Beyond Cyclic Nucleotides: Emerging Roles of Phosphodiesterases in Metabolic Disorders

Abstract

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)—thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.

Graphical abstract

Keywords

cyclic nucleotide phosphodiesterases / phosphodiesterase inhibitors / obesity / diabetes mellitus / metabolic syndrome

1. Introduction

Metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS), represent a growing global health burden with profound clinical, social, and economic implications [1]. According to recent epidemiological estimates, over 1 billion people worldwide are affected by overweight or obesity, and the prevalence of T2DM continues to rise, particularly in low and middle-income countries [2]. These conditions are not only closely linked to increased cardiovascular morbidity and mortality but also contribute to a wide range of comorbidities including hepatic steatosis and renal dysfunction [3].

At the core of these disorders lies a complex interplay of molecular and cellular mechanisms, with insulin resistance and chronic low-grade inflammation playing central roles in the pathogenesis of metabolic dysregulation [4]. Although lifestyle interventions such as caloric restriction and physical activity remain the cornerstone of prevention and treatment, their long-term efficacy is often limited by poor adherence and compensatory metabolic adaptations [5, 6]. Pharmacological agents such as metformin, Glucagon-Like Peptide-1 (GLP-1) receptor agonists, and thiazolidinediones have demonstrated benefits in improving glycemic control and insulin sensitivity, yet the need for safer and more durable therapies remains largely unmet [7, 8].

In recent years, cyclic nucleotides signaling pathways have emerged as critical regulators of metabolic homeostasis [9, 10]. The second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) govern a broad array of physiological processes, including mitochondrial biogenesis, lipolysis, insulin secretion, inflammation, vascular tone, and thermogenesis across metabolically active tissues such as adipose tissue, liver, skeletal muscle, and heart [11]. The intracellular levels of cAMP and cGMP are tightly controlled by phosphodiesterases, a superfamily of enzymes that hydrolyze these second messengers [12].

Among the phosphodiesterase (PDE) families, several isoforms, most notably PDE3, PDE4, and PDE5, have been identified as key modulators of metabolic signaling cascades [13, 14, 15]. These enzymes contribute to the spatial and temporal compartmentalization of cyclic nucleotide responses, providing tissue- and context-specific regulation of metabolic pathways. Pharmacological inhibition of PDEs offers a unique opportunity to selectively amplify beneficial cAMP- or cGMP-dependent signaling events. Notably, PDE5 inhibitors, historically used for the treatment of erectile dysfunction and pulmonary hypertension, have shown favorable effects on insulin sensitivity, endothelial function, and lipid metabolism in both preclinical and clinical studies [16, 17, 18, 19]. Similarly, PDE3 and PDE4 inhibitors have been investigated for their potential to modulate inflammation, lipolysis, and adipocyte function [20].

Finally, beyond their classical role in cyclic nucleotide degradation, both PDE3 and PDE4 have been shown to assemble into multiprotein macrocomplexes with A-kinase anchoring proteins (AKAPs), sarcoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), phospholamban (PLB), and the 5-hydroxytryptamine 4 (5-HT₄) receptor, thereby modulating distinct signaling pathways in a tissue-specific manner [21, 22, 23].

In this context, targeting cyclic nucleotide signaling through PDE inhibition could represent a promising therapeutic avenue for the management of metabolic diseases. This review aims to explore the molecular mechanisms by which the cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (cGMP-PKG) pathways regulates glucose and lipid metabolism, assess the current clinical evidence supporting their use, and discuss emerging insights into isoform-specific and tissue-targeted pharmacological strategies.

2. Methodology

Different databases, including PubMed, Web of Science, Scopus and Google Scholar, were used for the keywords of “Phosphodiesterases, Obesity, Type 2 Diabetes, Metabolic syndrome, Phosphodiesterases Inhibitors, Phosphodiesterases knockout mouse models”.

Inclusion criteria included all of the following keywords: “PDEs and obesity, PDEs and T2DM, PDEs and MetS, PDEi and metabolic disorders, PDEs knockout mouse models and metabolic disorders”.

Exclusion criteria were metabolic diseases apart from “obesity, T2DM and MetS”.

3. cAMP-PKA Signaling in Glucose and Lipid Metabolism

The cAMP–dependent PKA signaling cascade is a central regulatory pathway in cellular energy metabolism, integrating hormonal signals to coordinate glucose and lipid homeostasis across metabolically active tissues [24].

Signal initiation begins with the activation of a G protein-coupled receptor (GPCR), which stimulates adenylyl cyclase (AC) activity, catalyzing the conversion of adenosine triphosphate (ATP) into cAMP. Rapid increase in intracellular cAMP levels activates PKA, which phosphorylates a broad range of downstream effectors, thereby modulating lipolysis, gluconeogenesis, mitochondrial function, and thermogenesis [25] (Fig. 1).

To ensure signaling specificity, cAMP–PKA activity is compartmentalized into subcellular domains, primarily orchestrated by AKAPs. These scaffold proteins tether PKA in close proximity to both substrates and key regulators, including AC and PDEs, such as PDE4 [24].

In parallel to the canonical PKA pathway, cAMP also activates exchange protein directly activated by cAMP (EPAC), a guanine nucleotide exchange factor that regulates small GTPases [26]. This PKA-independent pathway has been implicated in the modulation of key metabolic processes, including glucose metabolism, insulin secretion, and energy homeostasis [27].

Data obtained from mouse models have demonstrated that targeted disruption of specific PKA subunits confers protection against diet-induced obesity and metabolic dysfunction. In this regard, knockout of PKA regulatory subunit RII\alpha results in reduced adiposity and improved glucose homeostasis via differential effects on PKA activity in liver and adipose tissue, while RII\beta-null mice exhibit resistance to diet-induced obesity and hyperglycemia [28, 29]. In humans, obesity is associated with a significant reduction in PKA regulatory subunit RII\beta expression in both visceral and subcutaneous adipose tissue, which correlates inversely with body mass index (BMI), insulin resistance, and homeostasis model assessment of insulin resistance (HOMA-IR): functionally, this is accompanied by blunted cAMP-induced PKA activity, particularly in visceral adipocytes.

In the liver, the cAMP–PKA axis plays a crucial role in promoting glucose production during fasting [30]. Upon glucagon stimulation, elevated cAMP levels activate PKA, which phosphorylates and activates key transcription factors such as cAMP response element–binding protein (CREB). This induces the expression of gluconeogenic genes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), often in concert with the CREB regulated transcription coactivator 2 (CRTC2), thereby enhancing hepatic gluconeogenesis and contributing to systemic glucose availability during fasting states [31].

PKA also phosphorylates and inhibits acetyl-CoA carboxylase (ACC), reducing malonyl-CoA levels and promoting fatty acid oxidation (FAO), while simultaneously suppressing de novo lipogenesis [32].

Glucose production can be influenced by PKA also through post-translational mechanisms, including phosphorylation of bifunctional enzymes that modulate glycolysis and gluconeogenesis: dysregulation of these pathways contributes to hyperglycemia in T2DM, highlighting its potential as a therapeutic target [33].

