Metabolically Healthy Obesity

Obesity, characterized by excessive body fat accumulation, is a significant public health concern globally and a major risk factor for numerous cardiometabolic diseases, including type 2 diabetes mellitus, hypertension, and dyslipidemia.^[1]However, a distinct phenotype exists within the obese population known as metabolically healthy obesity (MHO). Individuals with MHO maintain a high body mass index (BMI ≥ 30 kg/m² or higher, with some studies focusing on Class 2 or 3 obesity, BMI ≥ 35 kg/m²) but do not exhibit the typical metabolic complications associated with obesity.^[1]This subgroup challenges the traditional view that all obesity is inherently detrimental, suggesting a more complex interplay of factors determining metabolic health.

Biological Basis

The existence of metabolically healthy obesity indicates underlying biological mechanisms that differentiate it from metabolically unhealthy obesity. Research suggests that factors beyond overall body weight contribute to this phenotype. Key biological distinctions include differences in fat distribution, with MHO individuals often having reduced abdominal fat mass and increased gluteofemoral (hip and thigh) fat mass, which is considered a metabolically protective fat depot.^[2] Other reported contributors to the MHO phenotype involve aspects of lipodystrophy, adipogenesis (the formation of fat cells), inflammation, and mitochondrial function.^[2] Furthermore, a critical component of MHO is thought to be a protective genetic predisposition.^[1]Genome-wide association studies (GWAS) have been instrumental in identifying single-nucleotide polymorphisms (SNPs) and genetic variants associated with the MHO phenotype.^[2]These genetic insights can reveal specific biological pathways, potentially involving dietary behavior, lipid metabolism, insulin sensitivity, and immune responses, that confer resilience to metabolic dysfunction despite obesity.^{[1], [2]}

Clinical Relevance

The clinical relevance of metabolically healthy obesity lies in its potential to refine risk stratification and personalize treatment approaches for individuals with obesity. Identifying the genetic and biological markers of MHO can help distinguish individuals who are at lower immediate risk for cardiometabolic complications from those who require more aggressive intervention.^[2]This understanding can guide healthcare providers in developing targeted strategies for preventing and managing obesity-related diseases, moving beyond a “one-size-fits-all” approach. It also offers novel targets for therapeutic development aimed at improving metabolic health regardless of body weight.^[2]

From a societal perspective, understanding metabolically healthy obesity has significant implications for public health messaging and reducing the stigma associated with obesity. It highlights the heterogeneity of obesity, emphasizing that metabolic health is not solely determined by BMI. This can promote a more nuanced conversation about weight, health, and lifestyle, encouraging a focus on metabolic health markers rather than just body size. By identifying individuals with a protective genetic makeup, research into MHO contributes to a broader understanding of human metabolism and disease susceptibility, potentially informing future public health campaigns and personalized medicine initiatives.

Methodological and Statistical Limitations

Research into metabolically healthy obesity (MHO) faces several methodological and statistical constraints that can impact the reliability and generalizability of findings. Many studies suffer from limited sample sizes, which restrict the power to detect genetic factors associated with small to moderate increases in obesity risk or to identify significant differences when comparing various metabolic phenotypes . Whilers9028 itself has not been directly linked to obesity or metabolic disease in some studies, variations in bitter taste receptor genes are known to influence factors like obesity risk, glucose and insulin homeostasis, and circulating thyroid hormone levels, suggesting an indirect impact on metabolic health through altered nutrient sensing or dietary preferences.^[1] Similarly, variants in the TOX2 gene, specifically rs6093921 , hold relevance for metabolically healthy obesity.TOX2 acts as a transcriptional activator involved in the hypothalamo-pituitary-gonadal system, and its expression is associated with the regulation of the transcription factor TBX21.^[1] Research indicates that TBX21-deficient mice develop increased fat mass but exhibit improved insulin sensitivity, suggesting that polymorphisms inTOX2 that lead to decreased expression could indirectly contribute to a metabolically healthy obese phenotype by influencing TBX21 levels.^[1] Furthermore, the KCNQ1 gene, where rs2283208 is located, encodes a potassium channel vital for pancreatic beta-cell function and insulin secretion; thus, variations inKCNQ1can influence glucose regulation and insulin sensitivity, key determinants of metabolic health in individuals with obesity.

