Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity
Abstract
1. Introduction
2. Definitions and Diagnostic Criteria
2.1. Traditional Criteria of MHO
- The absence of metabolic syndrome components according to various definitions (e.g., NCEP ATP III, and IDF);
- Homeostasis model assessment of insulin resistance (HOMA-IR) below specific thresholds;
- Cardiometabolic risk factor clustering (including blood pressure, lipids, and glucose parameters);
- The absence of specific complications such as hypertension, dysglycemia, or dyslipidemia.
Criterion | Meigs (2006) [15] | Karelis (2004/2008) [4,16] | Wildman (2008) [17] | Aguilar-Salinas (2008) [18] | Lynch (2009) [19] | BioSHaRE-EU (2014) Less Strict [20] | BioSHaRE-EU (2014) Strict [20] | Zembic et al. (2021) [14] | Wang et al. (2023) [21] |
---|---|---|---|---|---|---|---|---|---|
Insulin sensitivity/resistance | |||||||||
HOMA-IR | ≤2.5 | ≤1.95 | ≤5.13 | - | - | - | - | - | - |
Matsuda index | - | ≥7.2 | - | - | - | - | - | - | - |
Blood pressure (mmHg) | |||||||||
Systolic | <130 | <140 | <130 | <140 | <130 | <140 | <130 | <130 | <140 |
Diastolic | <85 | <90 | <85 | <90 | <85 | <90 | <85 | - | <90 |
Anti-hypertensive medication | No | No | No | No | No | No | No | No | No |
Glucose metabolism | |||||||||
Fasting glucose (mg/dL) | <100 | <100 | <100 | <100 | <100 | <110 | <100 | - | <100 |
2h glucose (mg/dL) | <140 | - | - | - | - | - | - | - | - |
HbA1c (%) | <5.7 | - | - | - | - | - | - | - | - |
Diabetes diagnosis | No | No | No | No | No | No | No | No | No |
Glucose-lowering medication | No | No | No | No | No | No | No | - | No |
Lipids | |||||||||
Total or LDL cholesterol (mg/dL) | Total < 200 | Total < 200 | LDL < 130 | Total < 200 | Total < 200 | - | - | - | Total < 240 |
HDL cholesterol (mg/dL) | >40 M, >50 F | >50 | >40 M, >50 F | >40 | >40 M, >50 F | >40 M, >50 F | >60 M, >70 F | - | >40 M, >50 F |
Triglycerides (mg/dL) | <150 | <150 | <150 | <150 | <150 | <150 | <100 | - | <150 |
Lipid-lowering medication | No | No | No | No | No | No | No | - | No |
Anthropometric measures | |||||||||
Waist circumference (cm) | <102 M, <88 F | - | <102 M, <88 F | - | <102 M, <88 F | <102 M, <88 F | <94 M, <80 F | - | <90 M, <85 F |
Waist-to-hip ratio | - | - | - | - | - | - | - | <0.95 F, <1.03 M | - |
Other biomarkers/indices | |||||||||
C-reactive protein (mg/L) | - | - | <3.0 | - | - | - | - | - | - |
Number of criteria required | All | ≥4 | ≤1 | All | All | ≤2 | All | All | All |
2.2. Metabolic Dysfunction-Associated Steatotic Liver Disease as an Emerging Criterion in MHO Definition
3. Global Prevalence and Demographic Characteristics
- Sex: Most studies report a higher MHO prevalence among women compared to men, potentially reflecting sex differences in body fat distribution and adipose tissue function [6]. Recent discoveries highlight significant sex-specific mechanisms, including the identification of CTRP10’s female-specific role in maintaining metabolic health during obesity [31]. A 2024 study demonstrated that adipose tissue insulin resistance is more pronounced in men than women, with men showing 10-fold lower insulin sensitivity and decreased adipose expression of insulin receptor substrate 1 (IRS1) [32]. Analysis of 9631 Saudi adults found females had significantly higher age-adjusted prevalence of MHO than males (OR = 1.22, 95% CI 1.1–1.4, p = 0.009) [33]. These sex-specific differences extend to therapeutic responses, with emerging evidence suggesting that women and men may respond differently to interventions aimed at maintaining or restoring metabolic health in obesity.
