360-Degree Perspectives on Obesity

The World Health Organization defines obesity as an “abnormal or excessive accumulation of fat that poses a risk to health” [ 1 , 2 ]. However, can the medical community continue to treat obesity solely as a risk factor? This has been an unanswered question for more than 50 years, during which time obesity has continued to rise rapidly to pandemic proportions. Today, with an estimated 650 million adults and 124 million children affected in 2016, obesity is recognized as a complex, chronic, and multifactorial disease. The economic impact of obesity is substantial, with obesity-related healthcare costs alone projected to exceed USD 190 billion annually in the United States [ 2 ]. In addition, obesity is associated with reduced productivity, increased absenteeism, and reduced work capacity, resulting in significant economic losses at both the individual and societal levels [ 2 , 3 ]. The causes of obesity are multifaceted, including genetic, epigenetic, psycho-social, and microenvironmental factors. We are now gaining a better understanding of the upregulation of food cravings in the brain of obese individuals, as well as the role of gut hormones, adipose tissue, and gut dysbiosis in regulating appetite and satiety in the hypothalamus [ 4 ]. Oxidative stress triggers inflammatory cascades, while inflammation increases oxidative stress through various pathways, creating a reciprocal relationship. Dysbiosis, in turn, contributes to oxidative stress and inflammation through microbial-derived metabolites, lipopolysaccharides, and altered gut permeability. These interactions form a triad of intertwined mechanisms that perpetuate the pathophysiology of obesity and its complications [ 5 ]. Embracing a holistic approach that addresses oxidative stress, chronic inflammation, and dysbiosis is pivotal in developing effective preventive strategies and comprehensive management approaches to tackle the global obesity epidemic. Obesity has traditionally been viewed as a condition resulting from excessive storage of energy in fat cells due to an imbalance between energy intake and expenditure [ 6 ]. Current research, however, has shown that the sources and quality of nutrients in the diet may play a more important role than quantity in weight control and disease prevention [ 7 , 8 ]. These studies have suggested that alterations in the gut microbiota and branched-chain amino acid (BCAA) metabolism may play an important role in the development and progression of obesity [ 9 , 10 ]. The gut microbiota, a diverse community of microorganisms that inhabits the gastrointestinal tract, has been shown to regulate energy metabolism and immune function, among other physiological processes [ 11 ]. Meanwhile, BCAAs, a group of essential amino acids that cannot be synthesized by the body and must be obtained from the diet, have been implicated in the pathogenesis of obesity and related metabolic disorders [ 10 , 12 ]. While environmental factors such as diet and physical activity play an important role in the development of obesity, there is some increasing evidence that genetic factors also play a key role in determining an individual’s susceptibility to obesity. Polygenic forms of obesity are influenced by the interaction of several genetic factors and are more common than monogenic forms [ 8 ]. Understanding the genetic basis of obesity is important because it can provide valuable insights into the underlying mechanisms of the disease and help identify new targets for therapeutic intervention. From the perspective of fundamental research and the translation of results from experimental medicine into clinical practice, we consider the use of animal models to be an important tool for understanding the pathophysiology of obesity and developing effective interventions for its prevention and treatment. Among animal models, rodents have been extensively used because of their genetic, physiological, and metabolic similarities to humans. In particular, rodent models of obesity have provided valuable insights into the genetic basis of the disease and the mechanisms underlying its development and progression. In recent years, preclinical research has focused on the relationship between oxidative stress and chronic inflammation in obesity [ 13 , 14 ]. In particular, oxidative stress has been identified as a primary trigger of the inflammatory response. However, the psychogenic factor plays a decisive role in the development of obesity [ 15 ]. Research has shown that there is a strong association between stress and weight gain, with obesity being more common in people with PTSD [ 16 ]. Chronic inflammation, a common denominator in both obesity and PTSD, serves as a potential mechanistic link, impacting neural circuits involved in stress response, emotion regulation, and appetite control. Furthermore, the complex association between obesity, chronic inflammation, and mental disorders extends beyond PTSD, encompassing other psychiatric conditions su

Seeing as human obesity is influenced by numerous genes, polygenic models, as opposed to monogenic models, offer greater data on the nature of obesity [ 22 , 25 ]. The following are a few of the most popular polygenic models [ 22 ]. New Zealand obese mice resemble the ob / ob strain in many ways. Type 2 diabetes and obesity exclusively occur in males [ 22 , 24 , 25 , 37 ]. Tsumura and Suzuki obesity and diabetes mice –polygenic obesity, insulin resistance, polydipsia, hyperglycemia, polyuria, and hyperinsulinemia are characteristics of male TSOD mice [ 22 , 38 , 39 ]. Kuo Kondo-Ay mice –KK-Ay mice have unique adiposity and are grossly overweight. At eight weeks of age, they show hyperphagia, hyperglycemia, hyperinsulinemia, and glucose intolerance [ 22 , 38 , 40 ]. M16 mice –the M16 mouse develops early-onset obesity and moderate hyperglycemia alongside hyperphagia, hyperinsulinemia, and hyperleptinemia [ 25 , 41 , 42 ].