Other variants affect genes involved in fundamental cellular processes and immune responses. For example, variants in the QKI gene, including rs6928576 , rs6902153 , and rs10945918 , are found near the RN7SL366P pseudogene. QKI is an RNA-binding protein essential for various RNA processing events, such as splicing and stability, which are fundamental for proper cellular function and development, including metabolic processes. Alterations in QKIactivity due to these variants could therefore impact gene expression pathways involved in adipose tissue function, energy balance, or insulin signaling, influencing an individual’s metabolic health status despite obesity. Another intergenic variant,rs9736016 , is located between the Y_RNA region and the CXCR5 gene.^[1] CXCR5 is a chemokine receptor primarily involved in immune cell trafficking and the development of lymphoid organs.^[1]Given that chronic low-grade inflammation is a significant factor distinguishing metabolically healthy from unhealthy obesity, variations nearCXCR5 might modulate inflammatory responses, potentially contributing to a healthier metabolic profile in obese individuals.

Several additional variants are situated in intergenic regions or within pseudogenes, which can nonetheless exert regulatory effects on nearby functional genes. For instance, rs7149926 is found in the region between the MAGOH3P and BLZF2P pseudogenes. Similarly, rs17573102 is located between the UBL5P1 and ZCCHC10P2 pseudogenes, while rs2470315 lies in the CCDC179 - LINC02718 region. LINC02718 is a long intergenic non-coding RNA, a class of molecules known to regulate gene expression through various mechanisms, including chromatin remodeling and transcriptional control. Additionally, variants rs11753543 and rs9384860 are found in the SOCS5P5 - LINC02518 region, and rs7635777 is located between P2RY1 and HMGN2P13. Such genomic regions, even those not directly encoding proteins, are increasingly recognized for their roles in modulating gene expression and influencing complex traits like obesity and metabolic health, potentially affecting lipid metabolism, glucose homeostasis, or inflammatory pathways.^[3]These variants, by altering regulatory elements or non-coding RNA function, could subtly shift metabolic processes, contributing to the maintenance of metabolic health even in the presence of obesity, as observed in genome-wide association studies identifying new loci for anthropometric traits.^[4]

Conceptualization and Core Definition

Metabolically healthy obesity (MHO) defines a distinct phenotype within the broader spectrum of adiposity, characterized by the presence of obesity without the typical associated cardiometabolic complications such as type 2 diabetes, dyslipidemia, or hypertension.^[1]This conceptualization challenges the direct link between adiposity and metabolic disease, suggesting that some individuals possess a protective mechanism or genetic predisposition that allows them to maintain metabolic health despite excess body fat.^[1] While the precise biological mechanisms underpinning this resilience are not fully elucidated, research indicates associations with factors like reduced abdominal fat mass, increased gluteofemoral fat mass, and differences in lipodystrophy, adipogenesis, inflammation, and mitochondrial function.^[2]The existence of MHO highlights a critical distinction between adiposity as a physical trait and its metabolic consequences, prompting a re-evaluation of obesity as a uniformly pathogenic condition. This phenotype is often considered to represent a subgroup of the general population with a potentially protective genetic architecture against obesity-related diseases.^[1]The recognition of MHO is significant for understanding the heterogeneity of obesity and for developing more personalized approaches to prevention and treatment, moving beyond a sole focus on Body Mass Index (BMI) as a health indicator.

Operational Definitions and Diagnostic Criteria

Operational definitions of metabolically healthy obesity typically involve a dual assessment: an obesity criterion based on Body Mass Index (BMI) and a metabolic health criterion based on a panel of clinical biomarkers. For individuals of European descent, obesity is commonly defined as a BMI ≥ 30 kg/m², with further classifications into Class 1 (30 to < 35 kg/m²), Class 2 (35 to < 40 kg/m²), and Class 3 (≥ 40 kg/m²).^[1]In contrast, populations in the Asia-Pacific region often use a lower threshold, defining obesity as a BMI ≥ 25 kg/m² in accordance with regional guidelines from the World Health Organization and International Obesity Task Force.^[2]These variations underscore the importance of population-specific anthropometric criteria in defining obesity phenotypes.

