Role of leptin in obesity, cardiovascular disease, and type 2 diabetes

Citation: Vilariño-García, T.; Polonio-González, M.L.; Pérez-Pérez, A.; Ribalta, J.; Arrieta, F.; Aguilar, M.; Obaya, J.C.; Gimeno-Orna, J.A.; Iglesias, P.; Navarro, J.; et al. Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes. Int. J. Mol. Sci. 2024,25, 2338. https:// doi.org/10.3390/ijms25042338 Academic Editors: Antonio Lucacchini and David Della-Morte Received: 29 December 2023 Revised: 7 February 2024 Accepted: 9 February 2024 Published: 16 February 2024 Correction Statement: This article has been republished with a minor change. The change does not affect the scientific content of the article and further details are available within the backmatter of the website version of this article. Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). International Journal of Molecular Sciences Review Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes Teresa Vilariño-García1,†, María L. Polonio-González 2,†, Antonio Pérez-Pérez 2, Josep Ribalta 3, Francisco Arrieta 4, Manuel Aguilar 5, Juan C. Obaya 6, JoséA. Gimeno-Orna 7, Pedro Iglesias 8, Jorge Navarro 9, Santiago Durán10, Juan Pedro-Botet 11 and Víctor Sánchez-Margalet 2,12,* 1Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen del Rocio University Hospital, University of Seville, 41013 Seville, Spain; [email protected] 2Department of Medical Biochemistry and Molecular Biology, and Immunology, School of Medicine, Virgen Macarena University Hospital, University of Seville, 41009 Seville, Spain; [email protected] (M.L.P.-G.); [email protected] (A.P.-P.) 3Departament de Medicina i Cirurgia, University Rovira i Vigili, IISPV, CIBERDEM, 43007 Tarragona, Spain; [email protected] 4Endocrinology and Nutrition Service, Ramón y Cajal University Hospital, 28034 Madrid, Spain; [email protected] 5Endocrinology and Nutrition Service, Puerta del Mar University Hospital, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Cádiz University (UCA), 11001 Cádiz, Spain; [email protected] 6Chopera Helath Center, Alcobendas Primary Care, 28100 Alcobendas, Spain; [email protected] 7Endocrinology and Nutrition Department, Hospital Clinico Universitario Lozano Blesa, 50009 Zaragoza, Spain; [email protected] 8Endocrinology and Nutrition Service, Puerta de Hierro University Hospital, Majadahonda, 28220 Madrid, Spain; [email protected] 9Hospital Clínico Universitario de Valencia, 46011 Valencia, Spain; [email protected] 10 Endodiabesidad Clínica Durán & Asociados, 41018 Seville, Spain; [email protected] 11 Lipids and Cardiovascular Risk Unit, Hospital del Mar, Autonomous University of Barcelona, 08003 Barcelona, Spain; [email protected] 12 Institute of Biomedicine of Seville (IBIS), Hospital Universitario Virgen del Rocío/Virgen Macarena, CSIC, Universidad de Sevilla, 41013 Seville, Spain *Correspondence: mar[email protected] †These authors contributed equally to this work. Abstract: Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90–95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies. Keywords: type 2 diabetes mellitus; obesity; leptin; cardiovascular risk; inflammation Int. J. Mol. Sci. 2024,25, 2338. https://doi.org/10.3390/ijms25042338 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2024,25, 2338 2 of 21 1. Introduction Diabetes mellitus (DM) has evolved into a mounting epidemic over the past century, with a more conspicuous escalation in recent decades driven by the exponential surge in obesity. DM has emerged as one of the foremost global causes of mortality. Presently, it ranks as the seventh leading cause of death in the United States, with 400,000 deaths per year and 5.2 million deaths worldwide [ 1 ]. Type 2 DM (T2DM) arises from inadequate insulin production by the pancreas and insulin resistance [ 2 , 3 ]. The increase in DM prevalence is closely linked to the rise in overweight and obesity conditions. In 2022, the World Heart Federation revealed that 2300 million adults are affected by overweight/obesity, with expected increases even in low- and middle-income countries, primarily due to nutritional transition, i.e., the shift from traditional diets to westernized diets [ 4 ]. Obesity is involved not only in the etiopathogenesis of the most common global DM, T2DM, but also in the development of its complications. However, an increasing number of studies are exploring its role in T1DM as well [5]. Regarding complications in these patients, studies demonstrate that individuals with T2DM carry an elevated risk of cardiovascular disease (CVD) mortality across various ethnic and gender groups compared to those free from this disease. This mortality risk is further exacerbated when obesity coexists. Obesity contributes to 44% of deaths in individuals with T1DM and 52% of deaths in T2DM cases. Common CVD manifestations among people with DM include heart failure (HF), peripheral arterial disease (PAD), and coronary artery disease (CHD) [1,6]. The pathogeneses of DM and obesity share common pathways involving insulin resistance, oxidative stress, and prothrombotic and proinflammatory patterns. In an obese milieu, where overfeeding is stimulated, a disruption in the metabolic equilibrium occurs, resulting in the subsequent deposition of fat in organs not specialized in lipid storage (termed ectopic fat), such as the endothelium, liver, and skeletal muscle. This gives rise to metabolic alterations and disorders, including insulin resistance, atherosclerosis, and T2DM, culminating in cardiovascular, cerebrovascular, and hepatic diseases. Moreover, obesity leads to heightened leptin levels and inflammatory markers such as C-reactive protein (CRP), further exacerbating vascular and myocardial injuries [7]. Leptin is a protein classified within the adipokine family and is currently recognized as a hormone consisting of 167 amino acids with a molecular weight of 16 kD. It is predominantly synthesized in adipocytes, and its production is contingent upon the volume of fat deposits in the body [ 8 , 9 ]. Leptin traverses the blood–brain barrier (BBB) to exert its central action and interact with hypothalamic receptors situated in neurons across various nuclei, including the arcuate, paraventricular, and centromedial ones. The primary site of action is the arcuate nucleus within the hypothalamus, comprising two distinct populations of neurons. One releases neuropeptide Y, constituting the orexigenic pathway (appetite inducer), while the other secretes proopiomelanocortin, forming the anorexigenic pathway (satiety inducer). Numerous studies affirm that leptin inhibits the orexigenic pathway and stimulates the anorexigenic pathway, underscoring its pivotal role in body weight regulation [10–12]. As mentioned earlier, leptin is a hormone capable of effectively reducing food intake and body weight, initially suggesting its potential in obesity treatment. However, it has been observed that obese individuals exhibit high levels of circulating leptin and insensitivity to exogenous leptin administration. The inability of leptin to exert its anorexigenic effects in obese individuals and, consequently, the lack of clinical utility in obesity are defined as leptin resistance. Understanding the molecular mechanisms underlying leptin resistance is crucial for the effective application of leptin in obesity treatment. One key aspect is the necessity for leptin to cross the BBB to reach the hypothalamus and exert its anorexigenic functions. Several mechanisms within this context are not fully understood, and, in recent years, new strategies have been developed to restore the response to leptin in patients with obesity [12]. Int. J. Mol. Sci. 2024,25, 2338 3 of 21 Elevated levels of leptin may function as an indicator of leptin resistance. Mechanisms contributing to leptin resistance include genetic mutations, autoregulation of leptin, restricted tissue access, and molecular/cellular circulatory regulation [ 13 ]. The evidence indicates that central leptin resistance is a key factor in the development of obesity. Concurrently, the resultant leptin resistance associated with obesity can adversely affect various peripheral tissues, including the liver, pancreas, platelets, vasculature, and myocardium. This metabolic and inflammatory damage may arise from either resistance to leptin action in specific tissues or an excess of leptin action attributed to obesity-related hyperleptinemia. Several studies suggest that leptin deficiency poses a notable risk for obesity and CVD. Leptin resistance represents a complex and not fully understood pathophysiological phenomenon, emphasizing the need for further investigation due to its clinical implications [ 12 , 14 , 15 ]. Numerous research findings have established a connection between leptin, its resistance, and diseases like DM and obesity. These conditions often lead to severe complications, such as CVD, making it crucial to conduct comprehensive studies in this area. A deeper understanding of these associations can guide the development of preventive measures for at-risk individuals and potential therapeutic interventions. To contribute to this knowledge, we have reviewed the literature to underscore the potential role of leptin in cardiovascular disease among obese patients with T2DM. 2. Obesity and CVD The prevalence of obesity has surged uncontrollably since the 1960s, as evidenced by long-term follow-up surveys, including the Behavioral Risk Factor Surveillance System, the National Health Interview Survey, and the National Health and Nutrition Examination Survey (NHANES). This increase has reached epidemic proportions since 2008, solidifying its status as one of the paramount global health challenges. The prevalent parameter for assessing