In white adipose tissue (WAT), the cAMP-PKA signaling cascade exerts dual regulatory control over both adipogenesis and lipolytic processes [34]. PKA-dependent phosphorylation triggers the activation of activating transcription factor (ATF)/CREB transcription factors, which subsequently drives the transcriptional induction of key adipogenic master regulators, including peroxisome proliferator-activated receptor gamma (PPAR\gamma) and CCAAT enhancer binding proteins (C/EBPs), thereby promoting preadipocyte differentiation [35]. In mature adipocytes, cAMP promotes lipolysis via phosphorylation and activation of key enzymes such as hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and perilipin-1, while also promoting thermogenesis via induction of uncoupling protein 1 (UCP1) [36].

Brown adipose tissue (BAT), by contrast, utilizes cAMP signaling to regulate thermogenesis. Cold-induced sympathetic stimulation activates \beta-adrenergic receptors, leading to cAMP production, PKA activation, and transcription of thermogenic genes via CREB, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1\alpha), and PR domain-containing 16 (PRDM16) [37, 38]. These pathways also promote mitochondrial biogenesis and increased substrate oxidation, essential steps that collectively culminate in the expression and activation of UCP1.

Interestingly, cAMP also contributes to “WAT browning”, a transdifferentiation process by which white adipocytes adopt BAT-like features becoming beige/brite adipocytes, representing a promising strategy to fight obesity [39, 40].

Although less pronounced than in adipose and hepatic tissue, cAMP-PKA signaling also contributes to muscle glycogenolysis through phosphorylation of phosphorylase kinase, which activates glycogen phosphorylase to induce glucose release from glycogen stores during exercise. Moreover, PKA signaling has been implicated in enhancing glucose uptake through insulin-independent pathways under certain physiological contexts, although this remains less well-characterized [41]. In skeletal muscle, cAMP is also involved in acute regulation of contraction via modulation of calcium handling and long-term adaptation through enhanced glycolytic capacity and myofiber hypertrophy [42]. Moreover, epinephrine-induced cAMP production facilitates glycogenolysis during exercise and may help mitigate muscle atrophy under pathological conditions [43].

In pancreatic \beta-cells, cAMP signaling plays a dual role in enhancing insulin secretion and supporting \beta-cell mass and survival. Incretins such as GLP-1 and gastric inhibitory polypeptide (GIP) stimulate cAMP production via Gs-coupled receptors, enhancing glucose-stimulated insulin secretion via both PKA and EPAC-mediated pathways [27]. Importantly, dysregulation of cAMP signaling in \beta-cells contributes to glucolipotoxicity and \beta-cell failure in T2DM, further underscoring its therapeutic relevance.

Given the widespread metabolic impact of the cAMP pathway, its regulation is subject to intricate control mechanisms. A pivotal mechanism integrating the intracellular dynamics of cyclic nucleotides is the well-characterized cross-talk between the cAMP and cGMP pathways, primarily mediated by the dual-substrate phosphodiesterase 2 (PDE2). This enzyme hydrolyzes cAMP and is allosterically activated by cGMP, thereby establishing a robust negative feedback loop where elevated cGMP levels effectively limit cAMP accumulation [44, 45].

Such regulatory interplay has been extensively investigated in cardiac physiology, embryonic development, and vascular homeostasis, where tightly controlled cyclic nucleotide dynamics are crucial for functional integrity [46, 47].

Notwithstanding the established regulatory capacity of the PDE2-mediated cross-talk, the enzyme’s specific role in metabolic homeostasis remains a significant knowledge gap. Current evidence suggesting PDE2 involvement in metabolic regulation is tenuous, primarily stemming from a singular report that documented its expression and modulation within adipose tissue, correlating with obesity-related phenotypes in rodent models [48]. Crucially, this preliminary investigation did not include functional metabolic assessments, lacking data on the effects of PDE2 inhibition on key processes such as lipolysis rates, glucose uptake, or insulin sensitivity, thus leaving its direct contribution to adipocyte function largely unsubstantiated.

Together, these findings underscore the critical role of PKA in maintaining metabolic homeostasis and support its potential as a therapeutic target for the treatment of obesity and related metabolic disorders.

4. cGMP-PKG Signaling in Glucose and Lipid Metabolism

The cGMP-PKG signaling pathway plays a pivotal role in regulating energy homeostasis and glucose and lipid metabolism [10].

Upon cGMP elevation, PKG is activated and phosphorylates downstream effectors that influence energy balance, mitochondrial function, adipogenesis, and insulin sensitivity across multiple tissues [10, 12] (Fig. 1).

Emerging evidence indicates that modulation of this pathway influences both the development and thermogenic activity of adipocytes, with direct implications for metabolic health and resistance to obesity [15]. Loss of PKG impairs brown adipose tissue thermogenic function, as evidenced by decreased UCP1 expression and reduced mitochondrial content in PKG-I knockout mice [49]. Brown preadipocytes isolated from these mice also show defective differentiation with downregulation of thermogenic markers including PPAR\gamma, UCP1, and PGC-1\alpha. Conversely, PKG overexpression confers resistance to diet-induced obesity, enhancing insulin sensitivity, energy expenditure, BAT mitochondrial content, and expression of UCP1 and PGC-1\alpha [50]. Notably, cGMP pathway activation also promotes adipogenic and thermogenic programs in cultured human adipocytes [51].

Recent findings suggested that activation of the cGMP-PKG pathway in adipocytes promotes lipolysis, adiponectin secretion, and WAT browning, leading to enhanced thermogenesis and energy expenditure [15, 52].In addition, natriuretic peptides promote mitochondrial biogenesis and expression of UCP1 via PKG-dependent activation of p38 MAPK and PGC-1\alpha [53]. Moreover, PKG phosphorylates and activates HSL and perilipin, thereby facilitating lipolysis in a fashion complementary to \beta-adrenergic–cAMP–PKA signaling [54, 55]. cGMP-induced lipolysis has been demonstrated to occurs also in cardiac tissue where cGMP signaling is able to modulate cardiac energy metabolism in a cardiomyocyte-specific manner by promoting HSL-dependent lipolysis. This action facilitates triglycerides turnover and lipid compartmentalization, thereby limiting their accumulation particularly under fasting conditions [56]. In skeletal muscle, cGMP signaling improves glucose uptake, vascular perfusion, and mitochondrial respiration. Here, PKG enhances insulin sensitivity through vasodilation-mediated increases in skeletal muscle blood flow, thereby facilitating glucose delivery and disposal [57]. Although less extensively characterized, hepatic cGMP-PKG signaling has been shown to suppress gluconeogenesis and promote fatty acid oxidation [58]. PKG activation decreases the expression of key gluconeogenic enzymes, such as PEPCK and G6Pase, and promotes phosphorylation of transcriptional co-regulators like forkhead box protein O1 (FOXO1), reducing hepatic glucose output [59, 60]. cGMP–PKG signaling supports \beta-cell function and insulin secretion, particularly through enhancement of islet blood flow and protection from oxidative stress. Finally, in cardiometabolic disease models, PDE5 inhibition improves endothelial function, reduces cardiac hypertrophy, and enhances insulin signaling, highlighting overall systemic metabolic benefits [17, 61, 62].

Although the cAMP-PKA signaling pathway holds a preeminent role in governing central metabolic functions, including the rapid regulation of lipolysis, glycogenolysis, and thermogenesis, emerging literature suggests that cGMP-PKG signaling is crucial for metabolic adaptation, exerting a key influence on processes such as mitochondrial biogenesis, glucose uptake, and the modulation of insulin action. This necessitates an integrated view wherein the two signaling systems converge to ensure systemic metabolic flexibility. The convergence of these pathways is highlighted by a critical heterologous cross-talk mechanism, prominently featuring the cyclic nucleotide phosphodiesterases (e.g., PDE3-PDE5) [15].