The metabolic health component is generally determined by the absence of, or a limited number of, cardiometabolic risk factors. A common research criterion defines a metabolically healthy individual as one presenting with less than two of the following four metabolic traits: elevated blood pressure (systolic/diastolic blood pressure ≥ 130/85 mm Hg or on antihypertensive medication), impaired fasting plasma glucose (≥ 100 mg/dL, diagnosis of diabetes mellitus, and/or on antidiabetic medication), high plasma triglycerides (≥ 150 mg/dL), and low high-density lipoprotein cholesterol (HDL-C) (< 40 mg/dL in men or < 50 mg/dL in women).^[2]These diagnostic thresholds are typically assessed through overnight fasting blood samples for glucose, triglycerides, and HDL-C, along with blood pressure measurements, to categorize individuals into distinct metabolic phenotypes.^[2]

Classification Systems and Nomenclature

The concept of metabolically healthy obesity is integrated into broader classification systems that categorize individuals based on both their BMI and metabolic status, creating a more nuanced understanding of health risks. A widely used framework classifies individuals into four distinct phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUHNW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUHO).^[2]This categorical approach allows for the study of the complex interplay between body composition and metabolic health, revealing that metabolic health can vary independently of weight status.^[2] The primary terminology, “Metabolically Healthy Obese” (MHO), is widely adopted in scientific literature to describe this specific subgroup.^[1]Related descriptive phrases include “individuals who were metabolically healthy but significantly obese” and “obesity without cardiometabolic diseases,” emphasizing the key characteristics of the phenotype.^[1]This nomenclature helps distinguish MHO from metabolically unhealthy obesity (MUHO), where excess adiposity is accompanied by metabolic dysregulation, and also from metabolically unhealthy normal weight (MUHNW), highlighting that metabolic dysfunction is not exclusive to obesity.^[2]The recognition of MHO as a specific subgroup within the general population underscores its significance for investigating potential genetic associations and protective genotypes related to cardiometabolic disease.^[1]

Genetic Underpinnings of Metabolic Health in Obesity

Metabolically healthy obesity (MHO) is significantly influenced by an individual’s genetic makeup, suggesting a protective genetic predisposition against the cardiometabolic complications typically associated with obesity. Genome-wide association studies (GWASs) have been instrumental in identifying numerous single nucleotide polymorphisms (SNPs) linked to the MHO phenotype. For example, a study focusing on significantly obese women without cardiometabolic diseases identified 89 SNPs associated with genes that influence dietary behavior, obesity, cardiometabolic disease, and neuroimmune function.^[1]These findings underscore the complex genetic architecture distinguishing MHO individuals from those with metabolically unhealthy obesity.

Specific genes play crucial roles in metabolic pathways, with some variants showing differential associations across metabolic phenotypes. For instance, GCKR, ABCB11, CDKAL1, CDKN2B, NT5C2, and APOC1are linked to metabolically unhealthy phenotypes in normal weight individuals but not in those with obesity.^[2] Genes such as GCKR and CDKAL1are particularly important for glucose and insulin metabolism, withGCKRmodulating glucokinase activity and insulin secretion, andCDKAL1 being essential for normal mitochondrial function and adipose tissue morphology.^[2] Conversely, LPL, APOA5, and CETP, involved in lipid metabolism, are associated with metabolically unhealthy phenotypes among obese individuals.^[2]This complex polygenic architecture, where multiple inherited variants interact, contributes to an individual’s unique metabolic health profile despite obesity.^[2]

Adipose Tissue Physiology and Cellular Mechanisms

Beyond specific genetic variants, the physiological characteristics of adipose tissue and its cellular functions are pivotal in determining metabolic health in obese individuals. A key distinguishing factor for the metabolically healthy phenotype is a reduced abdominal fat mass coupled with an increased gluteofemoral fat mass.^[2] This differential fat distribution, alongside processes such as lipodystrophy, adipogenesis, inflammation, and mitochondrial function, are reported as key contributors to the MHO phenotype.^[2] For instance, the gene CDKAL1 is directly involved in maintaining normal mitochondrial morphology and adipose tissue function, linking genetic predisposition to these crucial cellular mechanisms.^[2]Furthermore, while obesity can be associated with inflammation, as evidenced by serum hs-CRP concentrations, the specific inflammatory profiles in MHO individuals likely contribute to their preserved metabolic health.^[2]

