Central obesity (CO), characterized by excessive visceral adipose tissue (VAT) accumulation, is increasingly recognized as a risk factor for cognitive decline, dementia, and Alzheimer’s disease (AD). This review summarizes current evidence linking CO, particularly VAT accumulation, to cognitive impairment and discusses the microbiota–gut–brain axis as a mechanistic framework for interpreting this association. Studies published in recent years suggest that VAT-related indices, such as waist circumference, waist-to-hip ratio, and imaging-derived VAT measures, are more closely associated with cognitive dysfunction than body mass index. Recent neuroimaging studies have linked VAT accumulation with brain atrophy, white matter abnormalities, altered functional connectivity, and increased AD-related pathological burden. Emerging multi-omics evidence further indicates that VAT expansion shows an association with gut microbial dysbiosis, altered microbial metabolites, impaired intestinal barrier function, systemic low-grade inflammation, insulin resistance, and neuroendocrine disturbances. These findings support a model in which VAT-related metabolic and inflammatory alterations may influence brain structure and function through microbiota-mediated, immune, endocrine, and barrier-related pathways. Current evidence is consistent with a VAT-centered model in which CO is associated with cognitive impairment through interconnected inflammatory, metabolic, endocrine, and microbiota-mediated mechanisms. The microbiota–gut–brain axis may provide a useful mechanistic framework linking peripheral metabolic dysfunction with AD vulnerability. Future longitudinal cohort studies and mechanistically informed intervention studies are needed to clarify temporal relationships and to determine whether VAT reduction or microbiota-targeted strategies can improve cognitive or neuroimaging outcomes.
Obesity reshapes systemic iron handling, yet the resulting iron phenotype is frequently misclassified at the bedside and in population studies. This review examines how excess adiposity disturbs iron metabolism and complicates iron-status assessment, with balanced attention to biology and measurement problems across adults and children. Adipose tissue is an endocrine, inflammatory, and iron-handling organ. In obesity, interleukin-6 drives hepatic hepcidin through JAK/STAT3 signaling, while leptin, adipose hypoxia, and adipose hepcidin expression may contribute additional signals. Hepcidin degrades ferroportin, reducing duodenal iron export and limiting macrophage iron release, producing hypoferremia and iron-restricted erythropoiesis despite normal or elevated ferritin. We and others have shown that women with obesity may have higher hepcidin, ferritin, and inflammatory markers but lower serum iron. Stable-isotope and intervention studies suggest weight loss reduces inflammation and hepcidin and improves iron absorption, whereas the World Health Organization and Biomarkers of Nutrition for Development frameworks recommend interpreting ferritin relative to inflammation. Iron status in obesity spans a continuum from absolute or functional iron deficiency to sufficiency and, in some individuals, hyperferritinemia with possible dysmetabolic iron overload. Reliable assessment requires a multi-marker strategy: ferritin interpreted alongside an inflammation marker such as C-reactive protein and supported by transferrin saturation, soluble transferrin receptor, reticulocyte hemoglobin, or other context-appropriate indices. Management should address reversible inflammation through weight loss and metabolic risk reduction, use oral or intravenous iron according to the likelihood of true deficiency and hepcidin-mediated oral refractoriness, and avoid reflexive phlebotomy for dysmetabolic hyperferritinemia without confirmed overload.
This review aims to summarize the current knowledge on the role of mechanical-gated ion channel PIEZO in body metabolism and metabolic diseases, as well as the latest evidence of PIEZO1 channels as a therapeutic strategy for metabolic diseases. PIEZO channels are mechanosensitive ion channels that play a crucial role in converting mechanical stimuli into biological signals. They participate in numerous physiological and pathological processes within the human body. Recently, the importance of PIEZO channels in body metabolism and metabolic diseases has garnered significant attention. This review summarizes the current status of research in carbohydrate and lipid metabolism, energy metabolism, and bone metabolism. It also examines the role and mechanisms of PIEZO channels in obesity, diabetes and its complications, osteoporosis, metabolic syndrome, and other diseases. Furthermore, we organize and discuss the potential for targeting PIEZO channels through multi-faceted therapeutic strategies to treat metabolic diseases. PIEZO channels play a crucial role in the body's metabolism, regulating the body's glucose metabolism, energy metabolism, lipid metabolism, and bone metabolism. Moreover, PIEZO channels are potential therapeutic targets for metabolic diseases, capable of preventing and treating obesity, diabetes and its complications, osteoporosis, metabolic syndrome, and other diseases.