5. Established and Emerging Therapeutic Use of PDE Inhibitors in Metabolic Disorders

Phosphodiesterase inhibitors are a diverse class of pharmacological agents that exert their effects by preventing the enzymatic hydrolysis of the second messengers cAMP and cGMP, thereby prolonging and amplifying cyclic nucleotide–mediated signaling [63]. PDE enzymes are divided into 11 families (PDE1–PDE11) based on their substrate specificity, regulatory mechanisms, and tissue distribution. Each isoform fine-tunes local cyclic nucleotide pools within specific subcellular microdomains, contributing to the spatial and temporal regulation of intracellular signaling networks [64]. Historically, PDEi have been developed and approved for non-metabolic indications, most notably, PDE5 inhibitors for erectile dysfunction and pulmonary hypertension, and PDE4 inhibitors for chronic obstructive pulmonary disease and inflammatory disorders [65, 66, 67].

Recent evidence has highlighted the broad expression of PDEs in key metabolically active tissues including adipose tissue, liver, skeletal muscle, pancreatic \beta-cells, and the cardiovascular system, underscoring their critical role in the regulation of glucose and lipid metabolism, mitochondrial function, and immunoinflammatory responses [68, 69]. As such, PDEi are emerging as attractive candidates for the management of metabolic disorders, including obesity, T2DM, MetS, and non-alcoholic fatty liver disease (NAFLD).

Chronic low-grade inflammation within adipose tissue represents a pivotal driver of the pathophysiology of MetS. Hypertrophic adipocytes and infiltrating immune cells, particularly pro-inflammatory macrophages, establish a sustained inflammatory milieu characterized by increased secretion of cytokines such as TNF-\alpha, IL-6, and monocyte chemoattractant protein 1 (MCP-1) [70]. This pro-inflammatory signaling disrupts insulin receptor signaling through serine phosphorylation of IRS proteins and promotes systemic insulin resistance. In parallel, inflammation-driven remodeling of the extracellular matrix and dysregulated adipokine secretion (e.g., decreased adiponectin, increased leptin and resistin) further impair metabolic homeostasis [71]. The chronic activation of nuclear factor kappa B (NF-\kappaB) and c-Jun N-terminal kinase (JNK) pathways within adipose tissue not only perpetuates local inflammation but also contributes to ectopic lipid deposition in the liver and skeletal muscle, fueling lipotoxicity, mitochondrial dysfunction, and systemic metabolic derangements [72]. Consequently, adipose tissue inflammation is now considered not merely a bystander but a central pathogenic mechanism underlying the development and progression of MetS and its cardiovascular and metabolic complications.

MetS itself is therefore defined as a cluster of interrelated cardiometabolic abnormalities (insulin resistance, abdominal obesity, dyslipidemia, hypertension, and hyperglycemia) that synergistically increase the risk of cardiovascular events and T2DM [73]. These pathological features are deeply connected to cyclic nucleotide-regulated signaling pathways, positioning PDEs as key molecular targets in these contexts. Preclinical studies investigating the effect of PDE blockade in metabolic disorders are summarized in Table 1 (Ref. [15, 18, 52, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86]).

Among PDEi, PDE5 inhibitors (PDE5i) such as sildenafil and tadalafil, promote nitric oxide (NO)-dependent vasodilation by blocking cGMP degradation in vascular smooth muscle [87]. Beyond their vascular effects, PDE5i enhance adipogenesis, induce browning of WAT, and improve mitochondrial respiration [88, 89, 90]. In preclinical and clinical settings, PDE5i have been demonstrated to improve insulin sensitivity, reduce systemic inflammation, and enhance endothelial function, mechanisms of paramount importance in MetS and T2DM [91, 92]. A randomized controlled trial using sildenafil (25 mg three times daily for three months) in individuals with pre-diabetes revealed significant improvement in insulin sensitivity, enhanced fibrinolytic balance, and reduction of urinary albumin excretion, although without augmentation of glucose-stimulated insulin secretion [61]. Similarly, 20 mg tadalafil daily administered to obese insulin-resistant patients improved \beta-cell compensation, particularly in those with severe obesity [93]. Preclinical studies showed that chronic administration of sildenafil improves insulin sensitivity, reduces inflammation, and preserves \beta-cell function via cGMP-PKG signaling, although context-specific effects have been reported, such as impaired glucose tolerance and lack of thermogenic gene induction in brown adipose tissue [83, 94]. Udenafil also enhanced mitochondrial oxidative phosphorylation, fatty acid oxidation, and PGC-1\alpha expression, promoting insulin sensitivity [89].

PDE3 inhibitors (PDE3i), including milrinone and cilostazol, modulate both cAMP and cGMP levels. While their approved uses are related to heart failure and intermittent claudication, PDE3B, highly expressed in adipocytes, liver, and pancreatic islets, has been implicated in energy homeostasis [95, 96]. Mice overexpressing Pde3b exhibit glucose intolerance and \beta-cell dysfunction, whereas Pde3b-deficient mice are protected from diet-induced obesity and display white-to-beige conversion of adipocytes [97, 98]. Genetic ablation of Pde3b also reduces inflammation via diminished NLRP3 inflammasome activation, enhances insulin sensitivity, and confers resistance to HFD-induced weight gain [99].

PDE1 inhibitors (PDE1i) regulate both cAMP and cGMP via a Ca²⁺/calmodulin-dependent mechanism. PDE1C inhibition enhances glucose-stimulated insulin secretion in pancreatic \beta-cells [100]. Moreover, chronic exposure to the highly selective PDE1i lenrispodun improves cardiac output, reduces arterial resistance, and enhances contractility in both animal models and clinical trials, supporting PDE1 relevance in cardiometabolic diseases [101, 102].

PDE4 inhibitors (PDE4i), including roflumilast and apremilast, are potent anti-inflammatory agents, modulating immune cell activity and cytokine release. In HFD-fed mice, roflumilast reduced weight gain, enhanced energy expenditure, improved glucose tolerance and insulin sensitivity, and attenuated steatohepatitis via PKA/CREB activation and PGC-1\alpha induction [77]. In psoriasis patients, roflumilast reduced BMI by ~4% over 24 weeks [103]. Additional human study support early fat mass loss and insulin sensitivity gains [104]. Apremilast, an orally administered phosphodiesterase-4 inhibitor currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases, inhibits cytokines such as IL-4, IL-5, TNF-\alpha, and IFN-\gamma, ameliorating systemic inflammation and insulin resistance [105].

PDE9 inhibitors (PDE9i) represent a novel class targeting natriuretic peptide-derived cGMP signaling and PDE9 is highly expressed in heart and adipose tissue modulating pathways involved in lipid oxidation and mitochondrial biogenesis [106]. Genetic deletion or pharmacological inhibition of PDE9 improves glucose homeostasis, enhances insulin sensitivity, and reduces hepatic steatosis in obese and diabetic mice and these effects are mediated via PKG activation and upregulation of mitochondrial and oxidative genes [52, 85].

