Obesity as a Complex Long-Term Disease: Molecular Causes, Whole-Body Effects, and New Digital Treatments

The relationship between obesity and hypertension is well established, with estimates indicating that obesity accounts for approximately 65–78% of cases of essential hypertension [10]. The mechanisms underlying obesity-related hypertension include insulin- and leptin-mediated activation of the sympathetic nervous system, which in turn stimulates the renin–angiotensin–aldosterone system (RAAS) and promotes renal sodium retention. Additionally, adipose tissue directly contributes to RAAS activation by increasing the production of angiotensinogen, angiotensin II, aldosterone, and pro-inflammatory cytokines.

Enhanced renal sodium reabsorption shifts the pressure natriuresis curve to the right, meaning that higher arterial pressure is required to excrete sodium and maintain fluid balance. This explains the sodium sensitivity observed in many obese individuals with hypertension and often necessitates the use of diuretic therapy. These interconnected pathophysiological mechanisms help explain why hypertension is one of the most common and clinically significant cardiovascular complications associated with obesity [11].

Dyslipidemia is a major contributor to the development of atherosclerotic CVD in individuals with obesity [12]. Numerous clinical trials, as well as Mendelian randomization studies, have demonstrated a causal role of apolipoprotein B (apoB)-containing lipoproteins in the initiation of atherosclerosis [13]. This process often begins early in life, with the uptake of cholesterol esters by macrophage-derived foam cells and their subsequent deposition within the vessel wall, leading to the formation of fatty streaks—a phenomenon that is accelerated by obesity-related insulin resistance (IR) and chronic inflammation.

Obesity is associated with the presence of overt atherosclerotic lesions even after adjusting for traditional metabolic risk factors such as hypertension, dyslipidemia, and hyperglycemia. Visceral adiposity, in particular, promotes systemic and vascular inflammation, which plays a key role in all stages of atherosclerosis, from the development of fatty streaks to plaque instability, rupture, and thrombosis [6].

IR, commonly seen in obesity, contributes to an atherogenic lipid profile characterized by elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, and an increased proportion of small, dense low-density lipoprotein (LDL) particles. This dyslipidemia is a central component of the metabolic syndrome. Additionally, endothelial dysfunction driven by decreased nitric oxide bioavailability in the context of oxidative stress and inflammation further accelerates atherogenesis [14,15].

Carotid intima-media thickness, a recognized early marker of atherosclerosis, has been consistently associated with chronic obesity, particularly with elevated body weight persisting from childhood through adulthood. This emphasizes the long-term vascular consequences of sustained excess adiposity [6].

HF and obesity are complex, frequently interrelated conditions. Obesity is present in approximately one-third of patients with HF and is even more prevalent among those with HF with preserved ejection fraction (HFpEF) [16,17]. Notably, the risk of incident HF increases by 41% for every 5-unit increase in BMI [18].

From a hemodynamic perspective, obesity leads to increased central blood volume and stroke volume, resulting in elevated cardiac output proportional to the degree of obesity. These changes promote structural cardiac adaptations, including left ventricle (LV) dilatation and compensatory hypertrophy. Additionally, obesity is associated with lower levels of brain natriuretic peptide, and the degradation of natriuretic peptides by adipose tissue contributes to plasma volume expansion and reduced ventricular compliance—key features in the pathophysiology of HFpEF.

Studies suggest that obesity-related HFpEF presents distinct phenotypic characteristics, such as more extensive biventricular remodeling, right ventricular dysfunction, impaired pulmonary vasodilation, pericardial restraint, and reduced exercise tolerance. Furthermore, atherosclerotic CVD associated with obesity may lead to LV systolic dysfunction, resulting in HF with reduced ejection fraction. Comorbid conditions commonly linked to obesity, such as obstructive sleep apnea (OSA) and obesity hypoventilation syndrome, further increase the risk of pulmonary hypertension and right ventricular failure [19].

Beyond structural abnormalities, metabolic dysfunctions induced by obesity—including IR and chronic systemic inflammation—play a significant role in the development and progression of HF [20]. These mechanisms underscore that obesity is not merely a risk factor but a central pathophysiological driver of multiple HF phenotypes. Therefore, addressing obesity is essential in both the prevention and effective management of HF and related cardiovascular diseases.

Insulin is a peptide hormone secreted by pancreatic β-cells in response to circulating levels of glucose and fatty acids. Its primary metabolic role is the maintenance of glucose and lipid homeostasis. Following food intake, elevated blood glucose levels stimulate insulin secretion. Insulin exerts its effects by binding to receptors on target cells, particularly within skeletal muscle, adipose tissue, and the liver. This interaction facilitates glucose uptake into cells, where it is utilized for energy metabolism, fatty acid synthesis, and protein synthesis [21].

IR, also referred to as impaired insulin sensitivity, is characterized by a diminished biological response of target tissues—primarily the liver, muscle, and adipose tissue—to insulin stimulation [22]. In insulin-resistant states, cells fail to respond adequately to insulin, impairing glucose uptake and resulting in elevated circulating glucose levels. To compensate, pancreatic β-cells increase insulin secretion, marking the onset of hyperinsulinemia. As IR persists over time, β-cells are chronically stimulated to produce insulin in excess. This compensatory mechanism, sustained over months or years, leads to β-cell dysfunction and eventual exhaustion, contributing to chronic hyperglycemia [21].

Obesity is a major contributor to the development of IR, with over 80% of obese individuals exhibiting some degree of IR during their lifetime [23]. The pathophysiological link between obesity and IR involves adipocyte dysfunction and activation of the innate immune response. Adipocyte cell death in obesity releases damage-associated molecular patterns, including intracellular molecules and extracellular matrix components, which act as endogenous danger signals. These molecules activate Toll-like receptors, initiating an inflammatory cascade characterized by increased expression of pro-inflammatory genes aimed at tissue repair [24].

Notably, in humans, alterations in glucose metabolism—manifested by elevated blood glucose levels, reduced insulin sensitivity, and compensatory hyperinsulinemia—can be observed up to 13 years prior to the clinical diagnosis of T2DM [21].