overweight and obesity conditions is the body mass index (BMI). Individuals with a BMI ≥ 25 kg/m 2 are categorized as overweight, while those with a BMI ≥ 30 kg/m 2 are classified as obese. However, the BMI scale has notable limitations, such as its inability to account for variations in body composition. Athletes with a higher lean body mass may be overestimated, whereas the elderly with reduced lean mass may be underestimated. Alternative methods for evaluating body composition include waist circumference, waist-to-hip ratio, height, skinfold thickness, and dual-energy X-ray absorptiometry. Waist circumference, specifically, serves as a straightforward and reliable measure for assessing abdominal obesity—an established CVD risk factor independent of BMI. This parameter is particularly valuable for individuals classified as normo- or overweight [16]. Obesity, recognized as a chronic metabolic disease, exerts a substantial impact on the cardiovascular system [ 17 ]. This influence stems from various mechanisms, including hemodynamic alterations, modifications in cardiac structure and function, inflammation, neurohumoral shifts, and cellular remodeling. Collectively, these factors contribute to a reduction in cardiac output, heightened peripheral resistance, augmented left ventricular (LV) mass, thickening of the LV wall, enlargement of internal dimensions, and compromised systolic function of the left ventricle [6,7,18]. Obesity can lead to structural remodeling of the heart, resulting in LV hypertrophy. For every 1 kg/m 2 increase in BMI, the risk of LV hypertrophy increases by 5.1%, and, for every 1 cm increase in waist circumference, the risk of LV hypertrophy increases by 2.6% [19]. Conversely, the enlargement of adipocytes may directly correlate with a phenotypic shift from M2 to M1 macrophages, triggering the production of leptin, angiotensin, proinflammatory cytokines (such as IL-1, TNF- α , and IL-6, etc.), and reactive oxygen species [ 20 ]. Moreover, the progression of inflammation, oxidative stress, and heightened leptin levels in obesity is strongly correlated with the development of CVD and hypertension [ 18 , 21 , 22 ]. Leptin demonstrates pleiotropic effects. In obese individuals, hyperleptinemia is insufficient for preventing the dysregulation of energy balance, suggesting that individuals with obesity may exhibit leptin resistance. Int. J. Mol. Sci. 2024,25, 2338 4 of 21 While most cases of obesity are associated with hypothalamic leptin resistance, the peripheral effects of leptin signaling or leptin resistance in obesity are not fully elucidated. Moreover, the net effects of hyperleptinemia or leptin resistance on CVD in obese individuals are complex and still under investigation. Obesity has been recognized as an independent predictor of CHD, influencing it indirectly through its effects on related comorbidities such as dyslipidemia, hypertension, glucose intolerance, endothelial dysfunction, and inflammation. It is associated with increased arterial stiffness, coronary artery calcification, thickening of the carotid intima-media, and a higher incidence of carotid stenosis, all contributing to premature vascular aging. This leads to an approximately twofold-higher risk of developing heart failure than a subject with a healthy weight. Studies have also shown correlations among stroke and BMI and waist-to-hip ratios. Population-based cohort studies have reported a 49% higher risk of atherosclerosis in obese patients compared to non-obese individuals. This is attributed to the release of proinflammatory adipokines by visceral adipose tissue, increased oxidative stress from heightened free radical production by adipose tissue, impaired autophagy, endothelial dysfunction, and activation of adipose tissue macrophages, T cells, and B cells within fat deposits, all contributing to plaque formation and fibrous lesions [6,7,18]. On the other hand, an obesity paradox emerged from various cross-sectional studies in patients with heart failure, in which a higher survival rate was observed in those who were overweight or obese (BMI > 27.8 kg/m 2 ). Consequently, a follow-up analysis was conducted in patients with chronic heart failure, revealing significantly lower mortality rates in those patients with an elevated BMI. This trend was also observed in cases of sudden cardiac arrest, coronary artery disease, and diabetes. Generally, obese subjects exhibit higher mortality rates; however, paradoxically, a higher mortality is often found in normal-weight patients compared to obese patients. This phenomenon, where survival rates are higher among obese patients, contrary to conventional expectations, is referred to as the “obesity paradox”, and it is most frequently observed in patients with CHD or HF. A possible explanation may be that people with obesity typically also present with an increased