Environmental and Lifestyle Influences

Environmental factors and lifestyle choices significantly contribute to both the development of obesity and the modulation of an individual’s metabolic health status. Modifiable factors such as a sedentary lifestyle, inadequate sleeping practices, and poor eating habits are widely recognized contributors to the general obesity epidemic.^[1]Additionally, less modifiable socioeconomic factors and the availability of proper nutrition also play a role in obesity prevalence.^[1]Specific dietary patterns, including daily energy intake and the consumption of fried foods, have been positively associated with an increased risk of obesity.^[2]Furthermore, non-modifiable demographic factors such as age and gender are known to influence obesity development, adding layers of complexity to the metabolic health profile observed in obese individuals.^[1]

Gene-Environment Interactions and Epigenetic Modulation

The interplay between an individual’s genetic background and their surrounding environment is a critical factor in the manifestation of MHO. Gene-environment interactions are considered fundamental in most instances of obesity development, where genetic predispositions can be either exacerbated or mitigated by external factors.^[1]Studies indicate that genetic factors interact with environmental elements, such as dietary patterns and physical activity, to influence both obesity risk and susceptibility to metabolic syndrome.^[2]This dynamic interaction highlights how lifestyle choices and environmental exposures can modify the expression of genetic susceptibilities, potentially explaining the maintenance of metabolic health despite obesity.^[2]Developmental and epigenetic factors further contribute to the MHO phenotype by influencing gene expression without altering the underlying DNA sequence. Epigenetic mechanisms, including DNA methylation and histone modifications, can regulate adipose morphology and function, thereby impacting metabolic health.^[5] These modifications, often influenced by early life experiences and environmental exposures, can lead to long-term changes in metabolic pathways and cellular functions, contributing to the observed variability in metabolic health among obese individuals.

The Phenotype of Metabolically Healthy Obesity

Metabolically healthy obesity (MHO) describes a distinct subgroup of individuals who, despite having a high body mass index (BMI) typically classified as Class 2 or 3 obesity (BMI ≥ 35 kg/m2), do not exhibit common cardiometabolic diseases such as type 2 diabetes, dyslipidemia, or hypertension.^[1] This phenomenon suggests a protective genetic predisposition that allows these individuals to maintain metabolic health despite excess adiposity.^[1]Understanding the biological mechanisms underlying MHO is crucial for identifying individuals at risk and developing targeted prevention strategies for obesity-related complications.^[2]The concept of MHO has been a subject of ongoing scientific debate, with some studies suggesting an increased risk of adverse outcomes like cardiovascular disease, while others support a protective benefit.^[1]This complexity highlights the need for comprehensive investigation into the molecular, genetic, and physiological factors that differentiate MHO individuals from those with metabolically unhealthy obesity (MUHO).^[1]Such research aims to uncover the homeostatic mechanisms that confer resilience against metabolic dysfunction in the presence of obesity.^[2]

Genetic and Epigenetic Influences on Metabolic Health

Genetic mechanisms play a significant role in determining an individual’s susceptibility to obesity and its associated metabolic complications.^[6]Genome-wide association studies (GWAS) have been instrumental in identifying single-nucleotide polymorphisms (SNPs) linked to the MHO phenotype, with one study identifying 89 statistically significant SNPs in a cohort of metabolically healthy obese women.^[1]These genetic variants are often associated with genes involved in biological pathways that influence diverse functions, including dietary behavior, cardiometabolic disease susceptibility, and even neuroimmune processes.^[1] Specific genes and their variants contribute to the metabolic profile observed in MHO. For instance, genes related to lipid metabolism, such as LPL, APOA5, and CETP, have been associated with metabolically unhealthy phenotypes in both normal weight and obese individuals.^[2] Other genes, including GCKR, CDKAL1, and CDKN2B, are linked to insulin and glucose metabolism, and their variants can impact glucose balance and insulin secretion.^[2]Epigenetic modifications, which involve changes in gene expression without altering the underlying DNA sequence, are also recognized as contributing factors to obesity, further highlighting the intricate regulatory networks at play.^[7]Furthermore, gene-environment interactions are considered obligatory for the development of obesity in most instances, suggesting that genetic predispositions interact with lifestyle factors to shape an individual’s metabolic trajectory.^[1]