The global surge in obesity is undeniably contributing to the increasing prevalence of T2DM, a chronic and progressive metabolic disorder characterized by the body's inability to produce sufficient insulin or to effectively utilize the insulin it produces. This dysfunction leads to elevated blood glucose levels (hyperglycemia), the hallmark of the disease. T2DM is now recognized as one of the most rapidly escalating global health emergencies of the 21st century [25].

Irrespective of the subtype, the sharp rise in obesity rates has been identified as a key factor in the parallel increase in diabetes mellitus (DM), which currently affects approximately 10.5% of the global population. Alarmingly, the incidence of DM among younger populations is also rising significantly [25,26]. T2DM, which accounts for over 90% of all diabetes cases worldwide, is strongly associated with overweight and obesity, aging, ethnicity, and a family history of diabetes. The disease is primarily driven by relative insulin deficiency caused by pancreatic β-cell dysfunction and peripheral IR [25].

While the immediate consequence of obesity may appear to be excessive weight gain, its long-term impact is more insidious. Progressive weight gain serves as a precursor to a variety of metabolic disorders, among which T2DM is particularly prominent. In T2DM, chronic hyperglycemia arises from reduced insulin sensitivity, primarily due to the loss of functional β-cell mass. Obesity significantly contributes to both the onset and progression of T2DM through mechanisms such as enhanced genetic and epigenetic susceptibility, microenvironmental changes that impair insulin signaling, β-cell dysfunction, and alterations in the microbiome–gut–brain axis.

The pathogenesis of T2DM also includes a substantial inflammatory component, which drives the progressive decline in β-cell insulin secretion alongside persistent IR [27]. This inflammation impacts early β-cell development and function, positioning overweight and obesity as potent accelerators of the disease process [28]. A significant proportion of individuals with obesity experience an intermediate phase known as "prediabetes" before progressing to overt hyperglycemia [29]. Although prediabetes is not classified as a distinct clinical entity, it represents a critical warning stage that warrants early intervention and comprehensive screening for T2DM and cardiovascular risk factors. Prediabetes is strongly associated with central obesity, hyperlipidemia, and hypertension [29].

In addition to those already diagnosed with T2DM, a large segment of the global population remains at high risk of future disease development due to impaired glucose tolerance or impaired fasting glucose. Notably, the progression to T2DM in these individuals is, in many cases, preventable through timely intervention. T2DM is both preventable and manageable through patient education, behavioral and lifestyle modifications, appropriate pharmacological treatment, and continuous medical support. Emerging evidence also supports the possibility of disease remission in certain cases [25]. However, the unpredictable nature of disease onset and the variable duration of the prediabetic phase mean that approximately 30–50% of individuals remain undiagnosed until complications arise and therapeutic intervention becomes necessary [25].

Obesity not only contributes to IR but may also precipitate early β-cell failure in some individuals with T2DM. Unfortunately, current pharmacological therapies have not demonstrated the ability to halt the progressive decline in β-cell function over time [26]. Interestingly, in a subset of individuals, T2DM may precede obesity. In these cases, inherent IR results in increased hepatic glucose production and compensatory hyperinsulinemia, which in turn may contribute to subsequent weight gain and the onset of obesity [30].

Obesity, particularly central (visceral) adiposity, is strongly associated with the development of atherogenic dyslipidemia. This dyslipidemic profile is typically characterized by elevated plasma triglyceride levels, reduced concentrations of high-density lipoprotein cholesterol (HDL-C), and the predominance of small, dense LDL particles [31]. It is estimated that approximately 60–70% of individuals with obesity exhibit abnormal lipid profiles, including increased serum triglycerides, very low-density lipoproteins, apolipoprotein B, and non-HDL cholesterol, accompanied by reduced HDL-C levels.

Although total LDL cholesterol levels may not always be markedly elevated in individuals with obesity, a qualitative shift in LDL subfractions is frequently observed. Specifically, there is an increased prevalence of small, dense LDL particles, which are considered particularly atherogenic due to several properties: they are more susceptible to oxidative modification, exhibit enhanced uptake by macrophages, more readily penetrate the arterial intima, and demonstrate reduced affinity for LDL receptors, leading to prolonged plasma residence time [32,33].

The pathogenesis of these lipid abnormalities is multifactorial and closely linked to the metabolic disturbances characteristic of obesity. Central among these are increased fluxes of free fatty acids and triglycerides from hypertrophied adipose tissue to the liver, systemic IR, and adipocyte dysfunction. The latter is marked by reduced secretion of adiponectin and elevated levels of pro-inflammatory cytokines such as TNF-α and IL-6 [7,34]. This pro-inflammatory state contributes both to hepatic overproduction of atherogenic lipoproteins and impaired clearance of circulating lipids, thereby promoting the dyslipidemic phenotype commonly observed in obesity-related metabolic disorders [35].

Epidemiological studies consistently demonstrate that individuals with general or abdominal obesity have a significantly higher risk—estimated to be two- to threefold—of developing dyslipidemia compared to non-obese counterparts. These findings underscore the pivotal role of excess adiposity in the disruption of lipid metabolism and the consequent elevation of cardiovascular risk [33].

From an epidemiological perspective, individuals with obesity and diabetes exhibit a significantly higher risk and mortality rate for various types of cancer [36]. A growing body of evidence links adult obesity to an increased incidence of numerous malignancies, including endometrial, postmenopausal breast, ovarian, esophageal adenocarcinoma, gastric cardia, colorectal, pancreatic, liver, gallbladder, kidney, thyroid, and prostate cancers, as well as non-Hodgkin's lymphoma and multiple myeloma [37,38]. Among these, the most pronounced associations are observed for endometrial and esophageal adenocarcinomas, where the relative cancer risk in obese individuals exceeds four times that of individuals with normal BMI [38,39,40].