amount of lean mass, which is associated with improved cardiorespiratory fitness [23]. The increase in LM may explain part of the obesity paradox as it is associated with improved cardiorespiratory fitness. Nevertheless, the paradox may reflect an epidemiological artifact rather than a true negative association between a normal weight and clinical outcomes [7,18]. Moreover, the World Health Organization defines metabolically healthy obesity as individuals with grade II obesity or higher who do not have DM. Other authors characterize it as obese individuals who do not have DM, hypertension, and/or hyperlipidemia. The definition of metabolically healthy obesity is not well-established, and there is ongoing debate regarding whether it constitutes a genuine entity or a transient phase in the progression of overall obesity [ 24 ]. Furthermore, obesity has recently been found to be an independent risk factor of myocardial fibrosis regardless of metabolic health [25]. Furthermore, the precise contribution of central and visceral obesity to the onset of cardiovascular disease (CVD) is still not fully understood. In a study involving one million men examining the impact of cardiorespiratory fitness and obesity during adolescence on subsequent chronic disability from CVD [ 26 ], it was observed that being overweight or obese was linked to disability across all the examined causes of CVD. These findings imply associations between low levels of cardiorespiratory fitness and obesity and the subsequent risk of chronic disability arising from CVD [27]. 3. Obesity and Diabetes Overweight and obesity are intricate conditions closely linked to T2DM [ 5 , 28 ]. Recently acknowledged as a disease by the World Health Organization (WHO), obesity, but not overweight, is considered a primary catalyst for insulin resistance. This resistance manifests in the liver, white adipose tissue, and skeletal muscle. Consequently, pancreatic beta cells Int. J. Mol. Sci. 2024,25, 2338 5 of 21 respond by inadequately secreting insulin in an attempt to overcome this resistance, a phenomenon observed in the early stages of the disease [28,29]. Given the escalating prevalence of type 2 diabetes mellitus (T2DM), researchers have primarily associated it with the increasing rates of obesity, peripheral insulin resistance, minority ethnic groups, and a family history of T2DM. The World Health Organization’s 2002 STEPS survey revealed a 21.5% prevalence of T2DM and a 54.8% prevalence of obesity. Subsequent surveys in 2013 showed a surge in T2DM prevalence to 45.8%. Projections for 2030 estimate that 552 million people worldwide could be affected by T2DM. In a meta-analysis comparing obese individuals to those with a normal weight conducted in the United States and Europe, obese men exhibited a 7-fold-higher risk, while obese women had a 12-fold-higher likelihood of developing T2DM [1,5]. Moreover, additional studies have demonstrated that the distribution of adipose tissue is a critical independent factor, irrespective of the degree of obesity, in the development of insulin resistance [ 30 ]. The authors conducted a comparison between a group of obese adolescents with a similar adiposity index. Adolescents with an impaired glucose tolerance (IGT) exhibited greater insulin resistance compared to those with a normal glucose tolerance [ 31 ]. Moreover, individuals with an impaired glucose tolerance exhibited elevated intramyocellular lipid content and increased visceral fat deposition, while experiencing a reduction in subcutaneous fat deposition. Ebe D’Adamo et al. [ 32 ] discovered that children with a high proportion of visceral fat and limited abdominal subcutaneous fat demonstrate higher insulin resistance and elevated plasma glucose levels during the second hour of the glucose tolerance test. Additionally, it has been reported that ectopic hepatic fat deposition in obese patients is a significant marker of insulin resistance and glucose dysregulation [ 5 ]. However, there are several additional risk factors for DM aside from obesity [ 5 ]. Thus, insulin resistance is associated with various conditions, including acanthosis nigricans, early puberty, hypertension, dyslipidemia, and polycystic ovary syndrome. Ethnicity also plays a role in the predisposition to type 2 diabetes mellitus (T2DM). The SEARCH study (Type 2 Diabetes Mellitus in Pediatric Age) found a higher predisposition in Native American children, followed by Asian, African American, Hispanic, and, lastly, non-Hispanic white children [33] Family history is a significant factor. In a study conducted by Almiri et al. [ 34 ], over half of the patients with prediabetes and all those with T2DM had a first-degree relative with T2DM. The participants with prediabetes (20%) and DM (70%) also had elevated triglyceride levels. A recent study conducted in Abu Dhabi [ 35 ] involving 216 