Adipose Tissue Remodeling and Fat Distribution

The distribution and function of adipose tissue are critical determinants of metabolic health in obese individuals. A key characteristic associated with the metabolically healthy phenotype is a reduced abdominal fat mass combined with an increased gluteofemoral fat mass.^[2] Conversely, elevated abdominal fat and lower gluteofemoral fat contribute to the metabolically unhealthy phenotype, emphasizing the organ-specific effects of fat storage.^[2] This differential fat distribution reflects distinct patterns of adipogenesis, the process of fat cell formation, and lipodystrophy, which involves abnormal fat distribution, both of which are reported as key contributors to the MHO phenotype.^[2] The cellular functions within adipose tissue, including its capacity for healthy expansion and lipid storage, are crucial for systemic metabolic homeostasis. For example, the gene CDKAL1not only influences insulin response but is also necessary for normal mitochondrial morphology and overall adipose tissue function.^[2]The ability of adipose tissue to efficiently store lipids, regulate adipokine secretion, and maintain a low inflammatory state can confer protection against insulin resistance and other metabolic dysregulations, even in the context of increased overall body fat.^[2]

Molecular and Cellular Mechanisms of Metabolic Resilience

The metabolic resilience observed in MHO individuals stems from well-functioning molecular and cellular pathways that effectively manage nutrient processing and energy homeostasis. Central to this are robust glucose and insulin metabolism pathways. Key biomolecules like theGCKRprotein, which encodes a regulator of glucokinase activity, modulate glucose balance and glucose-stimulated insulin secretion.^[2] Similarly, CDKAL1is involved in proinsulin conversion and insulin response upon glucose stimulation, whileCDKN2Balso plays a role in glucose metabolism.^[2]Efficient regulation of these processes prevents hyperglycemia and insulin resistance, which are hallmarks of metabolic dysfunction.

Beyond glucose, lipid metabolism is tightly controlled in MHO individuals, involving critical proteins and enzymes such asLPL, APOA5, and CETP.^[2] LPLacts as a key regulator of lipolysis, and its proper function can mitigate the link between insulin resistance and atherosclerosis.^[2] Furthermore, mitochondrial function, which is essential for cellular energy production, is a significant contributor to the MHO phenotype, with genes like CDKAL1 being vital for maintaining normal mitochondrial morphology within adipose tissue.^[2]The absence of chronic low-grade inflammation, indicated by lower serum hs-CRP concentrations, also contributes to the metabolically healthy state, as inflammation is a key driver of metabolic disease.^[2] Finally, certain genetic factors, such as variants in MC4R and BDNF, may influence obesity risk by modulating appetite and feeding behavior, contributing to the overall metabolic balance.^[2]

Adipose Tissue Remodeling and Energy Homeostasis

Metabolically healthy obesity (MHO) is characterized by a unique adipose tissue profile, featuring reduced abdominal fat mass and increased gluteofemoral fat mass, which are critical for metabolic health.^[2] This healthy phenotype is also linked to robust adipogenesis and optimal mitochondrial function, suggesting efficient energy metabolism and storage capacity within adipocytes.^[2] Genetic variations in genes like FTO and MC4R are known to influence adiposity and body mass, with specific pathways such as PFKFB3-driven glycolysis also playing a role in processes like vessel sprouting, which can impact fat tissue development and function.^{[8], [9], [10], [11]} Furthermore, specific microRNAs, such as miRNA-32, have been implicated in driving brown fat thermogenesis and trans-activating subcutaneous white adipose tissue, contributing to metabolic flexibility and energy expenditure in MHO individuals.^[12]Specific metabolic pathways are crucial for maintaining metabolic health despite obesity. Genes likeGCKRare involved in regulating glucokinase activity, which is essential for glucose balance and glucose-stimulated insulin secretion.^[2] Variants in GCKRcan influence insulin and fasting glucose levels, as well as triglyceride metabolism.^[2] Similarly, CDKAL1is critical for proinsulin conversion and insulin response, and it plays a vital role in maintaining normal mitochondrial morphology and adipose tissue function, which are key for efficient energy processing and preventing metabolic dysfunction in the context of obesity.^[2] The interplay of these genes and their products contributes to the metabolic regulation and flux control that differentiate metabolically healthy from unhealthy obese individuals, highlighting compensatory mechanisms that sustain metabolic health.