- Age: MHO is more common in younger individuals and decreases with advancing age, suggesting that metabolic health may deteriorate over time despite stable weight [6]. A longitudinal study of 9809 individuals found that genetic predisposition to higher BMI may protect against MHO conversion, though lifestyle factors did not predict conversion over 4 years [8].
- Ethnicity: Significant ethnic differences exist in MHO prevalence. Studies from Europe and North America have documented higher rates in populations of European descent compared to those of African, Hispanic, or South Asian ancestry [6]. A study examining 2350 Asian individuals with a BMI ≥ 25 kg/m2 reported that 13.3% met MHO criteria [34]. Recent analysis of Arab populations revealed leptin resistance as central to MHO-to-MUO progression, with significantly higher leptin levels in metabolically unhealthy groups [35].
- BMI: The prevalence of MHO typically decreases with increasing severity of obesity. Grade 1 obesity (BMI 30–34.9 kg/m2) shows approximately twice the prevalence of MHO compared to morbid obesity (BMI ≥ 40 kg/m2) [6].
4. Clinical Characteristics and Health Outcomes
4.1. Type 2 Diabetes Risk
4.2. Cardiovascular Disease Risk
4.3. Chronic Kidney Disease Risk
4.4. Cancer Risk
5. Pathophysiological Mechanisms Underlying MHO
5.1. Adipose Tissue Distribution Patterns
5.2. Adipose Tissue and Adipocyte Function
5.2.1. Lipogenic Capacity
5.2.2. Adipose Tissue Inflammation
5.2.3. Healthy Versus Unhealthy Adipose Expansion
5.2.4. Adipocyte-Specific Gene-Modified Animals
5.3. Genetic and Epigenetic Factors
5.3.1. Key Single-Nucleotide Polymorphisms
5.3.2. Population-Specific Genetic Associations
5.3.3. Epigenetic Contributions
5.3.4. Gene–Lifestyle Interactions
5.3.5. Epigenetic Memory of Obesity
5.4. Skeletal Muscle Characteristics
- Enhanced Mitochondrial Function: Muscle biopsies from subjects with MHO show higher mitochondrial content, enhanced oxidative enzyme activity, and more efficient respiratory chain function compared to individuals with MUO [38]. These differences correlate with improved insulin sensitivity and reduced intramyocellular lipid accumulation.
- Reduced Ectopic Lipid Deposition: Despite obesity, individuals with MHO maintain lower intramyocellular lipid content and altered lipid composition, with reduced ceramide and diacylglycerol species known to interfere with insulin signaling [38].
- Preserved Insulin Signaling: Molecular analyses of skeletal muscle from individuals with MHO demonstrate preserved insulin receptor substrate (IRS) phosphorylation and downstream Akt/PKB activation compared to subjects with MUO [52].
5.5. Liver Fat Content and Function
5.6. Lifestyle Factors
Nutritional Status and Targeted Dietary Interventions in MHO
- Replace saturated fats with PUFA-rich options (e.g., canola/soy/sunflower oils and fatty fish) to support adipose tissue expandability and insulin sensitivity mechanistically via PPARγ–LPCAT3 [93];
- Physical Activity: Individuals with MHO typically report higher levels of both leisure time and total physical activity compared to subjects with MUO [95]. A meta-analysis of 15 studies found that individuals with MHO engaged in approximately 30% more moderate-to-vigorous physical activity than their metabolically unhealthy counterparts. Meta-analysis of physical activity studies found that individuals MHO demonstrate higher physical activity levels, reduced sedentary behavior, and superior cardiorespiratory fitness compared to metabolically unhealthy obesity individuals, with higher fitness levels potentially preventing transition to metabolically unhealthy states [94]. Recent studies examining the effects of exercise on adipose tissue have revealed that “exercise is a potent behavioral intervention for preventing and reducing obesity and other metabolic diseases”: exercise appears to impose unique physiological stimuli that can alter angiogenesis and mitochondrial remodeling in adipose tissues, potentially promoting healthy adipogenesis. Studies in mice using 2H labeling techniques suggest that exercise may inhibit the generation of new adipocytes and extend the lifespan of existing adipocytes, potentially contributing to MHO [66].