The hypothalamus plays a consequential role in signaling between the gut and brainstem and in regulating signals responsible for energy input and output, among other functions [ 22 ]. Chemical models are obtained by generating lesions in specific nuclei of the hypothalamus [ 22 ]. The lesions generated there can be produced mechanically, through surgical intervention, by using radio waves or electrolysis, or chemically by deploying neuronal toxins such as bipiperidyl mustard, monosodium glutamate, ibotenic acid, gold thioglucose, and kainic acid [ 22 , 45 ]. Ovariectomy is used as a surgical model to study obesity in women [ 22 ]. Ventromedial hypothalamus damage. Hypothalamic paraventricular nucleus damage. Arcuate nucleus damage. Ovariectomy.

It is well known that the incidence of obesity has increased rapidly with urbanization, but despite the negative effects of an obesogenic society, there is high individual variability in body weight [ 48 , 49 ]. The concept of an innate cause of obesity was described as early as 1907 by Von Noorden, and numerous studies have since strengthened this hypothesis [ 48 , 49 ]. Stunkard et al. (1986) conducted a study of 540 adopted Danish twins and concluded that the weight of the twins in adulthood was the same as that of their biological parents, even when they were raised in adoptive families [ 50 ]. Bouchard et al. (1990) showed in their study that there is a statistically significant similarity between monozygotic twins in weight gain (under overfeeding conditions), and a systematic review of twin studies estimated the heritability of obesity to be 45–90% [ 48 , 51 ]. Wardle et al. (2008) supported the hypothesis of a genetic influence on obesity by demonstrating a significant concordance in body weight between monozygotic and dizygotic twins [ 52 ]. In recent years, new genes that play a crucial role in this complex trait have been identified as a result of the availability of new and highly accurate diagnostic methods, in particular whole-exome sequencing [ 48 , 49 ]. The genetic factors involved in obesity lead to variable phenotypes, and there are three broad clinical presentations: monogenic obesity, polygenic obesity, and syndromic obesity [ 49 ]. Polygenic obesity is the most common phenotypic expression of obesity. It is caused by a complex interaction between genetic susceptibility and the obesogenic environment. Overeating, a sedentary lifestyle, a lack of sleep, and stress all increase individual genetic susceptibility [ 49 , 53 ]. Monogenic obesity is inherited in a Mendelian pattern, is rare, and is characterized by a severe early onset, typically before 10 years old. It is most commonly caused by mutations of the genes involved in the leptin-melanocortin axis, which plays a pivotal role in the hypothalamic control of food intake. This type of obesity is frequently associated with endocrinologic dysfunction [ 49 , 54 ]. Syndromic obesity is a term used when severe obesity is associated with intellectual disability, dysmorphic features, organ abnormalities, or signs of hypothalamic dysfunction. It can be caused by the mutation of a single gene or a larger chromosomal region and transmitted in an autosomal or X linked manner, but it can also be caused by de novo genetic mutations. Over 100 syndromes associated with obesity have been described, but the most common are Prader–Willi (PWS) and Bardet-Biedl (BBS) syndromes. The identification of syndromic obesity is important because it is often associated with specific comorbidities that may require prevention or at least assessment and treatment [ 49 , 55 ]. PWS is the most common cause of syndromic obesity, with an incidence of 1 in 20,000–25,000 births worldwide. It has complex effects on the metabolic, endocrine, and neurological systems. The disease is characterized by severe neonatal hypotonia, feeding difficulties with failure to thrive in the first years of life, followed by hyperphagia and the gradual development of morbid obesity in later childhood, dysmorphic features, developmental delay behavioral problems, hypogonadism, growth hormone deficiency, and hypothyroidism [ 49 , 56 ]. PWS is caused by the inactivation of the critical Prader–Willi region of the paternal chromosome [ 48 ]. BBS is a non-motile ciliopathy characterized by retinal dystrophy (progressive night blindness, photophobia, and loss of central and color vision), obesity and its complications, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism, and genitourinary malformations. At least 19 different genes have been implicated in the disease, all