, adipocyte-specific NPRC knockout mice (NprcAKO) showed higher thermogenesis, improved insulin sensitivity, and increased glucose uptake into BAT. This recent finding also indicated that NPRC knockout mice were protected from developing insulin resistance and obesity as a result of a high-fat diet. Furthermore, in this diet-induced model of insulin resistance and obesity, adipocyte-specific NPRC deletion inhibited the development of inflammation [144]. The knockout of the NPRA gene, however, has been linked to increased fat mass and cardiac hypertrophy [145]. Guanylyl cyclase-A (GCA) heterozygous knockout [GCA(+/−)] mice fed a high-fat diet gained weight and developed glucose intolerance [144, 146]. However, mice overexpressing PKG (cGK-Tg mice) fed a high-fat diet had lower body weight, less visceral and subcutaneous fat depots, and less ectopic fat deposition, thereby showing a significant enhancement in insulin sensitivity and glucose tolerance [146]. Overall, these data suggest that the NPs/guanylyl cyclase (GC) cascades play a crucial role in conferring resistance to obesity and glucose intolerance. Besides, mice overexpressing BNP (BNP-Tg mice) fed a high-fat diet, had better body weight, and glucose tolerance, indicating that BNP attenuates diet-related obesity and insulin resistance [146]. A recent study conducted on mice overexpressing CNP, specifically in adipocytes (A-CNP-Tg mice), showed better glucose tolerance and insulin sensitivity in another model of high-fat diet-induced obesity, which was linked to increased insulin-stimulated protein kinase B (Akt) phosphorylation. These findings imply that adipocyte-specific CNP overexpression offers protection against adipocyte hypertrophy, increased lipid metabolism, inflammation, and impaired insulin sensitivity during high-fat diet-induced obesity [147].
Insulin resistance, increased lipotoxicity, and reduced-fat oxidative capacity are all linked to faulty NPR signaling in skeletal muscle during obesity. The physiologic activation of NPRA by circulating NP is further inhibited by upregulation of NPRC in skeletal muscle as glucose tolerance impairs with obesity [137]. In humans, a substantial positive relationship was initially discovered between insulin sensitivity and muscle NPRA protein expression, as evaluated by hyperinsulinemic-euglycemic clamp at a dosage that primarily shows insulin sensitivity in skeletal muscle [137]. However, the finding of a negative relationship between body fat and muscle NPRA expression is in line with the negative relationship between total saturated ceramide concentration and muscle NPRA expression, two parameters that adversely influence skeletal muscle and whole-body insulin sensitivity [137, 148, 149]. Coué et al. first documented a functional link between insulin sensitivity and skeletal muscle NPRA signaling, indicating that NPR signaling in skeletal muscle may alter insulin sensitivity in addition to plasma NP levels [137]. Furthermore, muscle NPRA protein was significantly reduced in obese people, but it increased in response to diet-induced weight loss and improved insulin sensitivity. Although the molecular mechanisms that modulate muscle NPRA protein expression remain elusive, the aforementioned findings suggest that muscle NPRA acts as a major determinant of insulin sensitivity [137]. Furthermore, as glucose tolerance deteriorates in obese with impaired glucose tolerance (IGT) and type 2 diabetes, overexpression of muscle NPRC might further suppress the physiologic activation of muscle NPRA, which ultimately results in NP system dysfunction. Given that muscle mass accounts for up to 40% of total body weight, even a small increase in muscle NPRC expression could significantly reduce plasma NP levels by increasing NP clearance rates [137, 150]. As glucose tolerance deteriorates independently of blood glucose concentrations in obese patients, muscle NPRC may be activated by high blood insulin levels, as it has previously been established in adipose tissue [150]. Despite the fact that the obese controls and IGT/type 2 diabetes groups were not age-matched, enhanced NPRC expression in skeletal muscle appeared to be independent of age, since there was no relationship between age and muscle NPRC protein expression [137]. These findings in human muscle were mainly duplicated in obese diabetic mice. Obese diabetic mice had higher levels of NPRC protein in their skeletal muscle, white fat, and brown fat, but only muscle NPRC protein was negatively correlated with plasma BNP levels, suggesting that increased plasma BNP clearance by the muscle could contribute to the NP system dysfunction seen in these mice. Findings by Birkenfeld et al. [133] are consistent with previous studies that have linked higher NPRC mRNA levels in white fat to metabolic impairment in rats and humans [146, 151, 152]. These results have also provided a molecular explanation for the close relationship between NP system dysfunction and insulin resistance in humans, irrespective of adiposity [153]. The concept of NP system dysfunction is corroborated by the results reporting that in NPRC knockout mice blood circulation half-life of NPs and their biological activity in target tissues is dramatically enhanced [154]. More importantly, altered NPRA-to-NPRC protein ratio in skeletal muscle was followed by a significant change in p38 MAPK phosphorylation in db/db versus db/+ animals, indicating a possible signaling impairment, given that p38 MAPK is a typical downstream molecular effector of the NPR signaling pathway [127]. Another study has recently reported that protection against diet-induced obesity and insulin resistance had been attributed to NPRC deletion in adipose tissue (NprcAKO) but not in skeletal muscle (NprcMKO). NprcAKO mice had less inflammation and enhanced energy expenditure, shifting lipid storage from liver to visceral fat. These data led to the conclusion that, when fed a high-fat diet, mouse adipose tissue devoid of NPRC is the primary location of NP-driven metabolic changes [144].
5. Conclusion
Evidence is accumulating that NPs participate in the physiological and pathophysiological regulation of many metabolic diseases including obesity, insulin resistance, and type 2 diabetes, in addition to their well-known actions in the cardiac, vascular, and renal systems. Although there are some conflicting results of the relationship between NP system deficiency and metabolic diseases, many recent studies have shown that the NP system is defective in those diseases. Reduced NPs synthesis, increased clearance, and/or altered NP receptor expression may impair the positive effects of NPs on target metabolic organs such as heart, skeletal muscle, and adipose tissue during obesity, insulin resistance, and type 2 diabetes. Impaired NPs system signaling causes lipid accumulation in adipose tissue, which leads to visceral adiposity, obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. The strong links between adipose tissue enlargement and dysfunction during obesity, insulin resistance, type 2 diabetes, and cardiovascular disease may have been explained by a number of metabolic pathways that are interrelated in the heart, liver, and skeletal muscles. In this perspective, NP insufficiency might be considered one of the pathways linking adipose tissue dysfunction to obesity, type 2 diabetes, insulin resistance, and cardiovascular disease. There is ample data showing that restoring NPs levels after NP injection leads to positive metabolic outcomes, which supports this idea. The positive association between increased levels of NPs and lower incidence of insulin resistance, obesity, and type 2 diabetes holds promise for future NPs applications. Adipocyte hypertrophy, increased lipid synthesis, and visceral and ectopic fat deposition are all prevented by NPs. Furthermore, promising approaches to converting white adipose tissue into thermogenic brown adipose tissue could offer an effective tool for correcting dysfunctional lipid metabolism during obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. In addition, translation of these promising results into clinical practice would open new avenues to treat obesity, type 2 diabetes, and associated diseases. Therefore, further research is needed to completely comprehend the complex interplay between NP system and adipose tissue, heart, liver and skeletal muscles during obesity, insulin resistance, and type 2 diabetes.
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