- Cardiorespiratory Fitness: Independent of self-reported physical activity, measured cardiorespiratory fitness is significantly higher in individuals with MHO versus MUO. The HERITAGE Family Study demonstrated that higher baseline fitness and greater fitness improvements with exercise training predicted transition from MUO to MHO status.
- Dietary Patterns: Specific nutritional biomarkers (particularly carotenoids and vitamin D) are reportedly useful characteristics of MHO [90]. Some studies report that individuals with MHO consume more fish and vegetables and fewer sugar-sweetened beverages and saturated fatty acids [91], though others find no clear differences in total energy intake and nutrient intake between MHO and MUO [92]. Recent molecular insights have revealed how specific dietary lipid composition influences adipose tissue function. The PPARγ-LPCAT3 pathway demonstrates that dietary n-6 PUFA intake directly modulates adipose tissue expandability through membrane lipid remodeling [93]. This finding suggests that the quality of dietary fats, particularly the omega-6 PUFA content, may be as important as total fat intake in determining metabolic health outcomes in obesity. While this area requires further research in human populations, it provides a mechanistic basis for understanding how dietary composition influences the MHO phenotype.
- Sleep Quality: Some evidence suggests that individuals with MHO maintain more favorable sleep patterns, with lower prevalence of sleep disorders and more consistent sleep duration compared to subjects with MUO.
6. Temporal Stability and Transition Patterns
6.1. Transition Rates and Patterns
6.2. Predictors of Transition
- Age: Older individuals have significantly higher transition rates, with higher age associated with increased transition risk [97].
- BMI: Higher baseline BMI predicts greater likelihood of transitioning to MUO [97].
- Epigenetic Factors: Recent evidence shows that specific DNA methylation patterns predict transition, with 26 CpG sites differentially methylated between stable and unstable MHO [83].
6.3. Health Consequences of Transition
7. Pharmacological and Non-Pharmacological Interventions
7.1. Lifestyle Interventions
- Weight Loss: The impact of weight loss interventions in MHO remains somewhat controversial. Some studies suggest that weight reduction in individuals with MHO leads to improvements in inflammatory markers, liver fat content, and insulin sensitivity [99]. However, other studies have reported minimal metabolic benefits or even paradoxical worsening of certain parameters following weight loss in subjects with MHO [4].
- The HERITAGE Family Study found that individuals with MHO showed smaller improvements in insulin sensitivity and lipid profiles following weight loss compared to subjects with MUO, suggesting potentially different response patterns [92]. This has raised questions about the risk-benefit ratio of aggressive weight loss interventions in all individuals with MHO.
- Physical Activity: Exercise interventions appear particularly beneficial for individuals with MHO, often producing metabolic improvements independent of significant weight loss. A randomized controlled trial demonstrated that six months of moderate-intensity exercise in subjects with MHO led to significant reductions in visceral fat, liver fat, and systemic inflammation despite minimal changes in body weight [92]. A meta-analysis of seven intervention studies found that energy-restricted diet interventions combined with exercise effectively improved metabolic profiles for individuals with MHO [30].
7.2. Pharmacological Approaches
- Thiazolidinediones: These PPARγ agonists promote subcutaneous adipocyte differentiation and reduce ectopic fat deposition. Clinical trials have shown that pioglitazone and rosiglitazone can induce an “MHO-like” phenotype, characterized by increased subcutaneous fat but reduced liver fat and improved insulin sensitivity [102,103].
- SGLT2 Inhibitors: Emerging evidence from both animal models and clinical studies suggests that sodium-glucose cotransporter-2 (SGLT2) inhibitors may promote “healthy adipose expansion” while reducing ectopic fat deposition and improving metabolic parameters [104,105,106]. In metabolic dysfunction-associated steatohepatitis models, SGLT2 inhibitors have been shown to attenuate hepatic steatosis, inflammation, and fibrosis despite minimal weight reduction or even adipose tissue expansion [105].