of which play a role in the normal functioning of the primary cilium, which appears to play a role in energy homeostasis [ 48 , 49 , 57 ]. Other causes of syndromic obesity include Cohen syndrome, Alström syndrome, X fragile syndrome, Borjeson–Forssman–Lehmann syndrome, 16p11.2 deletion syndrome, kinase suppressor of Ras2 (KSR2) variants, TUB mutations, ACP1, TMEM18, and MYT1L deletion [ 49 ]. The genes identified in monogenic obesity are most commonly involved in the hypothalamic leptin-melanocortin pathway. The central nervous system regulates food intake through the hypothalamic leptin-melanocortin axis, which receives signals from tissues. Signals are received from the gut by hormones such as ghrelin, peptide YY, cholecystokinin, glucagon-like peptide, and mechanoreceptors that measure distention, from the pancreas by insulin, or by the adipokine hormones (leptin and adiponectin). This axis is a key regulator of energy homeostasis and is activated by leptin and insulin receptors on the surface of neurons located in the arcuate nucleus. There are two types of neurons involved in the feedback loop: the pro-o

MC4R deficiency is the most common cause of monogenic obesity and is typically characterized by obesity, increased bone mineral density, increased linear growth in early childhood, hyperphagia, and severe hyperinsulinemia [ 48 , 60 ].

SIM1 is expressed in the hypothalamus, and its mutations are associated with hyperphagia and food impulsivity with consequent obesity, impaired concentration, memory deficit, emotional lability, or autism spectrum disorder [ 48 ].

Src homology 2 B adapter protein 1 (SH2B1) is a key endogenous positive regulator of leptin sensitivity. SH2B1 mutations are associated with severe early-onset obesity, insulin resistance, reduced height, hyperinsulinemia but without diabetes, delayed speech, and aggressive behavior [ 48 , 62 ].

Oxidative stress is defined as an imbalance between the production and scavenging of various ROS and reactive nitrogen species (RNS); this imbalance occurs either through the overproduction of reactive species or through a reduction in their defense mechanisms. ROS include molecules such as hydrogen peroxide (H 2 O 2 ), superoxide (O 2 •− ), and the hydroxyl radical (OH − ); at the cellular level, several sources of ROS are recognized: leakage of electrons from complexes I and III of the electron transport chain with formation of superoxide (electron leakage), increase in the redox status of macrophages and neutrophils in the presence of pathogens (respiratory burst), and formation of superoxide radicals in reactions catalyzed by NADPH oxidases (NOXs) and xanthine oxidase (XO) [ 63 , 64 , 65 , 66 ]. The mechanisms that protect the cell from the damaging action of free radicals work with the help of enzymatic and non-enzymatic antioxidant systems; the enzymatic system comprises enzymes (e.g., glutathione peroxidases (GPXs), catalase (CAT), superoxide dismutases (SODs), peroxiredoxins (PRDXs)) localized in different cell compartments (mitochondrial matrix, cytosol, peroxisomes) [ 67 ]. Endogenous cofactors (glutathione, lipoic acid) and exogenous antioxidants from the diet (vitamin C, vitamin E, carotenoids, polyphenols, selenium, and zinc) also contribute to antioxidant defense mechanisms [ 68 , 69 ]. Scientific data links oxidative stress to obesity. Some mechanisms, such as hyper-glycaemia, chronic inflammation, increased free radical formation, increased muscle lipids, hyperleptinemia, low antioxidant capacity, altered mitochondrial function, and endothelial dysfunction, may explain the association of obesity with increased ROS production. [ 70 , 71 , 72 ]. During prolonged hyperglycemia, advanced glycosylation end products (AGE) lead to the activation of some cell surface receptors (RAGE), which activate nuclear factor-kB (NF-kB). This activation initiates the transcription of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1), which promote ROS production and inflammation [ 73 , 74 ]. Another mechanism that favors free radical formation in obese patients with hyperglycemia is the stimulation of the polyol pathway, in which glucose is converted to sorbitol, a compound that has been shown to cause oxidative damage [ 75 ]. In addition, sorbitol formation by aldose reductase uses NADPH and thus indirectly reduces available reduced glutathione, which exacerbates the oxidative effect [ 76 , 77 ]. Inflammation is a known cause of oxidative stress in obesity. Overweight patients have low-grade chronic inflammation and increased oxidative stress. Several inflammatory