obese (90%) or overweight (7%) patients found that children with greater height, weight, and waist circumference for their age exhibited higher insulin resistance. Among this group, 7% already had diabetes, 8.2% had impaired glucose tolerance (IGT), and 18.1% had impaired fasting glucose. Adipose tissue serves as an energy depot, controlling lipid mobilization and playing a crucial role in energy regulation and glucose homeostasis. It comprises preadipocytes/adipocyteslike cells, macrophages, endothelial cells, fibroblasts, and leukocytes. Additionally, adipose tissue functions as an endocrine organ by secreting adipokines, such as leptin, adiponectin, resistin, visfatin, apelin, vaspin, hepcidin, chemerin, and omentin. These adipokines exert metabolic effects in muscle, liver, pancreas, and the brain [36]. Recently, studies have highlighted the significance of obesity-induced inflammation in predisposing individuals to develop DM, with this inflammation being mediated by immune cells in local tissues. It is noteworthy that the inflammation triggered by obesity shares many characteristics with inflammation induced by infection, involving both the innate and adaptive immune systems [ 37 , 38 ]. The inflammatory status in obesity may, at least in part, result from the activation of the cells of the immune system by leptin [ 13 , 39 , 40 ], including monocytes, T lymphocytes, and natural killer (NK) cells [41]. The relationship between the immune system, NK cells, obesity, and DM has been previously studied [ 42 ]. Thus, depleting NK cells appears to improve insulin resistance in individuals with a high percentage of body fat. However, in those patients without a Int. J. Mol. Sci. 2024,25, 2338 6 of 21 high-fat diet, NK cell depletion has been shown to have no impact on metabolic outcomes. Consistent with this hypothesis, the opposite approach, expanding NK cells with IL-15, worsens insulin resistance in those subjects with high-fat diets. It has also been observed that, as obesity increases, adipose tissue macrophages are activated, and they have two primary actions [ 42 ]. First, they produce chemokines that attract circulating NK cells, thereby increasing their number in epididymal fat; and second, they synthesize IL-15, activating and expanding NK cells in epididymal fat, further promoting the increase in adipose tissue macrophages (cross-activation). This cycle that is established induces inflammation in obesity and, consequently, insulin resistance through the actions of various mediators in the liver and muscle that release epididymal fat [ 42 ]. In this context, recent data also support the contribution of NK cells of visceral adipose tissue in the low-grade inflammation associated with insulin resistance [43]. 4. Diabetes and CVD In recent decades, DM has steadily increased and has become one of the leading global causes of death [ 1 ]. CVD also poses a significant burden on public health, representing the leading causes of death worldwide. CVD is responsible for approximately 17.9 million deaths annually, constituting 31% of all deaths globally. Consequently, cardiovascular prevention, early detection, and management of established CVD risk factors such as dyslipidemia, T2DM, and hypertension are crucial components of public health policy [ 44 ]. Among patients with T2DM, CVD stands as the leading cause of mortality, contributing to 52% of deaths [ 44 , 45 ]. This outcome is influenced significantly by both genetic and metabolic components. Furthermore, microvascular complications, such as nephropathy, retinopathy, and neuropathy, also play a role in mortality. The prevalent manifestations in these patients encompass heart failure (HF) and peripheral arterial disease (PAD), with coronary heart disease (CHD) following these as a prominent macrovascular disease [ 46 , 47 ]. Consequently, individuals with type 2 diabetes mellitus (T2DM) face an elevated risk of stroke. Within the National Health and Nutrition Examination Survey (NHANES) cohort, 26.3% of strokes were linked to DM, presenting a twofold-higher risk for ischemic stroke and a 50% increase for hemorrhagic stroke. Additionally, these patients experience heightened mortality rates following acute myocardial infarction and hypertension [ 46 , 47 ]. A majority of individuals with T2DM exhibit elevated blood pressure levels. Hypertension and DM are well-established risk factors for CVD. The presence of both conditions further amplifies this risk compared to individuals with either condition alone. This heightened risk is thought to result from a synergistic effect on both large and small blood vessels simultaneously, limiting the potential for compensatory collateralization which protects organs from the adverse consequences of vascular damage. The primary function of vasculature is to deliver oxygen and nutrients to tissues, such as