- GLP-1 Receptor Agonists and GIP/GLP-1 Dual Agonists: The pharmaceutical landscape for obesity treatment is experiencing an unprecedented transformation. These agents appear to induce favorable changes in body composition beyond simple weight reduction. Recent studies with tirzepatide, a GIP/GLP-1 receptor dual agonist, have demonstrated preferential reduction in visceral fat compared to subcutaneous fat, potentially promoting a more metabolically favorable fat distribution pattern [107]. A comprehensive 2024 review highlights tirzepatide achieving up to 22.5% weight loss, with emerging triple agonists like retatrutide showing even greater efficacy [108]. The dual GIP/GLP-1 agonist could reduce cardiovascular risk and prevent conversion to metabolically unhealthy phenotype while maintaining metabolic health during weight loss [109].
- Novel Adipokine-Based Therapies: Emerging approaches targeting adipose tissue function through adipokine supplementation or receptor modulation are under investigation. Recombinant adiponectin, adiponectin receptor agonists, and agents targeting the newly discovered adipokine family of C1q/TNF-related proteins (CTRPs) have shown promising metabolic effects in preclinical studies.
8. Clinical Implications and Risk Stratification
8.1. Risk Stratification Tools
- Simplified MHO Criteria: Zembic et al. proposed a simplified clinical definition of MHO (systolic blood pressure < 130 mmHg, waist–hip ratio < 0.95 for women or <1.03 for men, and absence of diabetes) that outperformed traditional metabolic syndrome criteria in predicting cardiovascular outcomes [14]. This definition has been validated in multiple cohorts including the UK Biobank, Flemengho, and Hortega studies.
- Metabolic-BMI: This composite measure incorporates both BMI and metabolic factors into a single risk score, potentially providing more nuanced risk assessment than either measure alone.
- Liver Fat Indices: Recent developments in 2024 include enhanced diagnostic accuracy through combination approaches. Non-invasive assessments, including vibration-controlled transient elastography (VCTE), magnetic resonance elastography (MRE), and serum biomarkers, have high accuracy to diagnose advanced fibrosis and cirrhosis [111]. The newly developed LiverPRO algorithm, which obtained European CE approval in 2024, reliably identifies clinically significant liver fibrosis and elevated liver stiffness, predicting the risk of liver-related events in primary care [112]. AI-powered models utilizing non-contrast MRI, including T1WI and T2FS, accurately stage liver fibrosis [113], and AI enhances diagnostic accuracy and efficiency, aiding clinicians in making more informed treatment decisions [114].
- Using multiparametric MRI to quantify liver fat content has been suggested as a more precise method for risk stratification when available [6]. This approach provides a direct measurement of a key determinant of metabolic health in obesity.
- Triglyceride–Glucose Index: This simple index combining fasting triglycerides and glucose levels has demonstrated utility for identifying insulin resistance and predicting transition from MHO to MUO [110].
- Novel Biomarkers: ITLN1 (Omentin-1), produced by specific mesothelial cell populations, has been identified as significantly higher in individuals with MHO compared to MUO [58]. This adipokine was exclusively expressed by mesothelial cells within visceral adipose tissue and was not present in subcutaneous adipose tissue. Plasma Omentin-1 levels were significantly higher in MHO compared to MUO, establishing it as a promising marker for visceral adipose tissue functionality. Additional biomarkers include circulating microRNAs (miR-122-5p, miR-151a-3p, miR-126-5p, and miR-21-5p) and point-of-care technologies integrating miR-34a-5p, YKL-40, and comprehensive metabolomic panels [25].
8.2. Clinical Monitoring Strategies
- Comprehensive metabolic panel including liver enzymes;
- Lipid profile including triglyceride/HDL ratio;
- Anthropometric measurements including waist-to-hip ratio;
- Blood pressure assessment;
- Screening for metabolic dysfunction-associated steatotic liver disease (ultrasonography or biomarkers);
- Assessment of inflammatory markers (e.g., hsCRP) when available [115].