triggers have been suggested, such as hypoxia in adipose tissue, mechanical stress due to the interaction between the extracellular matrix and hypertrophic adipose tissue, and increased intestinal permeability that may lead to the presence of gut-derived antigens in plasma and dietary components. The mechanism of obesity-related inflammation is not fully understood, but an increase in inflammatory markers has been observed in obesity [ 78 ]. It is thought that the pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β and IL-6) released by hypertrophic adipose tissue activate monocytes and their differentiation into macrophages with an increase in oxidative stress [ 79 ]. Activation of the NF-κB pathway by cytokines may also play a role in ROS production [ 80 , 81 ]. Furthermore, at the adipose tissue level, adipokines may stimulate chemotaxis with macrophage recruitment [ 82 ]. Adipokines, including leptin, adiponectin, visfatin, resistin, apelin, and plasminogen activator inhibitor type 1 (PAI-1), are secreted by dysfunctional adipose tissue and play a role in both inflammation and the initiation and maintenance of oxidative stress [ 78 , 83 ]. Leptin has a hypothalamic-mediated effect on food intake, and its plasma concentration is proportional to adipose tissue expansion. Several mechanisms explain the link between leptin and oxidative stress: direct production of H2O2 and OH-, decrease in antioxidant enzyme synthesis (paranoxaze-1), stimulation of monocyte proliferation and their transformation into macrophages, and also the production of inflammatory cytokines that increase NADPH oxidase production [ 70 ]. Visfatin, one of the recently discovered adipokines, increases the production of pro- and anti-inflammatory cytokines and generates ROS, particularly superoxide, and H2O2. It has been shown that visfatin-mediated ROS generation is associated with phosphorylation of the NF-κB pathway and is independent of activation of mitogen-activated protein kinases (MAPKs) [ 84 ]. Other mechanisms of free radical generation in obesity include mitochondrial and peroxisomal oxidation reactions during fatty acid degradation. Hyper-trophic adipocytes in obese patients have a lower density of i

6.1. Stress The discussion about obesity would not be complete without placing it in the background of everyday challenges, including stress and the extreme phenomenon of PTSD (which allows a better understanding of stress only by magnifying some of its features). Obesity cannot be reversed over a long period of time without resolving the trauma that caused it [ 118 ]. A major problem is the increasing stigmatization of the obese population; the prejudice associated with the personality and socio-professional performance of obese people only reinforces the vicious cycle of eating disorders [ 119 ]. The reduced physical activity that accompanies this new paradigm of living in a digital ecosystem, surrounded by an obesogenic digital food environment, reduces healthy ways of reducing stress and encourages the development of obesity [ 119 , 120 ]. Stress is a common contributor to the onset and progression of addiction [ 121 ]. Given that obese people report greater food cravings and consume larger portions in response to food cues (sights, sounds, and smells), obesity can be seen as a result of food addiction [ 122 ]. Moreover, flavor additives in ultra-processed foods increase palatability, promote hedonic eating, and interfere with homeostatic control of food intake [ 123 ]. Increased activation of mesocorticolimbic circuits, particularly dopamine and glutamate transmission in the nucleus accumbens (NAc), has been shown to correlate with weight gain and difficulty in weight loss. On the other hand, experimental data indicate that obese rats are more susceptible to the effects of cocaine, suggesting a bidirectional connection between weight gain and activation of the reward system [ 122 , 124 ]. Severe obesity has also been linked to decreased brain expression of D2 receptors, which indirectly stimulate endorphin release and appetite [ 125 ]. Strong and sustained activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis during stress leads to hyperglycemia, hypercortisolism, inflammation, and insulin resistance [ 126 , 127 ]. Furthermore, Kim points out that the main deleterious effects of stress are caused primarily by alterations in neural circuits that affect the functions of all body systems [ 128 ]. Brain-induced stress changes are reversible, with the prefrontal cortex (PFC) and the hippocampus (HPC) recovering more quickly than