This review summarizes current evidence on the treatment of obesity in the solid organ transplant setting and identifies evidence gaps. Lifestyle modification, pharmacotherapy, and metabolic and bariatric surgery are all potential options for management of obesity in the setting of solid organ transplantation. Limited available data on use of incretin-based pharmacotherapy in solid organ transplantation support its safety and effectiveness in appropriately-selected patients, however prospective large-scale studies are needed. Obesity treatment is an important component of transplant care, as obesity is associated with increased mortality and adverse graft outcomes. Lifestyle modification, anti-obesity pharmacotherapy, and metabolic and bariatric surgery can be employed safely in both pre- and post-transplant settings. Newer incretin-based pharmacotherapy, including glucagon-like peptide 1 (GLP-1) receptor agonists and dual GLP-1 receptor agonist/gastric inhibitory polypeptide offer potential for substantial weight loss and improved cardiometabolic outcomes. Bariatric and endoscopic metabolic procedures can be beneficial in carefully selected patients pre- or post-transplant. Precision approaches including sarcopenic obesity and measurement of body composition can help tailor interventions. These developments highlight the importance of multidisciplinary management and underscore the need for additional research within transplant populations.
Exercise is a cornerstone intervention for obesity and related metabolic diseases. However, its systemic benefits cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity, or improved peripheral insulin sensitivity alone. We review recent advances in exercise-responsive exerkines, with a focus on how these factors coordinate inter-organ crosstalk among major metabolic organs, including skeletal muscle, adipose tissue, liver, pancreas, and intestine. Both acute exercise and chronic training change the secretory profiles of multiple organs, giving rise to a broad spectrum of exercise-responsive factors, including proteins, metabolites, lipids, nucleic acids, and extracellular vesicle-associated cargo. Collectively, these exerkines coordinate inter-organ communication and regulate systemic energy homeostasis, inflammation, and tissue function, thereby promoting metabolic adaptation and mitigating lipotoxicity and insulin resistance. Among the candidates identified to date, IL-6, FGF21, GDF15, and myostatin have undergone relatively advanced translational investigation. Their development highlights both the therapeutic promise and the limitations of exerkine-based strategies, as illustrated by FGF21 analogues for metabolic diseases and the limited efficacy or tolerability reported for some GDF15-targeted interventions. Exerkines provide a molecular framework for understanding how exercise produces coordinated metabolic adaptations across organs. However, most candidate exerkines still require stronger human validation, clearer tissue-source attribution, defined receptor pathways, dose–response characterization, and long-term safety assessment. Exerkine-based strategies should therefore be viewed not as replacements for exercise, but as potential complementary approaches for populations with limited exercise capacity, including frail older adults, patients with cardiopulmonary disease, individuals with severe obesity or neuromuscular disorders, and those recovering from surgery or prolonged bed rest.