the heart, brain, or kidneys. Functional changes occurring in T2DM and hypertensive conditions significantly alter hemodynamic stress on the heart and other organs, leading to these consequences [ 46 ]. Patients with T2DM commonly exhibit increased arterial stiffness and dysfunction of vascular endothelial cells. Coexistence of hypertension exacerbates this phenomenon. Several mechanisms have been proposed to explain this pathophysiology. Elevated blood glucose is a significant determinant of both arterial stiffness and carotid intima-media thickness, with the latter being a well-established measure of blood pressure-related damage which independently predicts CVD events. Chronic hyperglycemia is associated with the accumulation of advanced glycation end products, contributing to arteriosclerosis. This could elucidate the impact of blood glucose on endothelial function. Additionally, hyperglycemia is associated with oxidative stress, inflammation, the formation of advanced glycation end products, abnormalities in calcium homeostasis, and apoptosis. These factors contribute to the structural remodeling of the heart [ 48 ]. A meta-analysis indicated that patients with T2DM with an increase in carotid intima-media thickness of 0.13 mm are associated with a nearly 40% higher risk of cardiovascular disease compared to control subjects [46]. Int. J. Mol. Sci. 2024,25, 2338 7 of 21 Certain cardiovascular disease (CVD) risk factors, including smoking, hypertension, hypercholesterolemia, or metabolic syndrome, independently contribute to CVD in patients with T2DM. In a study involving 371,221 veterans, it was observed that two-thirds of diagnosed patients with T2DM also had comorbid dyslipidemia and hypertension, conditions whose prevalence was doubled in patients with T2DM compared to those without T2DM [ 49 ]. The presence of metabolic syndrome traits in T2DM further increases the risk of CVD in individuals with chronically elevated blood glucose and impaired plasma glucose homeostasis. Given that excessive visceral fat and ectopic fat are the primary drivers of metabolic syndrome, special attention is recommended for the prevalent subgroup of patients with T2DM who are also viscerally obese and exhibit metabolic syndrome components, as they are considered a high-risk phenotype for adverse CVD outcomes [ 50 ]. Moreover, there are studies indicating that inflammatory markers such as CRP in T2DM can provide prognostic information. Elevated levels of CRP may imply a higher risk of CVD and PAD in these patients [1]. Regarding gender differences in T2DM, specific variations have been highlighted in the Early Rancho Bernardo study [ 51 ]. The study demonstrated that men with T2DM had a 2.4-times-higher risk of ischemic heart disease compared to men without it, while women had a 3.5-times-higher risk, along with higher myocardial infarction mortality, and experienced earlier occurrence [1]. Intensive glycemic control interventions have demonstrated a reduction in the risk of macrovascular complications compared to less intensive strategies. Regarding metformin, there is controversy surrounding its ability to prevent cardiovascular events, as some studies have failed to establish a clear relationship. However, findings from the SPREADDIMCAD trial, which included 304 patients with T2DM and coronary artery disease, confirmed the CVD-protective effect of metformin [ 52 ]. Patients treated with metformin exhibited a 46% risk reduction (p= 0.026) in recurrent CVD events compared to patients treated with sulfonylurea glipizide [44]. Recently, it has been confirmed that new antidiabetic drugs, such as SGLT2 inhibitors and GLP1 antagonists, are effective in reducing CVD consequences, independent of their impact on glucose levels [ 53 ]. Moreover, initiating positive lifestyle changes such as regular exercise, smoking cessation, and adopting a healthy diet at the onset of glucose abnormalities could be beneficial in preventing the development or progression of the disease and reducing the incidence of CVD [ 45 ]. In addition to antidiabetic agents, statins and new drugs that lower LDL levels such as PCSK-9 inhibitors have been reported to improve endothelial dysfunction, contribute to the regression of vascular plaque, and enhance microvascular reactivity in patients with T2DM and dyslipidemia. These findings suggest positive outcomes in terms of CVD morbidity and mortality for this class of drugs [54]. 