the amygdala [ 129 ]. In acute stress, hyperglycemia represents a survival-optimizing response, but prolonged allostatic load from chronic stress leads to a downward spiral of metabolic imbalance and increases the risk of T2D [ 129 , 130 ]. In metabolic syndrome, hyperinsulinemia favors activation of the sympathetic nervous system, as shown by increased plasmatic and urinary concentrations of norepinephrine (NE) [ 131 , 132 , 133 ]. Stimulation of the parasympathetic nervous system improves glycemic control and insulin sensitivity in prediabetic patients [ 134 ]. In addition, stress-induced hypercortisolemia leads to changes in the brain circuits that control food intake, favoring increased intake of palatable foods [ 129 ]. Trauma in childhood, in particular, has a very detrimental effect on brain development [ 135 ]. The metabolism of lipids is deeply affected by stress, as demonstrated by the effect of stress on enzymes such as hepatic lipase, lipoprotein lipase, cholesterol esterase, HMG-CoA reductase, acyltransferase, acyl-CoA dehydrogenase, and others [ 134 ].

It is unanimously accepted that obesity has been identified as a multifaceted risk factor for a range of serious medical conditions, including but not limited to type 2 diabetes, cardiovascular disease, gallstone disease, non-alcoholic fatty liver disease, acute pancreatitis, certain cancers, chronic kidney disease, ischemic stroke, obstructive sleep apnea, osteoarthritis, psychiatric comorbidities, and infertility [ 198 ]. Understanding the link between obesity and its associated complications is of paramount importance for developing effective prevention and management strategies. One of the main pillars of current public health policy is the association between T2D and obesity. As we know to date, T2D has reached epidemic proportions worldwide, and its strong association with obesity has been well established [ 199 ]. Obesity, characterized by excess adiposity, particularly visceral adipose tissue, is a major risk factor for the development of insulin resistance and subsequent T2D. The adipose tissue itself functions as an active endocrine organ, releasing a variety of adipokines, such as leptin, adiponectin, and resistin, which play crucial roles in glucose homeostasis and insulin sensitivity. In obesity, the dysregulation of adipokine secretion leads to a state of chronic low-grade inflammation and adipose tissue dysfunction, contributing to the pathogenesis of insulin resistance [ 200 ]. Additionally, adipose tissue expansion is accompanied by an increased release of free fatty acids into the circulation, which further promotes insulin resistance in peripheral tissues such as skeletal muscle and the liver. Adipose tissue dysfunction also impairs the production and release of adiponectin, an adipokine with insulin-sensitizing properties, further exacerbating insulin resistance [ 201 ]. Furthermore, obesity is closely linked to other metabolic abnormalities, including dyslipidemia, hypertension, and systemic inflammation, collectively referred to as metabolic syndrome. These comorbidities further contribute to the development and progression of T2D. Importantly, the bidirectional relationship between obesity and T2D creates a vicious cycle, as hyperglycemia resulting from insulin resistance promotes further adipose tissue dysfunction and exacerbates obesity [ 202 ]. In addition to the well-known metabolic and cardiovascular complications associated with obesity, emerging evidence suggests a link between the novel concepts of diabetes, non-alcoholic fatty liver disease (NAFLD), and thrombosis [ 203 ]. Insulin resistance, a key feature of T2D, plays a central role in the development and progression of NAFLD. It promotes hepatic lipid accumulation by enhancing the release of free fatty acids from adipose tissue and impairing lipid oxidation in the liver. On the other hand, NAFLD contributes to the development and exacerbation of insulin resistance by releasing inflammatory cytokines and adipokines that interfere with insulin signaling pathways. Moreover, both conditions are associated with systemic inflammation, oxidative stress, and dyslipidemia, which further fuel the pathogenesis of each other [ 204 ]. The presence of NAFLD in individuals with T2D is associated with an increased risk of developing advanced liver disease, including non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Conversely, T2D is a strong predictor of NAFLD progression and the development of complications, such as hepatocellular carcinoma [ 205 ]. While NAFLD is primarily considered