Obesity profoundly alters the metabolic and functional landscape of adipose tissue. These changes disturb the secretion profile of the tissue, increasing the production of hormones, adipokines, inflammatory cytokines, growth factors, enzymes, and free fatty acids [41]. These secreted molecules—collectively known as adipose-derived factors—play a central role in cancer initiation and progression by promoting cellular metabolic reprogramming [42]. The role of dysfunctional adipose tissue in supporting tumorigenesis is increasingly recognized as a critical element in cancer biology.

Moreover, dynamic interactions between adipocytes and cancer cells further contribute to the remodeling of adipose tissue. This bidirectional crosstalk induces both morphological and functional changes, impairing normal endocrine and paracrine signaling [43]. In an obese state, adipose tissue homeostasis is disrupted, facilitating the release of molecules that fuel the heightened metabolic and energetic demands of cancer cells [42,44].

During direct interaction with tumor cells, adipocytes undergo phenotypic transformation, including delipidation, driven by cancer-derived bioactive factors. This process markedly reduces the expression of key adipocyte markers, such as adiponectin, leptin (LEP), and fatty acid-binding protein 4 [42,44]. As a result, adipocytes acquire a fibroblast-like morphology and are termed cancer-associated adipocytes (CAAs) [45]. Sustained exposure to tumor-derived paracrine signals stimulates CAAs to secrete free fatty acids, inflammatory mediators, adipokines, and growth factors. These factors collectively contribute to the formation of a tumor-supportive microenvironment that plays an essential role in cancer development and progression [42].

Sleep deprivation has become increasingly prevalent in today's around-the-clock society, with growing evidence indicating its significant impact on overall health. Among the most common and serious sleep disorders is OSA, which is estimated to affect nearly one billion individuals worldwide [46]. OSA is defined by recurrent collapse of the pharyngeal airway during sleep, resulting in impaired gas exchange—specifically hypoxemia and hypercapnia—and intermittent surges in catecholamines and other counter-regulatory hormones [47].

Obesity is a well-recognized and modifiable risk factor for OSA, playing a key role in both its development and severity. The prevalence of OSA among individuals with obesity is nearly twice as high as in those of normal weight [48]. Epidemiological data show that up to 40% of obese individuals, and approximately 70% of those diagnosed with OSA, are classified as obese [48,49].

This association is largely driven by both mechanical and metabolic consequences of excess adipose tissue. Fat accumulation in the cervical and abdominal regions increases upper airway resistance through direct anatomical compression and by reducing lung volume. These changes contribute to airway collapsibility during sleep by diminishing caudal traction on the upper airway structures [49].

In addition to mechanical effects, obesity induces hormonal and inflammatory alterations that further exacerbate OSA. Dysregulation of adipokines—particularly leptin, adiponectin, and ghrelin—affects respiratory control, energy balance, and systemic inflammation. Leptin resistance and decreased adiponectin levels, commonly observed in individuals with obesity, impair neuromuscular control of the upper airway, thereby contributing to the pathogenesis of OSA [48,49].

The clinical relevance of this relationship is underscored by findings from the SLEEP-AHEAD study, which revealed that 86.6% of obese patients with T2DM had OSA. Furthermore, clinically significant OSA, defined by an Apnea Hypopnea Index (AHI) score greater than 15 events per hour, was diagnosed in over half of this cohort (53.1%) [38,50].

Encouragingly, even modest weight loss has been shown to produce meaningful improvements in OSA severity. Reductions in body weight are associated with significant decreases in the AHI score, emphasizing the central role of weight management in the prevention and treatment of OSA [48].

The global rise in obesity has been closely linked to an increasing prevalence of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), now considered the most common liver pathology associated with excess body weight [51,52]. MASLD represents a systemic metabolic condition frequently accompanied by IR, as well as both hepatic and systemic inflammation. Although simple hepatic steatosis remains its most prevalent form, approximately 10–20% of affected individuals develop non-alcoholic steatohepatitis, characterized by hepatic inflammation and progressive fibrosis. In a subset of patients, this condition can further evolve into advanced liver disease, including cirrhosis and hepatocellular carcinoma (HCC) [53].

In response to the multifactorial pathogenesis of fatty liver disease, the term metabolic-associated fatty liver disease has been proposed to more accurately encompass the metabolic dysfunctions underlying the condition [51,52]. Obesity is also recognized as an independent risk factor for HCC, particularly among individuals of European descent, with meta-analyses indicating that it approximately doubles the risk of developing this malignancy [54]. However, in the context of chronic hepatitis C virus infection, the relationship between obesity or BMI and HCC risk appears less consistent, with several studies reporting no significant association [55,56].

For many years, obesity has been regarded as a protective factor against osteoporosis, largely due to its positive association with bone mineral density (BMD), particularly at weight-bearing sites such as the lumbar spine and femoral neck. This assumption has been incorporated into clinical risk assessment models, including the Fracture Risk Assessment Tool—FRAX, where higher BMI is associated with a reduced estimated risk of fracture [57].

However, emerging epidemiological and clinical data increasingly challenge this paradigm, suggesting that the relationship between obesity and bone health is more nuanced. While obesity may confer protection against certain fracture types, it may simultaneously increase the risk of others, depending on skeletal site and individual characteristics [58].

Biochemical studies indicate that obese individuals tend to exhibit lower levels of bone turnover markers—particularly those related to bone resorption—suggesting a reduction in bone remodeling activity [58]. One proposed mechanism involves the accumulation of adipose tissue within the bone marrow, a phenomenon that increases with age and systemic adiposity. This shift is thought to result from mesenchymal stem cells favoring adipogenic differentiation at the expense of osteogenesis [58,59,60].

Moreover, the distribution of adipose tissue appears to be a key determinant of its impact on bone. VAT has been identified as an independent negative predictor of both bone turnover and microarchitectural quality, even when controlling for total BMI. In contrast, subcutaneous fat may exert a neutral or even protective effect on skeletal integrity [61,62].