Pharmacological blockade of PDE10A using the highly selective PDE10i MP-10 has been shown to activate BAT and enhance thermogenic capacity in vivo. In murine models of diet-induced obesity, chronic treatment with MP-10 promotes body weight reduction through elevated whole-body energy expenditure, concomitant with the induction of browning programs in WAT and an improvement in systemic insulin sensitivity [107].

Clinical studies testing the use of PDEi in metabolic disorders have predominantly focused on selective pharmacological agents that offer mechanistic precision. These include, but are not limited to, PDE5 inhibitors (e.g., sildenafil, tadalafil) and PDE4 inhibitors (e.g., roflumilast), which precisely modulate specific cyclic nucleotide signaling pathways governing lipolysis, insulin sensitivity, and energy expenditure. In sharp contrast, a minority of studies have explored the utility of non-selective or naturally derived modulators, such as caffeine and polyphenols, often tested in combination with other treatments. These natural compounds typically exert a broader, yet milder, spectrum of PDE inhibition alongside inherent thermogenic, antioxidant, and anti-inflammatory properties. While the selective inhibitors provide critical translational insights into the role of specific signaling cascades, the non-selective approach demonstrates that weaker, pleiotropic PDE modulation, particularly when synergized with other biological activities, can still significantly influence metabolic regulation. Both complementary approaches are vital, offering a broader and more nuanced understanding of the therapeutic potential of PDE-targeted strategies against metabolic dysfunction.

As summarized in Table 2, the majority of registered clinical trials (RCTs) investigating PDEi in obesity and related metabolic disorders are early-phase, with relatively small sample sizes and variable study designs. A significant proportion of interventions evaluated indirect modulators of PDE signaling, such as caffeine, aiming to stimulate thermogenesis and enhance energy expenditure, though most failed to demonstrate consistent clinical benefits in terms of weight reduction or body composition (Table 3). More targeted approaches, including the use of pentoxifylline and roflumilast, have shown modest but measurable improvements in insulin sensitivity and inflammatory markers in obese or prediabetic populations, underscoring the translational potential of PDE blockade in metabolic disease.

A comparative assessment of the clinical trials involving the use of PDEi for the management of obesity and related metabolic dysfunctions highlights distinct features between selective and non-selective phosphodiesterase inhibition. Selective PDEi, particularly those targeting PDE5 and PDE4, exhibit more consistent and mechanistically defined effects, including improvements in insulin sensitivity, endothelial function, and systemic inflammation. These outcomes likely reflect their well-characterized pharmacokinetic and pharmacodynamic properties and tissue-specific modulation of cyclic nucleotide signaling. Conversely, studies investigating non-selective or naturally-derived PDE modulators, such as caffeine, tea catechins, and polyphenols, report broader, though less specific, metabolic effects often intertwined with antioxidant or thermogenic actions. While these agents show modest efficacy in weight reduction and metabolic improvement, their limited isoform selectivity complicates the interpretation of causal mechanisms.

The examination of RCTs involving the use of PDEi in the context of T2DM (Tables 4,5) highlights a heterogeneous body of evidence, with most studies being small, early-phase investigations focusing on surrogate endpoints such as vascular function, hemodynamic parameters, and markers of end-organ damage (e.g., albuminuria, intima-media thickness). Several randomized controlled trials with PDE5i primarily addressed improvements in endothelial function and cardiac remodeling—surrogate measures of clinical relevance in the T2DM population—supporting the notion of pleiotropic effects via the NO–cGMP pathway and myocardial mechanics. Other compounds, including pentoxifylline and cilostazol, were mainly evaluated for renal and anti-atherothrombotic outcomes, with some trials documenting reductions in proteinuria and favorable modulation of inflammatory biomarkers. Although these findings provide encouraging signals on intermediate endpoints, the methodological heterogeneity—differences in primary outcomes, limited treatment durations, and underpowered sample sizes—substantially limits generalizability and precludes firm conclusions regarding long-term clinical benefit in T2DM.

Comparison of the clinical studies analyzing the effect of PDEi for the treatment of T2DM reveals notable differences in the clinical impact and mechanistic scope of selective versus non-selective phosphodiesterase inhibition in T2DM management. Selective PDEi, particularly PDE5 and PDE3 inhibitors, have demonstrated significant benefits in improving endothelial function, insulin-mediated glucose uptake, and peripheral perfusion, reflecting their targeted modulation of cGMP or cAMP signaling in metabolic tissues. These agents also show favorable effects on cardiovascular risk markers, supporting their potential as adjunctive therapies for metabolic and vascular comorbidities in diabetes. In contrast, non-selective or naturally derived PDE modulators, such as methylxanthines, polyphenols, and catechins, exert milder but broader metabolic actions, often associated with enhanced mitochondrial function, antioxidant capacity, and lipid metabolism. However, their heterogeneous composition and lower PDE selectivity limit the ability to attribute observed benefits to specific cyclic nucleotide pathways. Overall, while selective PDEi provide stronger mechanistic and clinical evidence of metabolic improvement, non-selective modulators continue to offer valuable insights into the systemic regulation of energy metabolism and redox balance in diabetic conditions.

Most available clinical studies dissecting the effects of PDEi in MetS are early-phase, single-center investigations with relatively small sample sizes and variable primary outcomes, spanning from vascular function and arterial stiffness to insulin signaling and erectile function (Tables 6,7).

The comparison between the clinical trials designed to test the use of PDEi for the management of MetS underscores both the mechanistic specificity and the translational heterogeneity of phosphodiesterase inhibition in the context of MetS. Selective PDEi, particularly those acting on PDE5 and PDE4, demonstrate consistent improvements in key features of MetS (e.g., insulin resistance, dyslipidemia, endothelial dysfunction, and systemic inflammation) through targeted modulation of cAMP and cGMP signaling in vascular and metabolic tissues. Their efficacy profiles, supported by controlled pharmacokinetic parameters, suggest a promising therapeutic role in restoring metabolic and vascular homeostasis. Conversely, non-selective or naturally derived PDE modulators, including caffeine, theobromine, and polyphenolic compounds, exhibit broader systemic effects that integrate metabolic, antioxidant, and anti-inflammatory pathways. While their outcomes appear less predictable and mechanistically defined, these agents contribute to a more holistic understanding of cyclic nucleotide signaling in complex metabolic disorders. Taken together, selective PDE inhibitors provide stronger mechanistic evidence and translational potential, whereas non-selective modulators highlight complementary, lifestyle-associated strategies that may synergize with pharmacological interventions in managing MetS.

Notably, the majority of available RCTs investigated the effect of PDE5 inhibitors in MetS or in overlapping cardiometabolic conditions such as T2DM and erectile dysfunction. These studies consistently demonstrated improvements in endothelial function, insulin sensitivity, and erectile function, supporting the concept of systemic metabolic and vascular benefits mediated via the NO–cGMP–PKG axis. However, most trials prioritized surrogate endpoints rather than long-term cardiometabolic outcomes.

Other PDE-targeting compounds have also been tested, albeit with limited translational relevance to MetS. Cilostazol, a PDE3 inhibitor, was evaluated for effects on adipokines and arterial stiffness, while levosimendan (a PDE3/4 modulator with inotropic effects) was tested in relation to skeletal muscle metabolism. More recently, exploratory observational protocols have focused on PDE3B in metabolic regulation, with ongoing studies aiming to delineate its role in lipolysis and energy balance.