a hepatic manifestation of the metabolic syndrome, emerging evidence suggests that it is also associated with an increased risk of thrombotic events. The mechanisms underlying the association between NAFLD and thrombosis are complex and multifactorial. One proposed mechanism is the systemic inflammation and endothelial dysfunction observed in NAFLD, which can promote a prothrombotic state. Inflammatory cytokines, such as TNF-alpha and IL-6, derived from the liver and adipose tissue, contribute to endothelial dysfunction and activation of the coagulation cascade [ 206 ]. Furthermore, NAFLD is often accompanied by metabolic abnormalities, including insulin resistance, dyslipidemia, and hyperglycemia, all of which can further contribute to the prothrombotic milieu. Additionally, NAFLD is associated with alterations in coagulation factors and fibrinolytic pathways, such as increased levels of plasminogen activator inhibitor-1 (PAI-1), decreased tissue plasminogen activator (tPA) activity, and elevated levels of fibrinogen [ 207 ]. These abnormalities may disrupt the delicate balance between coagulation and fibrinolysis, favoring thrombus formation. The bidirectional relationship between NAFLD and thrombosis highlights the interplay between liver dysfunction, metabolic derangements, and the coagulation system. Recognizing the association between obesity and thrombosis is crucial for risk assessment, prevention, and management strategies. The identi

Branched-chain amino acids (BCAAs)–leucine, isoleucine, and valine are essential amino acids that are not produced by the body and must therefore be obtained from food. All three BCAAs together make up about 20% of total protein and account for a third of the essential amino acids in the diet. However, bacteria that are part of the human microbiota have been found to be able to synthetase BCAAs [ 242 ]. Interestingly, there is increasing evidence that BCAAs, or branched-chain α-keto acids (BCKAs), in addition to hyperactivation of mTOR signaling, are involved in the induction of oxidative stress, mitochondrial dysfunction, apoptosis, and, more importantly, insulin resistance and/or impaired glucose metabolism, all of which are key factors in the pathogenesis of metabolic disorders [ 243 , 244 , 245 , 246 , 247 ]. The available data on the relationship between BCAAs (particularly leucine) and insulin resistance is contradictory. BCAAs have been shown to have different or even opposite effects depending on the metabolic state (predominance of either catabolic or anabolic activity) [ 248 ]. According to Cuomo et al. (2022), a low-BCAA diet is often associated with promoting metabolic health. High levels of BCAAs are associated with a number of metabolic disorders, including insulin resistance, obesity, and diabetes. Further studies in rats have shown that low consumption of BCAAs is associated with reduced insulin resistance and fat accumulation [ 242 ]. In fact, the relationship between BCAAs and insulin resistance is stronger than the relationship between insulin resistance and lipoprotein levels. Western diets containing more than 20% BCAAs are one of the major factors contributing to the increase in type 2 diabetes and obesity worldwide [ 242 ]. Metabolomics data has shown that an increase in blood levels of BCAAs can predict the onset of type 2 diabetes more than 10 years in advance [ 249 ]. On the other hand, an association has been found between high plasma leucine levels and reduced all-cause mortality [ 250 ]. In obese animals, leucine and isoleucine alleviate insulin resistance and promote the browning of white adipose tissue [ 251 ]. Some authors suggest that dietary supplementation with leucine in obesity improves mitochondrial dysfunction, reduces inflammatory processes, and decreases body weight [ 252 , 253 ]. As butyrate is known to improve human metabolism by increasing mitochondrial activity, reducing metabolic endotoxemia, and activating gluconeogenesis in the gut (via gene expression and/or hormone release), the beneficial effects of leucine supplementation may be explained by leucine-induced stimulation of colonic butyrate and propionate production by gut bacteria [ 254 ]. Recent data shed light on these conflicting results: leucine supplementation in situations where catabolic processes predominate improves lipid oxidation and mitochondrial function in skeletal muscle, whereas supplementation of this amino acid when the body is characterized by anabolic processes leads to BCAA accumulation with mitochondrial dysfunction and incomplete lipid oxidation [ 248 ].