Adipose tissue-derived hormones also play a significant role in bone metabolism. In obese individuals, elevated estrogen levels—primarily resulting from increased aromatase activity in adipose tissue—are thought to reduce bone resorption and promote bone formation, thereby exerting a protective effect on BMD [63]. However, the role of leptin remains controversial. While in vitro studies suggest a stimulatory effect on osteoblast activity and inhibition of osteoclast genesis, in vivo findings in both animal models and humans have produced inconsistent results [64].

Adiponectin, another key adipokine, has been shown to exert a beneficial influence on bone through both in vitro and in vivo models. Notably, its levels are typically reduced in individuals with obesity, potentially diminishing its positive skeletal effects [60].

Although obesity is frequently associated with higher BMD, particularly in individuals with greater lean mass [65,66], this does not necessarily translate into improved bone strength or reduced fracture risk. The net effect of obesity on bone health is modulated by several interacting factors, including fat distribution, systemic inflammation, and hormonal milieu. As such, obesity should not be regarded as uniformly protective against osteoporosis.

Despite decades of research, the underlying causes of obesity remain a topic of intense debate, often framed as the interplay between genetic predisposition and lifestyle factors. Genetic and epigenetic studies have provided a better understanding of the biological mechanisms underlying this phenomenon. One of the most popular indicators used to describe overweight is BMI [67].

A meta-analysis from 2022 has shown that BMI depends on additive genetic and environmental factors [67].

Epigenetics involves changes in gene expression unrelated to DNA sequence modifications [68], but rather to processes such as DNA methylation, histone modifications, and microRNA activity [68,69].

Environmental factors, including maternal diet and exposure to toxins, have been shown to lead to permanent epigenetic changes and an increased risk of obesity in offspring [68,70].

Furthermore, diet or smoking can alter DNA methylation and histone modifications, impacting genes involved in appetite regulation, lipid metabolism, and insulin sensitivity [67].

Obesity is usually polygenic in nature, which means that it depends on cumulating numerous genetic variants with small effects [71]. Modern GWAS studies have detected many single-nucleotide polymorphisms associated with obesity, which can be included in the group named polygenic risk score (PRS) [69,72]. Research shows that children with the highest PRS have a significantly increased risk of obesity, especially in unfavorable environments (e.g., lack of physical activity, diet) [69].

Although rare monogenic obesity syndromes (e.g., those caused by mutations in the LEP gene, leptin receptor gene (LEPR), melacortin 4 receptor (MC4R), and fat mass and obesity-associated gene (FTO)) provide valuable information about the pathways regulating body weight [73,74]. Characteristic features include early onset, lack of satiety, and often autosomal recessive inheritance (as a Bardet–Biedel Syndrome) [73,74,75].

In some cases, causal treatment such as leptin therapy [73] or MC4R agonists is possible; this will be discussed in more detail in the following chapter.

The FTO gene is one of the first genes found to be associated with obesity [11,12]. Its relationship with BMI was primarily identified and published by GWAS in 2007 [76]. The rs9939609 polymorphism in intron 1 of the FTO gene has a strong association with BMI, body weight, and obesity risk in multiple populations. In the 2007 study by Frayling et al., adults homozygous for the risk allele (≈16% of participants) weighed on average about 3 kg more and had 1.67-fold increased odds of obesity compared to those without the allele [71].

The effect of FTO may be partially modulated by environmental factors such as physical activity and diet [73].

The MC4R is a brain-expressed G-protein-coupled receptor that regulates appetite in the hypothalamus [75]. Mutations in this gene are one of the most common causes of monogenic obesity, and together with the genes encoding leptin and LEPR, MC4R explains 30% of extreme obesity in children [73]. Those with an MC4R mutation often exhibit hyperphagia and weight gain in childhood [73].

Leptin is a satiety hormone produced mainly by adipose tissue at levels proportional to fat mass and encoded by the LEP gene [75]. Mutations in LEP or LEPR lead to severe, early-onset obesity [73,77].

Recombinant leptin treatment has been shown to be effective in patients with leptin deficiency [77].

The etiology of obesity has traditionally been attributed to an imbalance between energy intake and expenditure, namely excessive caloric consumption and insufficient physical activity. However, this paradigm alone does not adequately account for the rapid global rise in obesity prevalence. Emerging evidence highlights the role of additional environmental factors, including alterations in gut microbiome composition [78], psychological stress [79], exposure to obesogenic chemicals [80], and dietary patterns [81], which collectively contribute to the complex pathophysiology of obesity.

Obesogens are endocrine-disrupting chemicals with obesogenic potential [82]. These chemicals promote adipogenesis and fat storage, disrupt appetite regulation, or alter energy metabolism, predisposing individuals to obesity [83]. Common sources include industrial chemicals (e.g., Bisphenol A (BPA), phthalates, perfluorooctanoic acid), agricultural and marine chemicals (e.g., tributyltin), food additives, certain preservatives, artificial sweeteners, and packaging-related compounds [84].

Obesogens act through multiple mechanisms, such as binding to nuclear receptors (e.g., peroxisome proliferator-activated receptor gamma [PPARγ]), and are a key regulator of fat cell differentiation, thereby stimulating adipocyte formation [82,83]. Others disrupt hormonal signals, leading to disturbed energy balance, or promote epigenetic modifications, such as DNA methylation [83]. Obesogens may also alter gut microbiome composition [83].

The timing of exposure is particularly important. Sensitive windows such as prenatal life, childhood, and adolescence appear to heighten vulnerability [85]. Researchers have shown an association between prenatal exposure to BPA and increased adiposity in children [84,86].

Another environmental factor related to obesity is a diet high in processed food, which is a source of obesogens (e.g., BPA) [85]. Furthermore, a high-fat diet activates inflammatory pathways (primarily nuclear factor kappa B), induces oxidative stress, and promotes IR [81,87]. Long-term consumption of simple sugars may lead to epigenetic modification of genes responsible for lipogenesis (e.g., SREBP-1c, FASN) and adipogenesis [85,88].