Together, all preclinical and clinical data analyzed and discussed above, suggest that PDE inhibitors, by selectively modulating intracellular cyclic nucleotide signaling, can enhance insulin action, stimulate lipid oxidation, suppress adipogenesis, reduce ectopic lipid deposition, and improve endothelial-metabolic cross-talk. Nevertheless, metabolic outcomes vary by PDE isoform, dosing duration, and tissue context, and some unfavorable effects, such as sildenafil-induced glucose intolerance under obesity, underscore the complexity of chronic modulation. Consequently, large-scale, long-term trials with isoform-selective and tissue-restricted PDE targeting are warranted to establish therapeutic efficacy, tolerability, and personalized applications in metabolic disease.

6. Conclusions

Collectively, these findings underscore the potential of PDEi as versatile modulators of metabolic homeostasis, capable of fine-tuning adipocyte thermogenesis, \beta-cell insulin secretion, and systemic anti-inflammatory and vasodilatory pathways. Translating these insights into clinical practice requires careful consideration of several factors. Long-term safety and isoform specificity remain paramount, as off-target effects or prolonged modulation of cyclic nucleotide signaling can have significant consequences. Tissue heterogeneity, including sex differences and organ-specific expression patterns, further influences both efficacy and susceptibility to adverse events. In addition, effective dose–tissue exposure, shaped by pharmacokinetic and pharmacodynamic properties, is essential to achieve meaningful target engagement. Finally, the long-term metabolic and cardiovascular outcomes of PDE modulation are still incompletely characterized. Together, these considerations highlight the need for well-designed, longitudinal studies to fully realize the therapeutic promise of PDE-targeted strategies in metabolic disorders.

References

[1] Chew NWS, Ng CH, Tan DJH, Kong G, Lin C, Chin YH, et al. The global burden of metabolic disease: Data from 2000 to 2019. Cell Metabolism. 2023; 35: 414–428.e3. https://doi.org/10.1016/j.cmet.2023.02.003.

[2] NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet (London, England). 2024; 403: 1027–1050. https://doi.org/10.1016/S0140-6736(23)02750-2.

[3] Bae JP, Nelson DR, Boye KS, Mather KJ. Prevalence of complications and comorbidities associated with obesity: a health insurance claims analysis. BMC Public Health. 2025; 25: 273. https://doi.org/10.1186/s12889-024-21061-z.

[4] Wu H, Ballantyne CM. Metabolic Inflammation and Insulin Resistance in Obesity. Circulation Research. 2020; 126: 1549–1564. https://doi.org/10.1161/CIRCRESAHA.119.315896.

[5] Yurista SR, Eder RA, Feeley M, Kodur N, Tang WHW, Nguyen CT. A Closer Look at ACC/AHA and ESC Guidelines for Managing Obesity and Overweight in Adults. JACC. Advances. 2023; 2: 100570. https://doi.org/10.1016/j.jacadv.2023.100570.

[6] American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2024. Diabetes Care. 2024; 47: S158–S178. https://doi.org/10.2337/dc24-S009.

[7] Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy. 2024; 9: 234. https://doi.org/10.1038/s41392-024-01931-z.

[8] Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar. Journal of the American College of Cardiology. 2020; 75: 1956–1974. https://doi.org/10.1016/j.jacc.2020.02.056.

[9] Lugnier C, Meyer A, Talha S, Geny B. Cyclic nucleotide phosphodiesterases: New targets in the metabolic syndrome? Pharmacology & Therapeutics. 2020; 208: 107475. https://doi.org/10.1016/j.pharmthera.2020.107475.

[10] Campolo F, Pofi R, Venneri MA, Isidori AM. Priming metabolism with the type 5 phosphodiesterase: the role of cGMP-hydrolyzing enzymes. Current Opinion in Pharmacology. 2021; 60: 298–305. https://doi.org/10.1016/j.coph.2021.08.007.

[11] Kelly MP, Nikolaev VO, Gobejishvili L, Lugnier C, Hesslinger C, Nickolaus P, et al. Cyclic nucleotide phosphodiesterases as drug targets. Pharmacological Reviews. 2025; 77: 100042. https://doi.org/10.1016/j.pharmr.2025.100042.

[12] Campolo F, Samidurai A. Editorial: Cyclic nucleotide phosphodiesterases (PDEs) signaling in the endocrine system. Frontiers in Endocrinology. 2025; 16: 1548972. https://doi.org/10.3389/fendo.2025.1548972.

[13] Waddleton D, Wu W, Feng Y, Thompson C, Wu M, Zhou YP, et al. Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. Biochemical Pharmacology. 2008; 76: 884–893. https://doi.org/10.1016/j.bcp.2008.07.025.

[14] Cardarelli S, Miele AE, Campolo F, Massimi M, Mancini P, Biagioni S, et al. Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms. International Journal of Molecular Sciences. 2022; 23: 8587. https://doi.org/10.3390/ijms23158587.

[15] Campolo F, Giampaoli O, Barbagallo F, Palmisano B, Di Maio A, Sciarra F, et al. Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning. Molecular Metabolism. 2025; 101: 102243. https://doi.org/10.1016/j.molmet.2025.102243.

[16] Gevi F, Campolo F, Naro F, Zolla L. The cardioprotective effect of sildenafil is mediated by the activation of malate dehydrogenase and an increase in the malate-aspartate shuttle in cardiomyocytes. Biochemical Pharmacology. 2017; 127: 60–70. https://doi.org/10.1016/j.bcp.2016.12.017.

[17] Pofi R, Giannetta E, Feola T, Galea N, Barbagallo F, Campolo F, et al. Sex-specific effects of daily tadalafil on diabetic heart kinetics in RECOGITO, a randomized, double-blind, placebo-controlled trial. Science Translational Medicine. 2022; 14: eabl8503. https://doi.org/10.1126/scitranslmed.abl8503.

[18] Venneri MA, Barbagallo F, Fiore D, De Gaetano R, Giannetta E, Sbardella E, et al. PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes. The Journal of Clinical Endocrinology and Metabolism. 2019; 104: 2623–2636. https://doi.org/10.1210/jc.2018-02525.

[19] Fiore D, Gianfrilli D, Giannetta E, Galea N, Panio G, di Dato C, et al. PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial. The Journal of Clinical Endocrinology and Metabolism. 2016; 101: 1525–1534. https://doi.org/10.1210/jc.2015-4252.

[20] Kraynik SM, Miyaoka RS, Beavo JA. PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue. Molecular Pharmacology. 2013; 83: 1155–1165. https://doi.org/10.1124/mol.112.084145.

[21] Ahmad F, Shen W, Vandeput F, Szabo-Fresnais N, Krall J, Degerman E, et al. Regulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) activity by phosphodiesterase 3A (PDE3A) in human myocardium: phosphorylation-dependent interaction of PDE3A1 with SERCA2. The Journal of Biological Chemistry. 2015; 290: 6763–6776. https://doi.org/10.1074/jbc.M115.638585.

[22] Weninger S, Van Craenenbroeck K, Cameron RT, Vandeput F, Movsesian MA, Baillie GS, et al. Phosphodiesterase 4 interacts with the 5-HT4(b) receptor to regulate cAMP signaling. Cellular Signalling. 2014; 26: 2573–2582. https://doi.org/10.1016/j.cellsig.2014.07.027.