Inflammatory and Immune Signaling Pathways

Inflammation is a significant contributor to the distinction between metabolically healthy and unhealthy phenotypes.^[2] The chemokine CCL2 (also known as MCP-1) plays a central role in insulin resistance, inflammation, and obesity by recruiting monocytes to adipose tissue.^[13] The Duffy antigen receptor for chemokines (DARC) is involved in regulating circulating concentrations of MCP-1 and other inflammatory mediators, indicating its importance in modulating the inflammatory response in obese individuals.^[14]Alterations in CC chemokine and CC chemokine receptor profiles within visceral and subcutaneous adipose tissue are observed in obesity, pointing to differential inflammatory signaling in various fat depots.^[15]Immune cells also contribute to the metabolic health status in obesity. For instance,KLRB1 (NKR-P1A), a C-type lectin receptor, is expressed by subsets of NK and T lymphocytes, and its expression has been shown to correlate with BMI.^{[1], [16]} Changes in CD161expression on mucosal associated invariant T (MAIT) cells can lead to alterations in mucosal immunity and gut microbiota homeostasis, which in turn affect dietary metabolism.^[1] Furthermore, Tob, a member of the APRO family, is known to regulate immunological quiescence and tumor suppression, suggesting a role in maintaining cellular and tissue health under metabolic stress.^[17]The reduction of plasma levels of soluble interleukin 1 receptor accessory protein in obesity also indicates a dysregulation in inflammatory signaling pathways.^[18]

Genetic and Epigenetic Modulators of Metabolism

The metabolically healthy obese phenotype often involves a protective genetic predisposition to obesity-related diseases.^[19]Genetic variations, including single nucleotide polymorphisms (SNPs), are associated with genes involved in biological pathways that influence dietary behavior and protect against metabolic disease development.^[19] Beyond direct gene sequences, regulatory mechanisms such as pseudogenes play a role by regulating parental gene expression via ceRNA networks, adding a layer of complexity to gene regulation in MHO.^[20]Post-translational modifications and protein modifications, such as the correlation between leptin andHSP70, also contribute to the intricate regulatory landscape, especially in conditions like type 2 diabetes.^[21]Epigenetic modifications are increasingly recognized as crucial in the development of obesity and its metabolic health status.^{[22], [23]} These mechanisms encompass gene expression, genetic imprinting, histone modification, and chromatin dynamics, all of which can alter gene activity without changing the underlying DNA sequence.^{[7], [24]}Environmental factors, including pollutants known as obesogens, can induce these epigenetic changes, thereby influencing metabolic pathways and contributing to the obesity phenotype.^[25]Furthermore, the regulation of alternative splicing in human obesity loci suggests a dynamic control over protein diversity and function, impacting various metabolic and signaling pathways.^[26] Coexpression network analysis in adipose tissue has revealed regulatory genetic loci for metabolic syndrome, underscoring the systems-level integration of these genetic and epigenetic controls.^[27]

Inter-organ Communication and Systemic Regulation

The maintenance of metabolic health in obese individuals involves complex inter-organ communication and systemic regulatory networks. The thyroid hormone pathway, for instance, plays a significant role in overall metabolism, and genetic variants within its genes have been associated with serum TSH and FT4 levels.^[28]Dysregulation in this pathway can have systemic metabolic consequences. Another critical signaling molecule is vasoactive intestinal peptide (VIP), which has been identified as important for obesity, suggesting its involvement in broader metabolic regulation and pathway crosstalk.^[29]Beyond endocrine and peptidergic signaling, the gut microbiota plays a role in host metabolism, and alterations in its homeostasis, potentially influenced by immune cells like MAIT cells, can manifest as changes in dietary metabolism.^[1] Genetic components also influence neural signaling that impacts metabolism; for example, GRIN2A, a member of the GRIN gene family, encodes proteins that form receptors for chemical messages, highlighting the role of the central nervous system in metabolic control.^[1] The intricate interplay between various organ systems, mediated by these signaling and metabolic pathways, creates a hierarchical regulation that determines the emergent metabolic phenotype, offering potential therapeutic targets for managing metabolically unhealthy states.