Gut microbiota dysbiosis refers to reduced microbial diversity and a decrease in bacteria-producing short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate; it leads to a weakened intestinal barrier, increased lipopolysaccharide penetration, and the activation of inflammation and IR [78,89].

SCFAs also perform signaling functions, including through GPR41/GPR43 receptors, influencing energy homeostasis and hormone secretion (GLP-1, PYY) [89]. Studies indicate that changes in the Firmicutes/Bacteroidetes ratio reduce the production of butyrate and other SCFAs, resulting in metabolic endotoxemia [78,87,88,89].

Insulin regulates systemic energy balance through distinct signaling cascades that control glucose, lipid, and protein metabolism. Upon insulin binding to its receptor, insulin receptor substrates (IRS) are phosphorylated and serve as key adaptor molecules that initiate downstream signaling [90,91]. Its primary actions are mediated by the PI3K-Akt pathway, which promotes glucose uptake, glycogen and lipid synthesis, and suppression of hepatic gluconeogenesis, and the Ras-MAPK pathway, which regulates growth and gene expression [90,91,92,93,94]. Crosstalk with nutrient and energy sensors, such as AMP-activated protein kinase (AMPK) and mTOR, further integrates anabolic and catabolic processes [80,95,96]. In insulin-sensitive WAT, the liver, and skeletal muscle, these pathways maintain metabolic flexibility and fuel homeostasis. However, selective impairment of IRS-PI3K-Akt signaling leads to reduced glucose disposal in muscle, enhanced lipolysis in WAT, and excessive gluconeogenesis in the liver, driving systemic IR [90,91,97,98]. The tissue-specific impairments and metabolic consequences are summarized in Table 1.

Understanding these tissue-specific mechanisms provides a foundation for targeted therapeutic strategies.

In white adipose tissue (WAT), insulin's principal role is to suppress lipolysis, thereby limiting the release of gluconeogenic substrates, notably free fatty acids, which otherwise fuel hepatic glucose production [92,95]. This antilipolytic effect is mediated through the PI3K-Akt pathway, which activates phosphodiesterase 3B (PDE3B), lowering intracellular cAMP and protein kinase A (PKA) activity [80,94]. Further modulation occurs via protein phosphatases such as PP1 and PP2A, which dephosphorylate lipolytic regulators, reinforcing insulin's suppression of lipolysis [80,99]. Beyond curbing lipolysis, insulin promotes lipogenesis—predominantly in the liver, but also in WAT—by activating SREBP-1c, and indirectly, ChREBP, transcriptional regulators of genes that encode lipogenic enzymes, driving de novo lipogenesis [94,97]. This lipogenic program is complemented by PPARγ, the master regulator of adipocyte differentiation and lipid metabolism, which also enhances glucose homeostasis by increasing the expression of GLUT4 [100,101].

In skeletal muscle, the main site of insulin-mediated glucose uptake, insulin signaling promotes the translocation of GLUT4 vesicles to the plasma membrane [90,94,100]. PI3K regulates this process through Akt2 phosphorylation and the activation of the small GTPase Rac1 [80,100]. The key mechanisms and metabolic consequences are summarized in Table 1.

Concurrently, insulin enhances glycogen synthesis in both muscle and the liver by inhibiting glycogen synthase kinase-3 (GSK3) and activating PP1, resulting in dephosphorylation and activation of glycogen synthase [90,94,99]. It further suppresses glycogenolysis by downregulating phosphorylase kinase activity, thereby favoring glucose storage in muscle [90,91]. In insulin resistance, excess lipid accumulation within muscle cells generates diacylglycerols and ceramides, which activate novel PKC isoforms such as PKCθ [90,91]. These PKCs phosphorylate IRS-1 on serine residues, inhibiting its tyrosine phosphorylation and thereby impairing PI3K-Akt signaling, which reduces GLUT4 translocation and glucose uptake [90,91]. These tissue-specific impairments are summarized in Table 1.

In the liver, insulin inhibits glucose output by activating the insulin receptor tyrosine kinase, which phosphorylates IRS1/2, recruits PI3K, and activates Akt2 [80]. This signaling cascade suppresses hepatic gluconeogenesis primarily through phosphorylation of forkhead box O1 (FOXO1), promoting its exclusion from the nucleus and downregulating transcription of key gluconeogenic genes, including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase [80,90].

A paradox of hepatic insulin resistance is that, while the insulin-resistant liver fails to suppress gluconeogenesis—contributing to hyperglycemia—it often remains sensitive to insulin's lipogenic effects, promoting de novo lipogenesis and hepatic steatosis. This selective resistance arises from divergent intracellular signaling: impairment of the PI3K-Akt axis limits suppression of glucose production, whereas Akt-mTORC1-SREBP-1c signaling, which drives lipid synthesis, remains relatively intact. Clinically, this phenomenon underlies the coexistence of hyperglycemia, hyperinsulinemia, and MASLD in patients with metabolic syndrome and T2DM, as summarized in Table 1 [92,97,98].

Stress-related mechanisms in obesity have emerged as a growing field of research, with mounting evidence that chronic psychosocial stress not only influences eating behaviors but also alters neuroendocrine processes responsible for body weight regulation [79,101,102]. A central component of these mechanisms is the hypothalamic–pituitary–adrenal axis, whose prolonged activation leads to elevated cortisol concentrations [79,101].

Persistently high cortisol promotes visceral adiposity, increases preference for calorie-dense foods, and disrupts satiety and hunger signaling [79,101]. Another important feature of stress-related obesity is the rise in circulating ghrelin following stress, which further drives comfort-food consumption [79,103], along with reducing leptin levels after stress—particularly pronounced in women—potentially impairing appetite suppression [102].

Standard weight-loss strategies that focus on caloric restriction and physical activity may fail in individuals experiencing chronic stress if the neuroendocrine drivers of appetite are not addressed [103]. An increasing number of researchers advocate for personalized interventions that integrate hormonal biomarker assessment with targeted behavioral therapies. Among the most frequently studied approaches are Cognitive Behavioral Therapy (CBT), Acceptance and Commitment Therapy (ACT), and mindfulness-based interventions such as Mindfulness-Based Stress Reduction (MBSR) [104,105,106,107,108,109].