[23] Asirvatham AL, Galligan SG, Schillace RV, Davey MP, Vasta V, Beavo JA, et al. A-kinase anchoring proteins interact with phosphodiesterases in T lymphocyte cell lines. Journal of Immunology (Baltimore, Md.: 1950). 2004; 173: 4806–4814. https://doi.org/10.4049/jimmunol.173.8.4806.

[24] Zaccolo M, Zerio A, Lobo MJ. Subcellular Organization of the cAMP Signaling Pathway. Pharmacological Reviews. 2021; 73: 278–309. https://doi.org/10.1124/pharmrev.120.000086.

[25] Zhang X, Xiao J, Jiang M, Phillips CJC, Shi B. Thermogenesis and Energy Metabolism in Brown Adipose Tissue in Animals Experiencing Cold Stress. International Journal of Molecular Sciences. 2025; 26: 3233. https://doi.org/10.3390/ijms26073233.

[26] Borland G, Smith BO, Yarwood SJ. EPAC proteins transduce diverse cellular actions of cAMP. British Journal of Pharmacology. 2009; 158: 70–86. https://doi.org/10.1111/j.1476-5381.2008.00087.x.

[27] Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, et al. cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes & Development. 2003; 17: 1575–1580. https://doi.org/10.1101/gad.1097103.

[28] Czyzyk TA, Sikorski MA, Yang L, McKnight GS. Disruption of the RIIbeta subunit of PKA reverses the obesity syndrome of Agouti lethal yellow mice. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105: 276–281. https://doi.org/10.1073/pnas.0710607105.

[29] London E, Nesterova M, Sinaii N, Szarek E, Chanturiya T, Mastroyannis SA, et al. Differentially regulated protein kinase A (PKA) activity in adipose tissue and liver is associated with resistance to diet-induced obesity and glucose intolerance in mice that lack PKA regulatory subunit type IIα. Endocrinology. 2014; 155: 3397–3408. https://doi.org/10.1210/en.2014-1122.

[30] Yang H, Yang L. Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy. Journal of Molecular Endocrinology. 2016; 57: R93–R108. https://doi.org/10.1530/JME-15-0316.

[31] Altarejos JY, Montminy M. CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nature Reviews. Molecular Cell Biology. 2011; 12: 141–151. https://doi.org/10.1038/nrm3072.

[32] Dyck JR, Kudo N, Barr AJ, Davies SP, Hardie DG, Lopaschuk GD. Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5’-AMP activated protein kinase. European Journal of Biochemistry. 1999; 262: 184–190. https://doi.org/10.1046/j.1432-1327.1999.00371.x.

[33] Ghanem SS, Al-Barazenji T, Badi R, Abdelalim EM. Bridging pancreatic and hepatic development: overlapping genes and their role in diabetes. Cellular & Molecular Biology Letters. 2025; 30: 113. https://doi.org/10.1186/s11658-025-00790-y.

[34] Rogne M, Taskén K. Compartmentalization of cAMP signaling in adipogenesis, lipogenesis, and lipolysis. Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones et Metabolisme. 2014; 46: 833–840. https://doi.org/10.1055/s-0034-1389955.

[35] Rosen ED, Spiegelman BM. Molecular regulation of adipogenesis. Annual Review of Cell and Developmental Biology. 2000; 16: 145–171. https://doi.org/10.1146/annurev.cellbio.16.1.145.

[36] Brasaemle DL, Subramanian V, Garcia A, Marcinkiewicz A, Rothenberg A. Perilipin A and the control of triacylglycerol metabolism. Molecular and Cellular Biochemistry. 2009; 326: 15–21. https://doi.org/10.1007/s11010-008-9998-8.

[37] Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998; 92: 829–839. https://doi.org/10.1016/s0092-8674(00)81410-5.

[38] Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metabolism. 2007; 6: 38–54. https://doi.org/10.1016/j.cmet.2007.06.001.

[39] Frontini A, Vitali A, Perugini J, Murano I, Romiti C, Ricquier D, et al. White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochimica et Biophysica Acta. 2013; 1831: 950–959. https://doi.org/10.1016/j.bbalip.2013.02.005.

[40] Tam CS, Lecoultre V, Ravussin E. Brown adipose tissue: mechanisms and potential therapeutic targets. Circulation. 2012; 125: 2782–2791. https://doi.org/10.1161/CIRCULATIONAHA.111.042929.

[41] Sato M, Dehvari N, Oberg AI, Dallner OS, Sandström AL, Olsen JM, et al. Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle. Diabetes. 2014; 63: 4115–4129. https://doi.org/10.2337/db13-1860.

[42] Berdeaux R, Stewart R. cAMP signaling in skeletal muscle adaptation: hypertrophy, metabolism, and regeneration. American Journal of Physiology. Endocrinology and Metabolism. 2012; 303: E1–17. https://doi.org/10.1152/ajpendo.00555.2011.

[43] Zhang B, Johnson MM, Yuan T, Nguyen TN, Okada J, Yang F, et al. Hepatic glycogen directly regulates gluconeogenesis through an AMPK/CRTC2 axis in mice. The Journal of Clinical Investigation. 2025; 135: e188363. https://doi.org/10.1172/JCI188363.

[44] Isidori AM, Cornacchione M, Barbagallo F, Di Grazia A, Barrios F, Fassina L, et al. Inhibition of type 5 phosphodiesterase counteracts β2-adrenergic signalling in beating cardiomyocytes. Cardiovascular Research. 2015; 106: 408–420. https://doi.org/10.1093/cvr/cvv123.

[45] Assenza MR, Barbagallo F, Barrios F, Cornacchione M, Campolo F, Vivarelli E, et al. Critical role of phosphodiesterase 2A in mouse congenital heart defects. Cardiovascular Research. 2018; 114: 830–845. https://doi.org/10.1093/cvr/cvy030.

[46] Barbagallo F, Rotilio V, Assenza MR, Aguanno S, Orsini T, Putti S, et al. PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis. International Journal of Molecular Sciences. 2020; 21: 2902. https://doi.org/10.3390/ijms21082902.

[47] Bubb KJ, Trinder SL, Baliga RS, Patel J, Clapp LH, MacAllister RJ, et al. Inhibition of phosphodiesterase 2 augments cGMP and cAMP signaling to ameliorate pulmonary hypertension. Circulation. 2014; 130: 496–507. https://doi.org/10.1161/CIRCULATIONAHA.114.009751.

[48] Coudray C, Charon C, Komas N, Mory G, Diot-Dupuy F, Manganiello V, et al. Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression. FEBS Letters. 1999; 456: 207–210. https://doi.org/10.1016/s0014-5793(99)00934-5.

[49] Haas B, Mayer P, Jennissen K, Scholz D, Berriel Diaz M, Bloch W, et al. Protein kinase G controls brown fat cell differentiation and mitochondrial biogenesis. Science Signaling. 2009; 2: ra78. https://doi.org/10.1126/scisignal.2000511.

[50] Nikolic DM, Li Y, Liu S, Wang S. Overexpression of constitutively active PKG-I protects female, but not male mice from diet-induced obesity. Obesity (Silver Spring, Md.). 2011; 19: 784–791. https://doi.org/10.1038/oby.2010.223.

[51] Mitschke MM, Hoffmann LS, Gnad T, Scholz D, Kruithoff K, Mayer P, et al. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2013; 27: 1621–1630. https://doi.org/10.1096/fj.12-221580.