8.3. Personalized Intervention Approaches
- MHO Maintenance: For metabolically healthy individuals with mild obesity and no other clinical indications for weight loss, interventions focused on maintaining metabolic health rather than aggressive weight reduction might be appropriate. Physical activity promotion, Mediterranean-style dietary patterns, and monitoring for transition to MUO could be emphasized.
- Targeting Specific Metabolic Parameters: For individuals with MHO with emerging metabolic abnormalities in specific domains (e.g., borderline elevated blood pressure or glucose), targeted interventions addressing these specific parameters might be prioritized over general weight loss.
- Aggressive Approach for High-Risk MHO: For individuals with MHO with significant risk factors for transition to MUO (e.g., elevated liver fat, family history of diabetes, and advancing age), more aggressive lifestyle and potentially pharmacological interventions may be warranted despite current metabolic health.
- A personalized treatment algorithm based on stratification of obesity phenotypes has been proposed [6]. While all individuals with obesity should receive basic lifestyle interventions, additional pharmacological treatments should be tailored to specific metabolic risk profiles, with particular attention to those showing early signs of transition from MHO to MUO.
9. Future Directions
9.1. Standardized Definition and Classification
- Non-invasive assessments of ectopic fat deposition (liver, pancreas, and heart);
- Markers of adipose tissue function and expandability;
- Novel biomarkers reflecting inflammatory status;
- Genetic and metabolomic profiles predicting long-term metabolic resilience.
9.2. Mechanistic Insights
- Systems biology approaches integrating genomic, transcriptomic, proteomic, and metabolomic data;
- Advanced adipose tissue phenotyping techniques examining depot-specific function;
- Investigation of gut microbiome contributions to metabolic health in obesity;
- Exploration of brain–adipose tissue communication pathways;
- Elucidation of sex-specific mechanisms explaining the higher prevalence of MHO in women.
9.3. Longitudinal Natural History Studies
- Predictors of maintained metabolic health versus transition to MUO;
- Critical time windows for intervention to prevent metabolic deterioration;
- Impact of life-stage transitions (puberty, pregnancy, and menopause) on MHO stability;
- Influence of aging on metabolic protection mechanisms.
9.4. Intervention Studies
- Randomized trials comparing different lifestyle intervention strategies in MHO;
- Evaluation of pharmacological approaches targeting specific mechanisms underlying MHO;
- Studies examining the impact of various weight loss approaches on long-term outcomes in MHO;
- Determination of optimal monitoring and intervention thresholds for preventing transition to MUO.
9.5. Novel Therapeutic Targets
- Approaches promoting adipose tissue expandability and healthy remodeling;
- Therapies targeting ectopic fat redistribution rather than total weight reduction;
- Interventions modulating adipose tissue immunometabolism;
- Treatments targeting specific adipokine signaling pathways identified in MHO.
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
BMI | Body mass index |
DOI | Digital object identifier |
IRS | Insulin receptor substrate |
MASLD | Metabolic dysfunction-associated steatotic liver disease |
MHNW | Metabolically healthy normal weight |
MHO | Metabolically healthy obesity |
MUO | Metabolically unhealthy obesity |
NAFLD | Non-alcoholic fatty liver disease |
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Tsuchiya, K.; Tsutsumi, T. Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity. Biomolecules 2025, 15, 1278. https://doi.org/10.3390/biom15091278
Tsuchiya K, Tsutsumi T. Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity. Biomolecules. 2025; 15(9):1278. https://doi.org/10.3390/biom15091278
Chicago/Turabian StyleTsuchiya, Kyoichiro, and Takahiro Tsutsumi. 2025. "Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity" Biomolecules 15, no. 9: 1278. https://doi.org/10.3390/biom15091278
APA StyleTsuchiya, K., & Tsutsumi, T. (2025). Beyond the BMI Paradox: Unraveling the Cellular and Molecular Determinants of Metabolic Health in Obesity. Biomolecules, 15(9), 1278. https://doi.org/10.3390/biom15091278