The Carbohydrate-Insulin Model (CIM) of obesity proposes that dietary carbohydrates particularly high-glycemic carbohydrates, drive weight gain by stimulating insulin secretion, thereby promoting fat storage, increasing hunger, and reducing energy expenditure (EE). According to this framework, hyperinsulinemia is viewed as the primary causal factor in obesity, with positive energy balance emerging as a downstream consequence of altered fuel partitioning. In contrast, the Energy Balance Model (EBM) conceptualizes obesity as the result of sustained excess energy intake (EI) relative to expenditure, with insulin dysregulation arising secondary to increased adiposity. This review critically evaluates the CIM across eleven complementary lines of evidence, including isocaloric and ad libitum dietary interventions, EE studies, population-level dietary trends, glycemic index (GI) manipulations, Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies, overfeeding experiments, the insulinotropic effects of protein, central effects of insulin on appetite, insulin spikes and 24-hour fat balance, temporal relationships between hyperinsulinemia and obesity, and de novo lipogenesis (DNL). Although some findings remain compatible with contemporary formulations of the CIM, several lines of evidence are difficult to reconcile with some of its central predictions (i.e. the insulinotropic yet anti-obesogenic effects of dietary protein, the central anorexigenic role of insulin). However, many studies aimed at directly testing its predictions are limited in their ability to definitively distinguish between competing models owing to design constraints, intervention-related confounding, or limitations in the available data. Any single line of evidence reviewed in this article may be insufficient, in isolation, to draw definitive conclusions regarding the validity of the CIM. However, when considered collectively, the available mechanistic, clinical, and epidemiological evidence suggests that the CIM may not provide a fully comprehensive explanation for the etiology of common obesity. While insulin dynamics and carbohydrate quality are undoubtedly relevant to metabolic health and body-weight regulation, the available evidence does not consistently support their role as the primary drivers of obesity proposed by contemporary formulations of the CIM.
Obesity affects a growing proportion of reproductive-age women, yet the postpartum period remains underrecognized as an opportunity for improving long-term maternal health. Pregnancy induces metabolic, inflammatory, and behavioral changes that, combined with pre-pregnancy obesity, may predispose women to persistent postpartum weight retention, incomplete metabolic recovery, and elevated lifetime risk of type 2 diabetes and cardiovascular disease. This narrative review synthesizes current evidence on the biological, behavioral, and structural determinants of postpartum health among women with obesity, with an emphasis on modifiable intervention targets. Recent findings suggest that postpartum metabolic recovery is often incomplete or delayed in women with obesity, characterized by persistent insulin resistance, dyslipidemia, and inflammation. Postpartum weight retention is a major driver of long-term cardiometabolic risk and is influenced by lactation, sleep disruption, mental health, diet and physical activity, and caregiving demands. Lactation confers meaningful metabolic benefits, yet women with obesity face disproportionate barriers to breastfeeding. Lifestyle interventions demonstrate modest though clinically important benefits, but engagement, reach, and sustainability are limited by health system gaps, competing postpartum priorities, and social determinants of health. Emerging work highlights the promise of digital tools, supportive health policies, and individualized risk-stratification approaches, while the rapid expansion of pharmacologic treatment of obesity raises new, important questions. The postpartum period represents an important yet underutilized opportunity to support the lifelong health of women with obesity. Optimizing postpartum care through precision-informed strategies and supportive policies may improve maternal cardiometabolic health, reduce long-term disease risk, and interrupt intergenerational transmission of obesity.
This narrative review aims to critically summarize available data on the association between adult acromegaly and metabolic dysfunction–associated steatotic liver disease (MASLD), with a particular focus on clinical associations and treatment implications. From a pathophysiological perspective, growth hormone (GH) may improve hepatic steatosis, inflammation, and fibrosis by acting directly on hepatocytes and indirectly (through insulin–like growth factor–1) on hepatic stellate cells, thereby inducing their senescence. Nonetheless, GH excess may also favor the development of hepatocellular carcinoma, possibly through mechanisms unrelated to hepatic fibrosis. From a clinical perspective, individuals with acromegaly have low rates of hepatic steatosis and visceral adipose tissue (VAT), but high insulin resistance (IR), which contradicts the generally observed positive association between IR and VAT or hepatic steatosis. By contrast, limited data do not support lower rates of hepatic fibrosis in acromegaly, possibly because GH excess is controlled after diagnosis. From a therapeutic perspective, published evidence, derived mainly from case series, suggests that surgical or pharmacological management of acromegaly increases hepatic steatosis and VAT, despite decreasing IR. However, the long–term effect of acromegaly control on hepatic inflammation and fibrosis remains largely unknown. Acromegaly is associated with IR, type 2 diabetes mellitus, hypertension and cardiovascular disease; however, acromegaly is inversely associated with VAT and MASLD. Further mechanistic and clinical studies are warranted to better elucidate the intriguing association between acromegaly and MASLD.