[52] Ceddia RP, Liu D, Shi F, Crowder MK, Mishra S, Kass DA, et al. Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9. Diabetes. 2021; 70: 2823–2836. https://doi.org/10.2337/db21-0100.

[53] Liu D, Ceddia RP, Collins S. Cardiac natriuretic peptides promote adipose ’browning’ through mTOR complex-1. Molecular Metabolism. 2018; 9: 192–198. https://doi.org/10.1016/j.molmet.2017.12.017.

[54] Nielsen TS, Jessen N, Jørgensen JOL, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. Journal of Molecular Endocrinology. 2014; 52: R199–222. https://doi.org/10.1530/JME-13-0277.

[55] Sengenès C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J. Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology. 2000; 14: 1345–1351.

[56] Khairallah RJ, Khairallah M, Gélinas R, Bouchard B, Young ME, Allen BG, et al. Cyclic GMP signaling in cardiomyocytes modulates fatty acid trafficking and prevents triglyceride accumulation. Journal of Molecular and Cellular Cardiology. 2008; 45: 230–239. https://doi.org/10.1016/j.yjmcc.2008.05.012.

[57] Bergandi L, Silvagno F, Russo I, Riganti C, Anfossi G, Aldieri E, et al. Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23: 2215–2221. https://doi.org/10.1161/01.ATV.0000107028.20478.8e.

[58] García-Villafranca J, Guillén A, Castro J. Involvement of nitric oxide/cyclic GMP signaling pathway in the regulation of fatty acid metabolism in rat hepatocytes. Biochemical Pharmacology. 2003; 65: 807–812. https://doi.org/10.1016/s0006-2952(02)01623-4.

[59] Gheibi S, Samsonov AP, Gheibi S, Vazquez AB, Kashfi K. Regulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes. Biochemical Pharmacology. 2020; 176: 113819. https://doi.org/10.1016/j.bcp.2020.113819.

[60] Zhang X, Yang S, Chen J, Su Z. Unraveling the Regulation of Hepatic Gluconeogenesis. Frontiers in Endocrinology. 2019; 9: 802. https://doi.org/10.3389/fendo.2018.00802.

[61] Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, et al. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. The Journal of Clinical Endocrinology and Metabolism. 2015; 100: 4533–4540. https://doi.org/10.1210/jc.2015-3415.

[62] Giannetta E, Isidori AM, Galea N, Carbone I, Mandosi E, Vizza CD, et al. Chronic Inhibition of cGMP phosphodiesterase 5A improves diabetic cardiomyopathy: a randomized, controlled clinical trial using magnetic resonance imaging with myocardial tagging. Circulation. 2012; 125: 2323–2333. https://doi.org/10.1161/CIRCULATIONAHA.111.063412.

[63] Amer MS. Cyclic nucleotides as targets for drug design. Advances in Drug Research. 1977; 12: 1–38. https://doi.org/10.1016/b978-0-12-013312-3.50004-2.

[64] Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nature Reviews. Drug Discovery. 2014; 13: 290–314. https://doi.org/10.1038/nrd4228.

[65] Corbin JD. Mechanisms of action of PDE5 inhibition in erectile dysfunction. International Journal of Impotence Research. 2004; 16 Suppl 1: S4–7. https://doi.org/10.1038/sj.ijir.3901205.

[66] Spina D. PDE4 inhibitors: current status. British Journal of Pharmacology. 2008; 155: 308–315. https://doi.org/10.1038/bjp.2008.307.

[67] Andersson KE. PDE5 inhibitors - pharmacology and clinical applications 20 years after sildenafil discovery. British Journal of Pharmacology. 2018; 175: 2554–2565. https://doi.org/10.1111/bph.14205.

[68] Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacology & Therapeutics. 2006; 109: 366–398. https://doi.org/10.1016/j.pharmthera.2005.07.003.

[69] Kelly ED, Ranek MJ, Zhang M, Kass DA, Muller GK. Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics. Annual Review of Pharmacology and Toxicology. 2025; 65: 415–441. https://doi.org/10.1146/annurev-pharmtox-031524-025239.

[70] Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. Journal of Atherosclerosis and Thrombosis. 2011; 18: 629–639. https://doi.org/10.5551/jat.7922.

[71] Bou Matar D, Zhra M, Nassar WK, Altemyatt H, Naureen A, Abotouk N, et al. Adipose tissue dysfunction disrupts metabolic homeostasis: mechanisms linking fat dysregulation to disease. Frontiers in Endocrinology. 2025; 16: 1592683. https://doi.org/10.3389/fendo.2025.1592683.

[72] Catrysse L, van Loo G. Inflammation and the Metabolic Syndrome: The Tissue-Specific Functions of NF-κB. Trends in Cell Biology. 2017; 27: 417–429. https://doi.org/10.1016/j.tcb.2017.01.006.

[73] Zheng L, Zeng A, Liu L, Tian W, Wang R, Zhang L, et al. Metabolic syndrome: molecular mechanisms and therapeutic interventions. Molecular Biomedicine. 2025; 6: 59. https://doi.org/10.1186/s43556-025-00303-5.

[74] Seo DH, Shin E, Lee YH, Park SE, Nam KT, Kim JW, et al. Effects of a Phosphodiesterase inhibitor on the Browning of Adipose Tissue in Mice. Biomedicines. 2022; 10: 1852. https://doi.org/10.3390/biomedicines10081852.

[75] Chung YW, Ahmad F, Tang Y, Hockman SC, Kee HJ, Berger K, et al. White to beige conversion in PDE3B KO adipose tissue through activation of AMPK signaling and mitochondrial function. Scientific Reports. 2017; 7: 40445. https://doi.org/10.1038/srep40445.

[76] Greene M, Thackeray JT, Kenk M, Thorn SL, Bevilacqua L, Harper ME, et al. Reduced in vivo phosphodiesterase-4 response to acute noradrenaline challenge in diet-induced obese rats. Canadian Journal of Physiology and Pharmacology. 2009; 87: 196–202. https://doi.org/10.1139/y09-001.

[77] Möllmann J, Kahles F, Lebherz C, Kappel B, Baeck C, Tacke F, et al. The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism. Diabetes, Obesity & Metabolism. 2017; 19: 496–508. https://doi.org/10.1111/dom.12839.

[78] Zhang HT. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Current Pharmaceutical Design. 2009; 15: 1688–1698. https://doi.org/10.2174/138161209788168092.

[79] Xu M, Yu X, Meng X, Huang S, Zhang Y, Zhang A, et al. Inhibition of PDE4/PDE4B improves renal function and ameliorates inflammation in cisplatin-induced acute kidney injury. American Journal of Physiology. Renal Physiology. 2020; 318: F576–F588. https://doi.org/10.1152/ajprenal.00477.2019.

[80] Ookawara M, Nio Y, Yamasaki M, Kuniyeda K, Hanauer G, Tohyama K, et al. Protective effect of a novel phosphodiesterase 4 selective inhibitor, compound A, in diabetic nephropathy model mice. European Journal of Pharmacology. 2021; 894: 173852. https://doi.org/10.1016/j.ejphar.2021.173852.

[81] Vollert S, Kaessner N, Heuser A, Hanauer G, Dieckmann A, Knaack D, et al. The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db/db mice. Diabetologia. 2012; 55: 2779–2788. https://doi.org/10.1007/s00125-012-2632-z.