5. Leptin Leptin, a 16 kDa protein encoded by the obesity gene (ob), was discovered in 1994 and plays a crucial role in the regulation of weight and energy homeostasis [ 8 , 55 ]. Despite its name, derived from the Greek word “leptos”, meaning thin, higher circulating levels of leptin have been observed in obese individuals compared to those with a normal weight [ 56 ]. It functions as a proinflammatory adipokine, contributing to the “low-grade inflammatory state” often seen in overweight and obese patients. Leptin is a key player in the field of immunometabolism [39]. Produced predominantly by subcutaneous white adipose tissue (WAT) rather than visceral adipose tissue [ 57 , 58 ], leptin expression is under the influence of various hormones, including insulin [ 59 ] and glucocorticoids [ 60 , 61 ], with an inverse circadian rhythm. Leptin exhibits autocrine, paracrine, and endocrine signaling capabilities to distant tissues [ 62 – 64 ]. Its secretion follows a circadian pattern, peaking at night and decreasing during the day. Women generally have higher leptin levels than men with the same weight, attributed to their higher percentage of lean body mass [65]. Int. J. Mol. Sci. 2024,25, 2338 8 of 21 Leptin exerts its effects on food intake and energy expenditure by binding to and activating the long form of its membrane receptor (LEPR-B), which is prominently expressed in the hypothalamus and other brain regions, resulting in appetite suppression. For this action, leptin needs to traverse the blood–brain barrier (BBB). As a result, leptin is classified as an “anorexigenic” hormone, promoting a reduction in appetite. However, in obese individuals, there is often a condition of hyperleptinemia due to leptin resistance, and, conversely, where leptin resistance is present, it can contribute to elevated leptin levels [ 66 , 67 ]. This intricate interplay highlights the complexities associated with the role of leptin in obesity and its impact on metabolic regulation. Leptin is implicated in CVD events, and hyperleptinemia has been linked to the presence and severity of coronary heart disease (CHD) and HF [ 18 , 68 – 70 ]. Additionally, leptin plays a significant role in reproductive processes [ 18 , 71 – 74 ]. The diverse roles of leptin in both cardiovascular health and reproduction underscore its multifaceted impact on various physiological functions within the body. Various studies have shown that circulating leptin concentrations decrease during fasting or energy restriction but increase during overfeeding as well as during surgical stress. These findings highlight the dynamic regulation of the leptin signaling system by different pathways to maintain body mass [12]. The leptin receptor LepR is expressed in various tissues, including adipose tissue, heart, muscle, lung, small intestine, liver, and the central nervous system, particularly the hypothalamus [ 75 ]. This widespread expression of leptin receptors facilitates the pleiotropic effects of leptin. Typically, leptin is released from adipocytes into the bloodstream, crosses the blood–brain barrier, and reaches specific areas of the brain, particularly the hypothalamus, which is involved in the regulation of energy balance [11]. LepR belongs to the type I cytokine receptor family, and t has six subtypes obtained through splicing (ranging from LepRa to LepRf) [ 76 ]. Following LepR autophosphorylation, leptin signaling takes place, triggering the Janus kinase (JAK) tyrosine kinase pathways and the signal transducer and activator of transcription (STAT), insulin receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and adenosine 5 ′ -monophosphate-activated protein kinase (AMPK) pathways [ 77 , 78 ]. The activation of each of these pathways contributes to the anorexigenic effects of leptin (appetite suppression, weight loss stimulation, and increased thermogenesis) [79–81]. Insulin serves as the primary regulator of leptin production. Prolonged elevation in insulin levels leads to an increase in leptin concentration, although this effect has only been demonstrated with prolonged insulin elevation [12]. LepRa can activate MAPK, IRS1, and PI3K [ 82 , 83 ], but LepRb (long isoform, also known as OB-R) is the only one capable of mediating intracellular JAK/STAT signaling, a very important pathway in energy homeostasis [ 84 ]. After LepR binds to leptin, LepR undergoes a conformational change, crucial for leptin signaling and the activation of JAK2, which autophosphorylates and phosphorylates tyrosine residues in the intracellular domain of functional LepR, allowing the binding of STAT proteins and their subsequent tyrosine phosphorylation, dimerization, and translocation to the nucleus, where they act as transcription factors (forming a dimer which enters the nucleus to regulate the expression of genes which govern food intake) [ 77 , 85 ]. The suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) can negatively regulate the JAK/STAT pathway, suppressing it, leading to negative feedback within this signaling pathway [86,87]. Another signaling pathway of the leptin receptor involves MAPK or ERK. Leptin binding results in the phosphorylation of protein tyrosine phosphatase 2 (SHP2) containing SH2, and growth factor receptor-bound protein 2 (Grb2) activates