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is an increasingly prevalent complication of obesity and metabolic dysregulation, with limited therapies targeting upstream drivers of disease. Adipose tissue has emerged as a central regulator of systemic metabolic homeostasis, where dysfunction contributes to excess free fatty acid flux, chronic inflammation, and hepatic steatosis. In this context, adipose tissue browning—the induction of thermogenically active beige adipocytes within white adipose depots—has gained attention as a potential therapeutic mechanism. Recent advances highlight that adipose browning modulates multiple pathways relevant to MASLD. These include enhanced mitochondrial β-oxidation and energy expenditure, leading to reduced lipid delivery to the liver, as well as endocrine signaling mediated by batokines such as fibroblast growth factor 21 (FGF21), irisin, and neuregulin 4 (Nrg4). Collectively, these pathways influence hepatic lipid metabolism, insulin sensitivity, and inflammatory and fibrotic processes. The preclinical studies consistently demonstrate metabolic and hepatoprotective benefits of browning; however, translational evidence in humans remains limited and heterogeneous. Factors such as reduced thermogenic capacity in obesity, inter-individual variability, and challenges in sustaining browning activation constrain clinical applicability. Overall, adipose tissue browning represents a promising component of a systems-based approach to MASLD. Future work should focus on integrating mechanistic insights with clinical investigation to clarify its therapeutic potential and to identify strategies that enable durable and patient-specific metabolic benefits.
This review aims to provide a summary of treatment strategies for hypothalamic obesity (HO) and the latest data on pharmacologic interventions for HO. We summarize new consensus diagnostic criteria for acquired HO, non-pharmacologic interventions such as diet and physical activity, medications including the newly FDA approved setmelanotide, metabolic and bariatric surgery, and emerging treatment strategies that address the complex pathophysiology of HO. Hypothalamic obesity is caused by hypothalamic injury that impairs energy balance, metabolism, and satiety and leads to refractory obesity that is resistant to traditional diet and exercise interventions. Despite recent progress, effective long-term management of HO remains challenging, with few controlled trials, significant heterogeneity in patient response, and lack of long-term follow up data. A new medication targeting the melanocortin-4 receptor (MC4R) pathway was recently approved for treatment with additional newer drugs in development [1].
Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot implicated in cardiometabolic and cardiovascular (CV) disease. Although cardiac magnetic resonance (CMR) and cardiac computed tomography (cCT) enable accurate volumetric quantification of EAT, their cost, limited availability, and—particularly for cCT—radiation exposure, restrict their use in preventive and longitudinal settings. Transthoracic echocardiography (TTE) is widely accessible and radiation-free, but its validity as a surrogate of volumetric EAT assessment and its broader clinical role remain incompletely defined. To systematically synthesize disease-specific evidence linking TTE-derived EAT thickness with major CV phenotypes and to quantitatively assess its association with volumetric EAT measured by CMR or cCT. A systematic search of PubMed and PubMed Central (January 2000–December 2025) identified adult studies evaluating associations between TTE-derived EAT thickness and coronary artery disease (CAD), atrial fibrillation (AF), or heart failure with preserved ejection fraction (HFpEF), and correlations between TTE-derived EAT thickness and CMR- or cCT-derived EAT volume. Correlation coefficients were pooled using a random-effects model after Fisher’s z-transformation. An exploratory meta-analysis assessed associations with major adverse cardiovascular events (MACE). Seventeen disease-specific studies consistently demonstrated associations between increased TTE-derived EAT thickness and CAD severity, AF burden and recurrence, and adverse HFpEF phenotypes. Five validation studies were included; four comparing TTE with CMR were pooled, yielding a moderate-to-strong correlation (r = 0.77, 95