Meta-analyses confirm that CBT achieves modest but clinically relevant reductions in body weight, while improving cognitive restraint and reducing emotional eating [104,106]. CBT often outperforms standard behavioral therapy, particularly in maintaining weight loss over time [106]. ACT, which focuses on enhancing psychological flexibility and acceptance of unpleasant experiences, has been shown to improve psychological well-being in the majority of trials and, in some cases, to reduce body weight and alleviate eating-related difficulties [105]. Evidence also suggests that ACT can mitigate obesity-related stigma, thereby supporting long-term health behavior change [107]. Mindfulness-based programs, including MBSR, are effective in lowering perceived stress and biological markers such as cortisol and ghrelin [108,109], as well as reducing BMI and fat mass [108,110]. Clinical trials in pediatric populations have demonstrated that an eight-week mindfulness intervention combined with nutritional education leads to sustained reductions in body weight, body fat, and hunger and stress hormones [108]. In adults, mindfulness programs targeting stress-related eating have been associated with decreases in visceral adiposity and cortisol levels [109].

The available evidence suggests that optimal treatment of stress-related obesity lies in integrating neuroendocrine assessment with individualized behavioral intervention selection. Individuals whose primary challenge is emotional eating may benefit most from CBT [104]; those with high levels of experiential avoidance may respond better to ACT [105,107]; and individuals with high stress reactivity may gain more from mindfulness-based programs [108,109,110]. Despite promising findings, there is a lack of randomized controlled trials directly testing biomarker-informed personalization strategies [111]. Future studies should stratify participants by hormonal profile to determine, with scientific rigor, which interventions are most effective for specific subgroups [104,107].

In conclusion, stress-related obesity requires a multifaceted approach that combines understanding of neuroendocrine mechanisms with evidence-based psychotherapeutic tools [79,101,103]. Integrating hormone profiling with targeted behavioral therapy may enhance treatment efficacy, and further research is needed to develop comprehensive, personalized therapeutic protocols supported by robust clinical evidence [104,107].

Leptin and ghrelin are two important hormones that have opposite effects on appetite and energy regulation. Ghrelin increases hunger and promotes food consumption by binding to specific receptors and activating appetite-stimulating neurons in the arcuate nucleus of the hypothalamus. In contrast, leptin works to decrease appetite and limit food intake [125]. In people with obesity, the blood level of leptin is elevated, while the level of ghrelin, which stimulates hunger, is unexpectedly reduced. However, obese individuals are resistant to leptin, meaning that despite high levels, its effects are diminished. Leptin is primarily produced by fat tissue, but small amounts are also generated in the stomach. This hormone influences many biological processes, such as puberty onset, immune responses, blood cell formation, wound healing, and bone growth. Once released into the bloodstream, leptin crosses the blood–brain barrier and binds to specific receptors in the hypothalamus. There, it influences various neurons and helps control the expression of neuropeptides that regulate food intake—decreasing the activity of orexigenic (appetite-stimulating) peptides such as neuropeptide Y and AgRP, while increasing anorexigenic (appetite-suppressing) peptides such as POMC and CRH. Leptin also helps counteract the action of ghrelin, the hunger-stimulating hormone, by interfering with the ghrelin-activated pathways in the hypothalamus. Through these mechanisms, leptin acts as a feedback signal that informs the brain about the body's energy stores and contributes to the regulation of body weight. Additionally, gastric leptin—produced in the stomach—may play a role in short-term appetite control and meal size, especially in response to gut hormones and insulin released after eating [126]. Leptin resistance limits the effectiveness of leptin therapy for obesity, but targeting leptin receptors and downstream signaling in specific brain regions may help. One approach is improving leptin delivery across the blood–brain barrier (BBB). However, many strategies fail due to BBB alterations in obesity. Modified forms of leptin, such as Tat-leptin or PASylated leptin, and synthetic leptin-like molecules with better brain access and stability, show promise in animal models. Conventional leptin therapy has limited effects in humans, but combining leptin with other hormones such as amylin, GLP-1, CCK, or insulin has shown stronger weight-loss effects in animals. However, one promising combo—leptin with pramlintide—was halted due to antibody development. Targeting leptin signaling regulators such as suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) could improve leptin sensitivity. Inhibiting PTP1B, for instance, has reduced body weight and improved metabolism in animal studies. Drugs such as trodusquemine cross the BBB and show promising results. Intranasal leptin delivery is another potential method, shown to reduce appetite and liver fat in obese rats, but practical challenges remain, such as cost and inconsistent absorption. Interestingly, high leptin levels in obesity may actually worsen leptin resistance. Lowering leptin to physiological levels using anti-leptin antibodies in animals has reduced food intake and body weight, suggesting a novel therapeutic direction. Overall, restoring leptin sensitivity through improved delivery methods, combination therapies, or targeting leptin signaling pathways, offers promising strategies for treating obesity, although clinical challenges remain [127,128].

Ghrelin is mainly produced by enteroendocrine cells in the stomach's fundus, as well as in the intestine, pancreas, and brain, including the arcuate nucleus (Arc) of the hypothalamus. Ghrelin becomes biologically active when acylated by the enzyme GOAT, forming acyl-ghrelin. Ghrelin levels rise before meals, drop after eating, and gradually increase again. These fluctuations are closely linked to hunger sensations. In animal studies, ghrelin injections into the Arc stimulate appetite and influence neurons involved in feeding behavior. Ghrelin may also act centrally by reducing serotonin-related appetite suppression. Although earlier studies suggested the vagus nerve was necessary for ghrelin's effect on eating, later research indicates a direct action in the brain. Ghrelin may impact blood sugar control by speeding up gastric emptying, reducing insulin secretion, and promoting glucagon release. Fasting ghrelin levels are lower in obesity but increase with weight loss. Insulin may suppress ghrelin, partly explaining this pattern. Ghrelin secretion rises during fasting and is inhibited by meal-related reflexes. While ghrelin levels correlate with hunger and meal size, its direct role in causing hunger remains unclear. It may help prepare the body for nutrient intake and storage. Research in obese individuals and those undergoing Roux-en-Y gastric bypass (RYGB) has shown mixed results. Ghrelin-targeting drugs are under development and may clarify ghrelin's role further. Due to ghrelin's role in stimulating appetite and fat storage, antagonists or inverse agonists have been considered as potential treatments for obesity. However, research results are inconsistent—some studies report reduced food intake and weight loss, while others show the opposite effect. This highlights the complexity of ghrelin's action and the need for further investigation before such therapies can be reliably applied [129].