[82] Arcaro CA, Assis RP, Oliveira JO, Zanon NM, Paula-Gomes S, Navegantes LCC, et al. Phosphodiesterase 4 inhibition restrains muscle proteolysis in diabetic rats by activating PKA and EPAC/Akt effectors and inhibiting FoxO factors. Life Sciences. 2021; 278: 119563. https://doi.org/10.1016/j.lfs.2021.119563.

[83] Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 2007; 56: 1025–1033. https://doi.org/10.2337/db06-0883.

[84] Ellati RT, Dokun AO, Kavoussi PK, Steers WD, Annex BH, Lysiak JJ. Increased phosphodiesterase type 5 levels in a mouse model of type 2 diabetes mellitus. The Journal of Sexual Medicine. 2013; 10: 362–369. https://doi.org/10.1111/j.1743-6109.2012.02854.x.

[85] Mishra S, Sadagopan N, Dunkerly-Eyring B, Rodriguez S, Sarver DC, Ceddia RP, et al. Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice. The Journal of Clinical Investigation. 2021; 131: e148798. https://doi.org/10.1172/JCI148798.

[86] Tomaszewski MR, Meng X, Haley HD, Harrell CM, Mcdonald TP, Miller CO, et al. Magnetic resonance imaging detects white adipose tissue beiging in mice following PDE10A inhibitor treatment. Journal of Lipid Research. 2023; 64: 100408. https://doi.org/10.1016/j.jlr.2023.100408.

[87] Cheitlin MD, Hutter AM, Jr, Brindis RG, Ganz P, Kaul S, Russell RO, Jr, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. Technology and Practice Executive Committee. Circulation. 1999; 99: 168–177. https://doi.org/10.1161/01.cir.99.1.168.

[88] Zhang X, Ji J, Yan G, Wu J, Sun X, Shen J, et al. Sildenafil promotes adipogenesis through a PKG pathway. Biochemical and Biophysical Research Communications. 2010; 396: 1054–1059. https://doi.org/10.1016/j.bbrc.2010.05.064.

[89] Yu HM, Chung HK, Kim KS, Lee JM, Hong JH, Park KS. PDE 5 inhibitor improves insulin sensitivity by enhancing mitochondrial function in adipocytes. Biochemical and Biophysical Research Communications. 2017; 493: 631–636. https://doi.org/10.1016/j.bbrc.2017.08.140.

[90] Song DG, Pak S, Shin DC, Soedono S, Cho KW, Park Y, et al. Phosphodiesterase 5 Inhibitor Improves Insulin Sensitivity by Regulating Adipose Tissue Macrophage Polarization in Diet-Induced Obese Mice. Diabetes & Metabolism Journal. 2025. https://doi.org/10.4093/dmj.2024.0308. (online ahead of print)

[91] Swiecicka A. The efficacy of PDE5 inhibitors in diabetic patients. Andrology. 2023; 11: 245–256. https://doi.org/10.1111/andr.13328.

[92] Antinozzi C, Sgrò P, Di Luigi L. Advantages of Phosphodiesterase Type 5 Inhibitors in the Management of Glucose Metabolism Disorders: A Clinical and Translational Issue. International Journal of Endocrinology. 2020; 2020: 7078108. https://doi.org/10.1155/2020/7078108.

[93] Moon KH, Park SY, Kim YW. Obesity and Erectile Dysfunction: From Bench to Clinical Implication. The World Journal of Men’s Health. 2019; 37: 138–147. https://doi.org/10.5534/wjmh.180026.

[94] Johann K, Reis MC, Harder L, Herrmann B, Gachkar S, Mittag J, et al. Effects of sildenafil treatment on thermogenesis and glucose homeostasis in diet-induced obese mice. Nutrition & Diabetes. 2018; 8: 9. https://doi.org/10.1038/s41387-018-0026-0.

[95] Degerman E, Ahmad F, Chung YW, Guirguis E, Omar B, Stenson L, et al. From PDE3B to the regulation of energy homeostasis. Current Opinion in Pharmacology. 2011; 11: 676–682. https://doi.org/10.1016/j.coph.2011.09.015.

[96] Hood WB, Jr. Controlled and uncontrolled studies of phosphodiesterase III inhibitors in contemporary cardiovascular medicine. The American Journal of Cardiology. 1989; 63: 46A–53A. https://doi.org/10.1016/0002-9149(89)90393-7.

[97] Guirguis E, Hockman S, Chung YW, Ahmad F, Gavrilova O, Raghavachari N, et al. A role for phosphodiesterase 3B in acquisition of brown fat characteristics by white adipose tissue in male mice. Endocrinology. 2013; 154: 3152–3167. https://doi.org/10.1210/en.2012-2185.

[98] Härndahl L, Wierup N, Enerbäck S, Mulder H, Manganiello VC, Sundler F, et al. Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology. The Journal of Biological Chemistry. 2004; 279: 15214–15222. https://doi.org/10.1074/jbc.M308952200.

[99] Ahmad F, Chung YW, Tang Y, Hockman SC, Liu S, Khan Y, et al. Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue. Scientific Reports. 2016; 6: 28056. https://doi.org/10.1038/srep28056.

[100] Han P, Werber J, Surana M, Fleischer N, Michaeli T. The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. The Journal of Biological Chemistry. 1999; 274: 22337–22344. https://doi.org/10.1074/jbc.274.32.22337.

[101] Golshiri K, Ataabadi EA, Jüttner AA, Snyder GL, Davis RE, Lin A, et al. The Effects of Acute and Chronic Selective Phosphodiesterase 1 Inhibition on Smooth Muscle Cell-Associated Aging Features. Frontiers in Pharmacology. 2021; 12: 818355. https://doi.org/10.3389/fphar.2021.818355.

[102] Khalsa SS, Victor TA, Kuplicki R, Yeh HW, Vanover KE, Paulus MP, et al. Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology. 2022; 47: 1844–1853. https://doi.org/10.1038/s41386-022-01331-3.

[103] Gyldenløve M, Sørensen JA, Fage S, Meteran H, Skov L, Zachariae C, et al. Effects of oral roflumilast therapy on body weight and cardiometabolic parameters in patients with psoriasis - results from a randomized controlled trial (PSORRO). Journal of the American Academy of Dermatology. 2024; 91: 64–71. https://doi.org/10.1016/j.jaad.2024.02.036.

[104] Muo IM, MacDonald SD, Madan R, Park SJ, Gharib AM, Martinez PE, et al. Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2019; 12: 743–759. https://doi.org/10.2147/DMSO.S182953.

[105] Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. British Journal of Pharmacology. 2010; 159: 842–855. https://doi.org/10.1111/j.1476-5381.2009.00559.x.

[106] Wunder F, Tersteegen A, Rebmann A, Erb C, Fahrig T, Hendrix M. Characterization of the first potent and selective PDE9 inhibitor using a cGMP reporter cell line. Molecular Pharmacology. 2005; 68: 1775–1781. https://doi.org/10.1124/mol.105.017608.

[107] Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, et al. A novel thermoregulatory role for PDE10A in mouse and human adipocytes. EMBO Molecular Medicine. 2016; 8: 796–812. https://doi.org/10.15252/emmm.201506085.

Funding

Italian Ministry of Research(P2022CE79J)