ERK. Likewise, JAK2 activates signaling through Grb2 and SHP2. LepR activation facilitates interaction and the formation of JAK2/IRS1 complexes to regulate protein kinase B (Akt) from PI3K, which is a dimer and has a component which regulates this signaling by acting as a catalyst [ 83 , 88 ]. Int. J. Mol. Sci. 2024,25, 2338 9 of 21 The JAK2/STAT3 pathway is primarily responsible for regulating changes in gene expression, while the PI3K pathway plays a significant role in the acute effects of leptin, producing rapid cellular responses by promoting changes in ion channels and, therefore, cellular activity, such as the regulation of food intake and blood pressure. The JAK/STAT3, MAPK, and PI3K pathways via SH2-B collectively appear to regulate energy balance [76,89] (Figure 1). Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 9 of 22 JAK/STAT pathway, suppressing it, leading to negative feedback within this signaling pathway [86,87]. Another signaling pathway of the leptin receptor involves MAPK or ERK. Leptin binding results in the phosphorylation of protein tyrosine phosphatase 2 (SHP2) containing SH2, and growth factor receptor-bound protein 2 (Grb2) activates ERK. Likewise, JAK2 activates signaling through Grb2 and SHP2. LepR activation facilitates interaction and the formation of JAK2/IRS1 complexes to regulate protein kinase B (Akt) from PI3K, which is a dimer and has a component which regulates this signaling by acting as a catalyst [83,88]. The JAK2/STAT3 pathway is primarily responsible for regulating changes in gene expression, while the PI3K pathway plays a significant role in the acute effects of leptin, producing rapid cellular responses by promoting changes in ion channels and, therefore, cellular activity, such as the regulation of food intake and blood pressure. The JAK/STAT3, MAPK, and PI3K pathways via SH2-B collectively appear to regulate energy balance [76,89] (Figure 1). Figure 1. Signal transduction of leptin receptor. Leptin signaling is based on the autophosphorylation of the leptin receptor, triggering the JAK2-STAT3, IRS/PI3K, MAPK-ERK, and AMPK pathways. JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; PDE, phosphodiesterase; Akt, protein kinase B; SHP2, tyrosine-protein phosphatase 2 containing SH2; Grb2, growth factor receptor-bound protein 2; MAPK, mitogen-activated protein kinase; PTP, tyrosine-protein phosphatase; STAT, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; SOCS3, cytokine signaling 3 suppressor; AMPK, 5′-adenosine monophosphate-activated protein kinase. The regulation of AMPK by the leptin receptor is tissue-specific [90]. Thus, in the hypothalamus, leptin inhibits AMPK to reduce appetite [91], whereas leptin stimulates AMPK activity in skeletal muscle, increasing fatty acid oxidation [92]. In fact, AMPK is pivotal in energy homeostasis and in the majority of diseases associated with metabolic Figure 1. Signal transduction of leptin receptor. Leptin signaling is based on the autophosphorylation of the leptin receptor, triggering the JAK2-STAT3, IRS/PI3K, MAPK-ERK, and AMPK pathways. JAK, Janus kinase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; PDE, phosphodiesterase; Akt, protein kinase B; SHP2, tyrosine-protein phosphatase 2 containing SH2; Grb2, growth factor receptor-bound protein 2; MAPK, mitogen-activated protein kinase; PTP, tyrosine-protein phosphatase; STAT, signal transducer and activator of transcription; ERK, extracellular signal-regulated kinase; SOCS3, cytokine signaling 3 suppressor; AMPK, 5 ′ -adenosine monophosphate-activated protein kinase. The regulation of AMPK by the leptin receptor is tissue-specific [ 90 ]. Thus, in the hypothalamus, leptin inhibits AMPK to reduce appetite [ 91 ], whereas leptin stimulates AMPK activity in skeletal muscle, increasing fatty acid oxidation [ 92 ]. In fact, AMPK is pivotal in energy homeostasis and in the majority of diseases associated with metabolic syndrome, such as diabetes, obesity, hypertension, etc., and this is why AMPK-activating drugs reverse many of the metabolic defects associated with insulin resistance [93]. In the hypothalamus, leptin interacts with a receptor, suppressing hunger and stimulating satiety. Some of these interactions involve neuropeptide Y (a hunger promoter) or proopiomelanocortin (POMC) neurons by binding to the same type of receptors. Here, these neurons are also targeted by insulin; thus, the actions of leptin and insulin are interconnected and contribute to desirable metabolic control. Insulin is responsible for maintaining proper energy storage and utilization, while leptin reduces the ongoing energy intake. Therefore, both are necessary for the central regulation of energy expenditure and glucose homeostasis [ 94 ]. Additionally, leptin enhances the synthesis of the alpha-melanocyte- Int. J. 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