Obesity is a multifactorial, chronic, and relapsing non-communicable disease characterized by excessive adipose tissue accumulation and metabolic dysfunction. Increasing evidence indicates that biological sex influences not only the development and distribution of adipose tissue but also responses to obesity treatments, including metabolic-bariatric surgery. This narrative review synthesizes current evidence on sex-related differences in metabolic outcomes after bariatric surgery. Bariatric surgery induces substantial weight loss and marked improvement of obesity-related complications in both men and women along sex-specific differences in body composition changes, adipose tissue remodeling, adipokine secretion, inflammatory responses, and thermogenic adaptations. Estrogen signaling contributes to a more favorable adipose tissue phenotype through anti-inflammatory effects, enhanced adipokine profiles, preservation of lean mass, and stimulation of white adipose tissue beiging, a process by which an inducible form of thermogenic adipocytes within white adipose tissue (beige adipocytes) acquire thermogenic characteristics similar to brown adipose tissue. In women, menopausal status represents a key biological modifier of these responses. In contrast, androgen excess is associated with visceral fat accumulation and insulin resistance. Despite largely comparable rates of remission of major obesity-related complications between sexes, variances in adiposity, hormonal milieu, and postoperative metabolic outcomes suggest different underlying mechanisms. Although remission rates of obesity-related complications appear broadly comparable between sexes, the underlying metabolic and endocrine adaptations differ. Biological sex represents a determinant of post-bariatric metabolic remodeling. This review highlights the relevance of biological sex in obesity and its treatment, emphasizing the need for sex-stratified studies to elucidate underlying mechanisms and support the development of more precise, personalized strategies in obesity management. Biological sex influences metabolic and compositional outcomes following bariatric surgery, including adipose tissue remodeling, adipokine secretion, and body composition changes. The direction and magnitude of reported sex differences are not fully consistent across studies. Apparent sex-related differences are frequently shaped by baseline disparities in age, BMI, adiposity, and complications. Menopause critically modifies adipose tissue distribution, inflammatory status, and thermogenic activity, and should be systematically considered in future studies. Procedure selection (e.g., SG vs. RYGB) and heterogeneity in follow-up duration further limit direct comparisons.
Community-based interventions (CBIs) are widely used to address behavioral risk factors for non-communicable diseases, yet evidence of their effectiveness in low- and middle-income countries (LMICs) remains limited. This study systematically reviewed evidence on the effectiveness of CBIs promoting physical activity (PA) and/or reducing sedentary behavior (SB) among community-dwelling adults in LMICs. We searched PubMed, Embase, Scopus, and the Cochrane Library (2000–2024) for CBIs in LMICs. Primary outcomes were changes in PA and/or SB. Descriptive and graphical depictions were used to draw inferences. We selected 24 studies (11 RCTs) from 15,396 for review. Most studies (n = 16) reported significant improvements in PA outcomes. Changes were observed in Metabolic Equivalents (+ 100 - +2,700), moderate-to-vigorous PA (+ 7 to + 60 min/week), and steps/day (+ 3,000). Broadly, interventions were delivered using digital/technology format (n = 10), peer-led/community health worker-facilitated (n = 8), and Environmental restructuring (n = 6), with the digital interventions depicting the most consistent significant improvements. Two studies directly measured SB as a primary outcome. Short- (≤ 6 months; n = 11) and medium-duration (6–12 months; n = 4) interventions more frequently reported significant PA improvements than long-duration interventions (> 12 months; n = 9). PA/SB-focused CBI demonstrated proportions of significant effects similar to those of broader lifestyle interventions (88.9
Lifestyle modification is a well-established approach for improving metabolic health and reducing ectopic fat accumulation in the liver. The Melbourne Consensus has recently highlighted intrapancreatic fat deposition (IPFD) as an important fat depot, playing a key role in the development of both endocrine and exocrine pancreatic diseases. Nevertheless, the existing literature on the impact of lifestyle modification on IPFD has not been systematically synthesized. We conducted a comprehensive systematic review and meta-analysis to assess the effects of lifestyle modification on IPFD. A systematic literature search was conducted in PubMed and Embase databases to identify interventional studies evaluating the effects of lifestyle modification on IPFD measured by magnetic resonance-based techniques. Data were meta-analyzed using a random-effects model. Statistical heterogeneity was assessed using the I² statistic, and publication bias was evaluated with Egger’s test. A total of 23 studies were included. Lifestyle modification resulted in a significant reduction in IPFD (standardized mean difference [SMD] -0.26, 95