Peptide YY (PYY) is a hormone mainly produced by open-type enteroendocrine cells in the distal small intestine and colon. These cells often also secrete GLP-1 and sometimes other gut hormones. PYY exists in two main forms: PYY(1–36), the initially secreted form, and PYY(3–36), the active form created by enzymatic cleavage. PYY is also found in the pancreas and brain. PYY levels rise about 15–30 min after eating, peak after 1–1.5 h, and stay elevated for several hours. PYY(3–36) is thought to reduce appetite, although human studies show inconsistent results. While intravenous PYY(3–36) strongly reduces food intake in animals, this effect is less clear and possibly non-physiological in humans. Central administration of PYY(1–36) in animals can even increase eating. PYY may help regulate blood sugar by slowing gastric emptying, improving insulin sensitivity, and supporting pancreatic cell function. However, PYY(3–36) does not seem to directly affect insulin secretion in humans. Obesity's impact on PYY secretion is unclear. Some studies report lower fasting and post-meal PYY levels in obesity, while others do not. Responses also vary by age and weight-loss status. PYY(3–36) is released in response to the digestion of all macronutrients, but this response may be reduced in people with T2DM. Overall, while PYY(3–36) may influence appetite, gastric emptying, and glucose control, its exact physiological role remains uncertain, partly due to research challenges such as side effects from infusion and limited tools for studying its receptor pathways [130]. Early studies showed that peripheral PYY(3-36) administration reduced food intake and body weight in both animals and humans, but its short half-life and side effects, such as nausea, limited its clinical use. Subcutaneous and intranasal delivery had limited success, with high doses poorly tolerated. As a result, efforts have shifted toward developing PYY(3-36) analogs with improved stability and reduced side effects. Some analogs, especially when combined with semaglutide, have shown promising results in animals. However, translating these findings to humans remains difficult due to species differences and past trial discontinuations [129].

GLP-1 is produced in the gut, brainstem, and to a lesser extent in the pancreas. It acts through a single receptor, GLP1R, to regulate energy balance. Research has identified several brain regions with GLP1R that are important for controlling food intake and responding to GLP-1 receptor agonists (GLP1RAs). These effects are largely mediated by the central nervous system via adrenergic and AMPK pathways, which stimulate brown adipose tissue (BAT) activity. When GLP1R is selectively reduced in the hypothalamus, animals show lower BAT activity, reduced energy expenditure, and increased weight gain. Although gut-derived GLP-1 is present in low concentrations in the blood, its absence does not lead to increased food intake or weight gain in mice, even with high-fat diets. This suggests that gut-derived GLP-1 is not essential for weight regulation. GLP-1 receptors are widely distributed in the brain, including in areas such as the hypothalamus, brainstem, and amygdala. Studies in rodents show that central administration of GLP-1 suppresses appetite, and this effect disappears in GLP1R-deficient mice or when blocked by an antagonist. In humans, GLP-1 or GLP1RA administration increases satiety and reduces hunger. Brain imaging studies show that GLP-1 reduces activity in brain regions associated with reward and food motivation, such as the amygdala, insula, and orbitofrontal cortex. Similar brain responses occur during food intake and GLP-1 infusion. In people with obesity, GLP1RA treatment, such as exenatide, alters brain connectivity in the hypothalamus, and these changes are linked to differences in appetite reduction between individuals. These effects are seen both in those with and without T2DM [114]. Between 2012 and 2014, several centrally acting drugs, including GLP1RAs such as LIR and the combination of naltrexone and bupropion, were approved for long-term weight management. In 2021, semaglutide 2.4 mg weekly was added, showing nearly double the weight loss seen with earlier treatments, marking a major advance in obesity therapy. The later approval of oral semaglutide further expanded options for patients, particularly those with T2DM seeking non-injectable treatments. GLP1RAs not only improve glycemic control and support weight loss in people with and without diabetes, but they may also offer long-term cardiovascular, renal, and metabolic protection. These benefits, along with sustained weight loss and low risk of rebound, support broader use of GLP1RAs in obesity treatment. However, more real-world studies are needed to confirm their long-term safety, effectiveness, and impact on quality of life. GLP-1 may also influence reproductive and inflammatory processes, suggesting a broader role in managing metabolic and hormonal imbalances. Despite promising data, the complexity of GLP-1's effects highlights the need for further research, especially in real-life settings and comorbid conditions such as fatty liver disease [131].

Cholecystokinin (CCK) is released by intestinal I-cells in response to dietary fats and proteins, through receptors such as GPR40 and the calcium-sensing receptor. It acts mainly on vagal afferent neurons, reducing food intake and slowing gastric emptying. CCK also stimulates pancreatic enzyme release and gallbladder contraction. CCK affects vagal neurons both by immediately altering their activity and, over time, by changing receptor and neurotransmitter expression—effects enhanced by leptin and blocked by ghrelin. In obesity, vagal neurons become less responsive to CCK, leading to reduced satiety signaling and altered energy balance. CCK also activates specific brain regions such as the hypothalamus and brainstem, especially after fat ingestion, and this brain response is blocked by CCK-1 receptor antagonists. Although CCK contributes to satiety and may support pancreatic function, its effects are blunted in obesity due to reduced vagal sensitivity and lower neuronal excitability [132]. Building on the success of GLP-1–based drugs, researchers have developed enzyme-resistant and long-acting CCK analogs—such as glycated CCK-8, (pGlu-Gln)-CCK-8, and PEGylated versions of CCK-8, CCK-9, and CCK-10—to improve stability and effectiveness. In obese and diabetic rodent models, these modified peptides reduced appetite, body weight gain, blood glucose, and lipid levels. Although PEGylation improved pharmacokinetics, it did not significantly enhance efficacy beyond the native modified peptide. Combining CCK with other hormones such as GLP-1, amylin, or leptin shows promise for synergistic effects in treating obesity and T2DM, highlighting the therapeutic potential of CCK-based strategies [133].