Obesity, a chronic disease with significant complications in all age groups, has reached pandemic proportions. In Europe, obesity is the fourth most common risk factor for developing a non-communicable disease and has been associated with increased cardiac mortality, a higher risk of thirteen types of cancer, and reduced quality of life [ 119 ]. In this complicated puzzle represented by the pathology of obesity, it is unlikely that only one drug will be the silver bullet that represents a complete solution to such a large problem. Therefore, the best therapeutic results are obtained by combinations of drugs that also allow for lowering the doses and decreasing the side effects. Current medication includes four drugs approved by the FDA for short-term use (phentermine, phendimetrazine, diethylpropion, and benzphetamine) and six medications (orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, semaglutide, and setmelanotide) for long-term use [ 273 ]. Established guidelines advise that drug treatment should be stopped or modified if at least 5% weight loss is not achieved after 12 weeks of drug treatment [ 274 ]. However, given that weight loss leads to a significant reduction in the chronic complications of obesity, the number of drugs currently in use is extremely small. Even in this context, recent data indicate that anti-obesity medications are underused, with only 2% of the obese population taking them [ 19 , 274 ]. There are many possible reasons for this: insufficient knowledge about these drugs, low accessibility due to high prices, low adherence due to side effects, the modest weight loss that these drugs can achieve, the poor reputation of drugs withdrawn from the market due to poor safety profiles, and the stigma associated with obesity that reduces access to health-care services [ 119 ]. A detailed understanding of the pathophysiological mechanisms underlying the onset of obesity has led to the discovery of new drugs and therapeutic strategies with the potential to alleviate this disease. Although a wide range of drugs are already used in obesity therapy, extensive preclinical and clinical ongoing studies aim to discover and bring to market new weight-loss drugs. It is hoped that the new molecules will bring benefits in terms of fewer side effects, greater weight loss, longer periods of optimal weight maintenance, and a lower cost/benefit ratio compared to current anti-obesity medication. The increased interest in this area of research is reflected in the plethora of non-invasive approaches for treating obesity, including drugs that target numerous pathophysiological pathways (from the central nervous system, gastrointestinal tract, adipose tissue, kidney, liver, and skeletal muscle) but also modern delivery systems, gene therapy, and vaccines [ 275 ]. A synthetic overview of the pharmacotherapy for obesity from its beginnings to date is presented in Table 2 . A comprehensive review of obesity-promoting factors should include drugs that cause significant weight gain, such as glucocorticoids, antipsychotics (clozapine and olanzapine), antidepressants (tricyclic antidepressants and paroxetine belonging to selective serotonin reuptake inhibitors), antidiabetics (sulfonylureas and thiazolidinediones), antiepileptics (valproate), antihypertensives (beta-blockers), and oral contraceptives, to name but a few [ 432 , 433 ]. Fortunately, drugs have a variable risk of associated weight gain, with significant variation within classes; this characteristic allows switching from a molecule associated with significant weight gain to one with a lesser effect on BMI [ 434 ]. Despite advances in understanding the multifaceted nature of obesity, effective interventions that promote sustained weight loss and prevent weight regain remain elusive. Behavioral changes play a pivotal role in obesity prevention and management. However, achieving long-term adherence to healthy behaviors remains a significant challenge [ 435 ]. Further research is needed to identify novel strategies that can motivate individuals to adopt and maintain healthy lifestyles. Investigating personalized approaches, such as tailored dietary recommendations, physical activity programs, and psychological interventions, can optimize behavioral changes and enhance their sustainability. Exploring new targets and pathways, leveraging emerging technologies, and conducting rigorous clinical trials can lead to the discovery of novel pharmacological interventions. Additionally, investigating combination therapies and personalized medicine approaches may optimize treatment outcomes by tailoring interventions to individual characteristics and underlying biological mechanisms. Research should focus on identifying the most effective combinations, dosage regimens, and treatment durations to maximize weight loss, minimize adverse effects, and prevent weight regain. Addressing the challenges in obesity prevention and treatment requires multidisciplin