Obesity is a complex condition encompassing behavioral, psychological, and physiological factors, frequently associated with elevated mental health burden. Digital Mental Health Interventions (DMHIs) have emerged as promising tools to enhance accessibility, personalization, and scalability of psychological care in obesity management. However, evidence on their effectiveness across delivery modalities and outcomes remains fragmented. This systematic review aimed to evaluate the effectiveness of DMHIs on obesity-related clinical, behavioral, and psychological outcomes; examine whether specific delivery modalities are differentially associated with particular outcomes; and identify methodological gaps to guide future research and implementation. A systematic search was conducted in PubMed, Scopus, PsycINFO, Cochrane Library, Web of Science, and Google Scholar. The review followed PRISMA guidelines, applying rigorous inclusion criteria and independent screening by two reviewers. Quality appraisal was performed using the Cochrane Risk of Bias Tool (RoB 2.0), and studies rated as high risk of bias were excluded. Due to heterogeneity in study design and outcomes, data were synthesized narratively, and no claims of statistical superiority between modalities were made. Thirty-eight randomized controlled trials were included. DMHIs effectively targeted behavioral and psychological aspects of obesity when based on evidence-based psychotherapeutic frameworks - often independently of weight-related improvements. No single delivery format emerged as universally superior; rather, each modality appeared to serve distinct therapeutic purposes. Outcomes were more favorable in interventions that incorporated human guidance, although this finding should be interpreted cautiously because of heterogeneity and the absence of meta-analytic comparisons. Digital mental health approaches—particularly when integrated into stepped-care or hybrid models—represent scalable, person-centered strategies to improve both physical and emotional well-being in adults with obesity.
This review examines infancy as a sensitive period for the development of reward learning and self-regulation and evaluates how early experiences with food and non-food rewards shape obesity risk. We sought to address three questions: how biological susceptibility influences early reward processing, how caregiving practices use food as a reward, and how non-food reinforcement modifies the relative reinforcing value of food (RRVfood) during early development. Recent evidence indicates that obesity risk may depend less on absolute food motivation and more on the relative reinforcing value of food (RRVfood), a behavioral economic construct reflecting how motivated one is for food in the context of available non-food alternatives. Studies show that feeding to soothe, instrumental feeding, and restriction can strengthen food-based reward learning, particularly among biologically susceptible infants. Conversely, enriched environments, responsive parenting, and cognitively, socially, and physically engaging non-food activities support self-regulation and lower obesity risk, even in socioeconomically disadvantaged contexts. Early obesity risk reflects an imbalance in reinforcement rather than excessive food motivation alone. Shifting the balance toward non-food rewards represents a promising, strength-based direction for future mechanistic and intervention research.
As life expectancy increases and the proportion of older adults grows worldwide, understanding how aging influences components of energy metabolism has become increasingly relevant. Diet-induced thermogenesis (DIT)—the increase in metabolic rate following food intake—accounts for approximately 10
This review aims to synthesize recent evidence to clarify the causal and mechanistic roles of lipid metabolism disorders as core drivers of type 2 diabetes mellitus (T2DM), and to summarize emerging therapeutic advances targeting key nodes within pathophysiological cascade, thereby providing an integrated, translational framework for the precision management of T2DM. Normoglycemic obese individuals with insulin resistance (IR) frequently exhibit elevated plasma free fatty acids (FFAs), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), alongside reduced high-density lipoprotein cholesterol (HDL-C). These observations indicate that dyslipidemia is not merely a comorbidity but an important early driver of T2DM progression. Lipid metabolism disorders initiate a unifying pathological cascade: ectopic lipid spillover induces systemic IR in the liver and skeletal muscle; lipotoxic stress directly compromises pancreatic β-cell function; and progressive disruption of inter-organ axes, including the gut–adipose–liver axis and brain–periphery axis, further exacerbates systemic metabolic deterioration. Recent evidence supports emerging therapeutic strategies, including traditional medicine-based approaches and interventions targeting lipotoxicity and the gut–brain–liver–fat axis to restore metabolic health. Lipid metabolism disorders are not merely complications of T2DM, but critical drivers of disease progression. Adipose dysfunction acts as the initiating event, triggering a pathological cascade that induces systemic IR, impairs pancreatic β-cell function via lipotoxic intermediates, and disrupts inter-organ communication networks. Targeted interventions along this axis therefore represent a promising strategy for precision therapy.