Bariatric surgery is a highly effective treatment for obesity, leading to significant and lasting weight loss, along with beneficial metabolic changes. Procedures such as gastric banding, sleeve gastrectomy (SG), and RYGB alter gastrointestinal structure and function, influencing hormone responses and nutrient absorption. Gastric banding is adjustable, safe, and minimally invasive. SG removes about 80% of the stomach, preserving the pylorus, and has become widely used due to its strong efficacy and low complication rate. RYGB creates a small gastric pouch that bypasses part of the small intestine, offering the greatest weight loss but with a higher risk in modified versions with shorter common limbs [134]. Bariatric surgery significantly alters endocrine function due to structural changes in the gastrointestinal tract and new nutrient pathways. These changes may increase pancreatic sensitivity and impact various hormones, including GLP-1, ghrelin, CCK, PYY, TSH, and T3, with notable reductions in thyroid hormones. GLP-1 plays a key role in linking hormonal shifts to glucose regulation. Other effects include increased bone turnover, potential hypothalamic inflammation, and improved insulin sensitivity and beta-cell function. However, some of these mechanisms remain under debate [135]. Bariatric surgery, particularly Roux-en-Y gastric bypass, enhances incretin response—especially GLP-1 secretion—leading to improved oral glucose tolerance and insulin sensitivity. Studies show that GLP-1 levels rise significantly after RYGB, regardless of whether nutrients are delivered via the stomach or jejunum, likely due to increased exposure of distal GLP-1—producing cells to nutrients. Research has also highlighted the role of bile acids in post-surgery metabolic improvements. After RYGB, serum bile acid levels rise and correlate with improved insulin sensitivity. In mouse models, diverting bile to the ileum mimicked many RYGB benefits, such as reduced weight, improved glucose tolerance, and increased GLP-1 secretion—especially under low-fat diet conditions. These effects depended on the presence of GLP-1 receptors. Additionally, novel findings suggest that gut immune cells (β7+ intraepithelial lymphocytes) help regulate GLP-1 availability. Mice lacking these cells showed higher circulating GLP-1, were resistant to metabolic diseases, and had better glucose control, indicating that GLP-1 receptor signaling in the gut plays a broader role in metabolic regulation [136]. Recent studies have explored the role of ghrelin in the weight-loss effects of bariatric surgery, especially sleeve gastrectomy. A meta-analysis confirmed a significant ghrelin drop after SG, while results after Roux-en-Y gastric bypass remain inconsistent. Despite their different mechanisms—SG being restrictive and RYGB combining restriction with malabsorption—both procedures yield significant weight loss. Notably, SG patients show a marked and lasting decrease in ghrelin and appetite, suggesting this may compensate for the absence of malabsorption. A study by Karamanakos et al. confirmed sustained appetite suppression and ghrelin reduction in SG patients, unlike those who underwent RYGB [137]. Studies have shown that postprandial CCK levels rise after RYGB, despite the duodenum—normally the main site for CCK release—being bypassed. This may be due to alternative stimulants such as parasympathetic input or increased CCK cell activity in the distal intestine. While elevated CCK might aid satiety and glucose control, some data suggest higher CCK levels in poor RYGB responders. Comparatively, sleeve gastrectomy leads to a greater and more sustained increase in CCK than RYGB, while the impact of gastric banding on CCK remains unknown. Obesity is linked to lower postprandial PYY3-36 levels, while PYY3-36 infusion reduces food intake. After bariatric surgery, postprandial PYY levels rise across various procedures—including gastric banding, sleeve gastrectomy, and RYGB—with effects visible within weeks and lasting at least a year. Animal studies suggest PYY plays a key role in surgery-induced weight loss [138]. Each bariatric procedure results in a distinct pattern of gut hormone changes, with Roux-en-Y gastric bypass showing particularly strong synergistic effects that promote satiety and reduce food intake. Among these, GLP-1 and PYY3-36 have the most robust evidence supporting their role in suppressing appetite after surgery. Additionally, early postoperative increases in hormones such as glicentin and oxyntomodulin after both RYGB and sleeve gastrectomy are associated with more favorable weight-loss outcomes and could serve as early indicators of insufficient weight reduction, helping to identify patients who may need extra support. GLP-1 also contributes to improved insulin secretion shortly after surgery, even in individuals without T2DM, and may be involved in the development of postprandial hypoglycemia. Ongoing studies are testing GLP-1 receptor antagonists such as Ex-9 as potential treatments for this condition. Based on these insights, combinations of gut hormone receptor agonists are being developed to replicate the beneficial hormonal profile seen after bariatric surgery, offering promising new treatment strategies for obesity and T2DM [119].

The regulation of appetite and energy balance involves a complex interaction between central and peripheral signals, in which gut-derived hormones such as leptin, ghrelin, GLP-1, PYY, and CCK play critical roles. While hormonal therapies targeting these pathways have shown varying degrees of success, their efficacy is often limited by compensatory mechanisms and physiological resistance, as seen in leptin resistance or ghrelin's inconsistent effects. Bariatric surgery emerges as the most effective long-term intervention for obesity, not only through anatomical changes but also by inducing favorable hormonal shifts—particularly increased levels of GLP-1 and PYY—that enhance satiety and improve glucose metabolism. These findings support the development of combination therapies and hormone analogs that mimic the post-surgical endocrine environment, offering a promising direction for future obesity treatment strategies.