Phenotypic Characterization and Diagnostic Utility

Metabolically healthy obesity (MHO) is a distinct phenotype characterized by excess adiposity without the typical cardiometabolic complications often associated with obesity.^[2]While there is no universally accepted standard definition, MHO generally refers to individuals who are obese but lack metabolic abnormalities such as type 2 diabetes, hypertension, or dyslipidemia.^[2]This phenotypic distinction holds significant diagnostic utility, as individuals categorized as MHO exhibit significantly lower prevalence of hypertension and diabetes, along with more favorable cardiometabolic variables, compared to their metabolically unhealthy obese (MUHO) counterparts.^[2]Recognizing MHO allows clinicians to differentiate individuals who, despite their body mass index, currently present a different metabolic risk profile, which is crucial for appropriate initial risk assessment and patient counseling.

The prevalence of MHO can vary depending on the diagnostic criteria used, with studies reporting MHO in approximately 31.7% of obese individuals in the US and 33–48% in Korea.^[2]For instance, some research has focused on severely obese individuals (BMI ≥ 35 kg/m2) who are free from any manifestations of cardiometabolic disease, including those on relevant medications or with a history of related conditions.^[1]This careful phenotyping underscores the importance of a comprehensive clinical evaluation to accurately classify patients, enabling more nuanced discussions about their current health status and potential future risks. Furthermore, understanding the factors that contribute to metabolic health despite obesity, such as reduced abdominal fat mass and increased gluteofemoral fat mass, or distinct patterns of lipodystrophy, adipogenesis, inflammation, and mitochondrial function, is vital for developing targeted diagnostic markers.^[2]

Genetic Insights and Personalized Risk Stratification

The identification of metabolically healthy obesity has spurred investigations into its underlying genetic architecture, suggesting that MHO individuals may possess a protective genetic predisposition against obesity-related diseases.^[1]Genome-wide association studies (GWASs) have been employed to identify genetic variants, including single-nucleotide polymorphisms (SNPs), associated with the MHO phenotype.^[2]For example, research has identified numerous SNPs linked to MHO, some of which are associated with genes influencing dietary behavior, and others connected to obesity, cardiometabolic disease, or neuroimmune disease.^[1] These genetic insights are paramount for personalized risk stratification, as they offer the potential to identify individuals at higher metabolic risk within both obese and normal-weight populations, even before clinical manifestations appear.^[2] The discovery of specific genetic markers associated with MHO can guide the development of personalized medicine approaches, allowing for more precise predictions of outcomes and tailored prevention strategies. While these findings require validation in larger cohorts, they lay the groundwork for understanding why some individuals remain metabolically healthy despite excess weight.^[2]Such genetic profiling could complement traditional clinical assessments to refine risk models, identify individuals who might benefit most from early interventions, or conversely, those who may not require aggressive medical management despite their BMI. The ability to discern a protective genetic profile could transform how clinicians assess risk and offer guidance on lifestyle modifications or pharmacological treatments based on an individual’s unique genetic susceptibility.^[1]

Prognostic Value and Therapeutic Implications

The MHO phenotype carries significant prognostic value, influencing predictions of long-term outcomes and disease progression. While individuals with MHO currently lack metabolic complications, the long-term trajectory and the stability of this healthy metabolic state are ongoing areas of research.^[1]However, current evidence indicates that MHO subjects exhibit less insulin resistance compared to metabolically unhealthy obese individuals, suggesting a protective benefit in the short to medium term.^[1]This distinction is critical for guiding treatment selection and monitoring strategies, as it suggests that a “one-size-fits-all” approach to obesity management may not be appropriate.

Understanding the mechanisms that maintain metabolic health in MHO individuals, such as favorable fat distribution or unique inflammatory profiles, can inform the development of novel therapeutic targets and prevention strategies for cardiometabolic diseases.^[2]For example, insights into these protective factors could lead to interventions designed to emulate the metabolically healthy state in other obese individuals. Therefore, the recognition of MHO impacts patient care by necessitating a more nuanced approach to obesity, where metabolic health status, alongside BMI, becomes a key determinant in clinical decision-making, monitoring frequency, and the intensity of preventive or therapeutic interventions.