Despite significant progress in understanding the causes and contributing factors of obesity, the implementation of effective interventions has been disappointingly slow. Barriers to translating scientific evidence into practical solutions range from systemic issues, such as limited funding and resource allocation, to societal factors, such as cultural norms and social inequalities. The prevailing societal norms that promote sedentary lifestyles and unhealthy food environments contribute to an obesogenic environment ( Figure 1 ). Moreover, cultural practices, traditions, and beliefs about food, body image, and physical activity influence individual behaviors and can pose challenges to the adoption of healthier habits [ 457 , 458 ]. Addressing these cultural and societal influences requires targeted and culturally sensitive interventions that respect and take into account different perspectives and values. Negative attitudes, stigma, and discrimination towards individuals with obesity are significant barriers that impede access to care, social support, and positive health-seeking behaviors. In addition, psychological factors such as stress, depression, and low self-esteem can undermine motivation and hinder sustained behavior change efforts [ 459 ]. Furthermore, the complexity of obesity demands a comprehensive and integrated approach across multiple sectors, including healthcare, education, urban planning, and food policy. The fragmented nature of these sectors hinders coordinated efforts and impedes the translation of knowledge into practical action [ 460 ]. The lack of coordinated efforts among stakeholders, including policymakers, healthcare providers, and community organizations, has also hindered progress. Policy interventions have proven to be effective in reshaping environments and promoting healthier choices. Examples include implementing sugar-sweetened beverage taxes, food and nutrition labeling regulations, and restrictions on the marketing of unhealthy foods and beverages to children. These policy changes have the potential to influence consumer behaviors, reduce the use of unhealthy products, and encourage the adoption of healthier alternatives. Creating supportive environments that facilitate physical activity and healthy eating is crucial for obesity prevention. Promoting walkable communities, building bike lanes, and establishing parks and recreational facilities can encourage regular physical activity. Additionally, improving access to affordable, nutritious foods through initiatives such as farmers’ markets, urban gardens, and healthy food retail programs can enhance healthy eating behaviors [ 461 ]. Education plays a pivotal role in empowering individuals with knowledge and skills to make informed choices regarding their health. School-based interventions that incorporate nutrition education, physical activity programs, and healthy lifestyle curricula have shown positive outcomes in preventing obesity among children. Similarly, workplace wellness programs that offer health education, physical activity opportunities, and healthy food options can contribute to obesity prevention among adults. Engaging communities in obesity prevention efforts foster social support, promotes collective action, and addresses local needs and priorities. Community-based programs, such as family-focused interventions, peer support groups, and community gardens, have shown promise in promoting healthy behaviors and reducing obesity rates. By involving community members in the planning and implementation of interventions, these initiatives can have a lasting impact on obesity prevention [ 461 , 462 ]. Preventive measures for children are particularly important because of the long-term health effects of obesity in early life. Promoting breastfeeding, implementing nutrition standards in schools, and restricting the marketing of unhealthy foods to children are effective strategies that can shape healthier behaviors from an early age. By investing in comprehensive early intervention programs, we can build a strong foundation for lifelong health and reduce the risk of obesity-related complications [ 463 ]. Addressing obesity in adults requires a multifaceted approach that combines policy changes, community engagement, and individual empowerment. Implementing workplace wellness programs, offering nutrition and physical activity counseling, and providing access to evidence-based weight management programs are effective strategies to support adults in their weight management journey. By equipping adults with the necessary tools and resources, we can improve health outcomes and reduce the burden of obesity-related chronic diseases. The obesity pandemic demands urgent and concerted efforts to implement effective preventive measures. By leveraging policy changes, environmental modifications, educational initiatives, and community engagement, we can make substantial progress in curbing the obesity crisis. These examples of su