This review provides an overview of adipose tissue plasticity and adipogenesis as central processes regulating adipose tissue expansion, remodeling, and metabolic function in health and obesity, highlighting their relevance as potential therapeutic targets. Adipogenesis is a tightly regulated process involving the differentiation of adipose progenitor cells into mature adipocytes through coordinated transcriptional cascades, primarily driven by peroxisome proliferator–activated receptor (PPAR)γ and CCAAT/enhancer–binding protein (C/EBP) family members. This process is further modulated by multiple signaling pathways, including wingless–related integration site (Wnt), bone morphogenetic proteins (BMPs), and insulin signaling, which collectively regulate adipocyte differentiation and metabolic function. Under physiological conditions, the adipose tissue exhibits remarkable plasticity, with adipogenesis supporting lipid buffering capacity and tissue renewal. In obesity, however, chronic nutrient excess and hormonal dysregulation impair this process, favoring adipocyte hypertrophy, hypoxia, and chronic inflammation. These alterations disrupt adipokine secretion and promote ectopic lipid deposition, thereby contributing to metabolic disorders, including insulin resistance and cardiometabolic disease. Adipose tissue plasticity and adipogenesis are critical determinants of metabolic health. Dysregulation of these processes underlies adipose tissue dysfunction and contributes to the development of obesity-related comorbidities. Targeting adipogenesis and promoting healthy adipose tissue remodeling represent promising strategies for restoring metabolic homeostasis and mitigating obesity-associated diseases.
Waist circumference (WC) in combination with body mass index (BMI) provides unique opportunities to capture the heterogeneous nature of obesity and identify phenotypes that convey the greatest health risk. This review summarizes evidence supporting global recognition that WC and BMI should be routinely documented in health care. Differences in risk stratification when WC and BMI are used in categorical versus continuous models are examined, and strategies to increase routine measurement in clinical settings are discussed. Leading authorities worldwide including the Lancet Obesity Commission and the European Association for the Study of Obesity recognize obesity as a heterogeneous condition requiring combined interpretation of WC and BMI to identify distinct phenotypes. Obesity-related risk differs substantially depending on whether WC and BMI are treated as categorical or continuous measures. Current risk stratification systems rely on categorical approaches that have clinically relevant limitations, including loss of risk resolution from applying a single WC cut-point across BMI categories. Evidence further shows that associations between WC and adverse outcomes strengthen after adjustment for BMI, and that when WC and BMI are modeled simultaneously as continuous variables, WC consistently emerges as a stronger predictor of health outcomes, while associations with BMI are attenuated or reversed. WC and BMI combined are simple tools that facilitate the identification of obesity heterogeneity and phenotypes associated with elevated health risk. Risk estimates differ depending on whether WC and BMI are modeled as categorical or continuous variables, with implications for how obesity-related risk is assessed and interpreted in practice. Recommendations for their optimal combined use, including a proof-of-concept nomogram to support clinical interpretation, are provided. Despite guideline recommendations worldwide, BMI and WC remain infrequently documented in clinical practice. This implementation gap represents a missed, low-cost opportunity to improve public health messaging, risk stratification, and clinical management of obesity-related risk.