Key Variants

RS ID	Gene	Related Traits
rs9028	RTP4	metabolically healthy obesity
rs7149926	MAGOH3P - BLZF2P	metabolically healthy obesity
rs6928576 rs6902153 rs10945918	QKI - RN7SL366P	metabolically healthy obesity
rs17573102	UBL5P1 - ZCCHC10P2	PHF-tau measurement metabolically healthy obesity
rs2283208	KCNQ1	metabolically healthy obesity
rs2470315	CCDC179 - LINC02718	metabolically healthy obesity
rs6093921	TOX2	metabolically healthy obesity
rs11753543 rs9384860	SOCS5P5 - LINC02518	metabolically healthy obesity
rs9736016	Y_RNA - CXCR5	multiple sclerosis metabolically healthy obesity
rs7635777	P2RY1 - HMGN2P13	metabolically healthy obesity

Frequently Asked Questions About Metabolically Healthy Obesity

These questions address the most important and specific aspects of metabolically healthy obesity based on current genetic research.

1. Why do some people stay healthy even with a high BMI?

This is the core of metabolically healthy obesity. These individuals often have a protective genetic makeup and tend to store fat in metabolically protective areas like their hips and thighs, rather than around their abdomen. This allows them to maintain good metabolic health despite having a higher body mass index.

2. Can my family history explain why I struggle with weight?

Yes, genetics play a significant role in your weight and metabolic health. Your family history can indicate a predisposition due to specific genetic variants that influence how your body handles diet, fat metabolism, and insulin sensitivity, making weight management different for everyone.

3. Does where I store fat matter more than my total weight?

Absolutely. Research suggests that your fat distribution is very important for metabolic health. Individuals with metabolically healthy obesity often have less abdominal fat and more fat in their gluteofemoral (hip and thigh) regions, which is considered a more protective fat depot.

4. Does my ethnic background change my obesity risk?

Yes, it can. Many large genetic studies have primarily focused on populations of European or Korean ancestry. This means that the genetic risk factors for obesity and metabolic health might vary significantly or be different for individuals from other ethnic backgrounds.

5. Is a DNA test useful for understanding my weight?

A DNA test could offer insights into your genetic predisposition for certain metabolic pathways, like how your body processes fats or responds to insulin. While it’s not a complete picture, identifying these genetic markers can help explain individual differences and inform personalized health approaches.

6. Can new treatments help my metabolism, no matter my weight?

Yes, understanding metabolically healthy obesity is opening doors for new therapeutic developments. The goal is to find targets that can improve key aspects of metabolic health, such as insulin sensitivity or inflammation, regardless of an individual’s body weight, moving beyond just focusing on BMI.

7. Why do some doctors define “healthy weight” differently?

There’s currently no universally accepted, standardized definition for metabolically healthy obesity. Different researchers and clinicians may use varying criteria to classify individuals, which can lead to inconsistencies in how “healthy” or “unhealthy” weight is assessed across studies and practices.

8. My sibling is thin, but I’m not. Why the difference?

Even within families, genetic predispositions can vary. While you share many genes, individual differences in specific genetic variants influencing fat distribution, metabolism, and even dietary behavior can lead to different body compositions and metabolic health outcomes between siblings.

9. Can I overcome my genetic predisposition for weight gain?

While genetics play a significant role, they are not your sole destiny. Research suggests that genetic insights can reveal pathways related to dietary behavior and insulin sensitivity, implying that targeted lifestyle choices can potentially confer resilience to metabolic dysfunction, even with a genetic predisposition.

10. Why does my body store fat differently than my friends’?

Your body’s unique genetic makeup influences how and where it distributes fat. Some individuals may have genetic factors that favor storing fat in protective areas like the hips and thighs, while others might be more prone to accumulating metabolically less favorable abdominal fat.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[6] Scuteri, A et al. “Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.”PLoS Genet, 2007.

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[8] Dina, C., et al. “in FTO contributes to childhood obesity and severe adult obesity.”Nat. Genet., vol. 39, pp. 724–726, 2007.

[9] Ehrlich, A. C., and F. K. Friedenberg. “Genetic Associations of Obesity: The Fat-Mass and Obesity-Associated (FTO) Gene.”Clin. Transl. Gastroenterol., vol. 7, p. e140, 2016.

[10] Evans, D. S., et al. “Genetic association study of adiposity and melanocortin-4 receptor (MC4R) common variants: replication and functional character-.” PLoS One, vol. 7, p. e41537, 2012.

[11] De Bock, K., et al. “Role of PFKFB3-Driven Glycolysis in Vessel Sprouting.” Cell, vol. 154, pp. 651–663, 2013.

[12] Ng, R., et al. “miRNA-32 Drives brown fat thermogenesis and trans-activates subcutaneous white.” Nat. Cell Biol., 2017.

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