Why do some individuals with obesity remain metabolically healthy?

A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.

Physical activity in relation to metabolic health and obesity: The Feel4Diabetes study.

AIM: To examine physical activity levels in association with metabolic health and estimate the stability of metabolically healthy obese (MHO) phenotypes over a 2-year period. METHODS: In total, 2848 men and women from families at risk of the development of diabetes were recruited. Participants were classified as obese or non-obese and metabolic health was defined using five existing definitions. Physical activity was estimated with the International Physical Activity Questionnaire and pedometers. RESULTS: Prevalence of the MHO phenotype varied among definitions (0% to 20.2%). Overall, the MHO were more active than the metabolically unhealthy obese (MUO). Daily sitting hours (odds ratio [OR] = 1.055, 95% confidence interval [CI]: 1.009-1.104) and daily steps (per 500; OR = 0.934, 95% CI: 0.896-0.973) were remarkable predictors of metabolic health in individuals with obesity; and likewise, in individuals without obesity. After 2 years, 44.1% of baseline MHO adults transitioned to MUO, while 84.0% of the MUO at baseline remained at the same phenotype. Although physical activity was not a major determinant in phenotype transitioning, daily steps were associated with the maintenance of metabolic health over time in the non-obese group. CONCLUSION: A universally accepted definition for MHO is needed. Being physically active can contribute to a metabolically healthy profile even in the presence of obesity; still, MHO is a transient condition and physical activity alone may not be an adequate factor for its maintenance.

Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders.

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders. These people store fat in subcutaneous adipose tissue (SAT) rather than in visceral adipose tissue (VAT). However, the molecules participating in this specific scenario remain elusive. Rab18, a lipid droplet (LD)-associated protein, mediates the contact between the endoplasmic reticulum (ER) and LDs to facilitate LD growth and maturation. In the present study, we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice. Rab18 adipocyte-specific knockout (Rab18 AKO) mice had a decreased volume ratio of SAT to VAT compared with wildtype mice. When subjected to high-fat diet (HFD), Rab18 AKO mice had increased ER stress and inflammation, reduced adiponectin, and decreased triacylglycerol (TAG) accumulation in SAT. In contrast, TAG accumulation in VAT, brown adipose tissue (BAT) or liver of Rab18 AKO mice had a moderate increase without ER stress stimulation. Rab18 AKO mice developed insulin resistance and systematic inflammation. Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT, similar to the counterpart mice. Furthermore, Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress, indicating the involvement of Rab18 in alleviating lipid toxicity. Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT. In conclusion, our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

MHO or MUO? White adipose tissue remodeling.

In this review, we delve into the intricate relationship between white adipose tissue (WAT) remodeling and metabolic aspects in obesity, with a specific focus on individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). WAT is a highly heterogeneous, plastic, and dynamically secreting endocrine and immune organ. WAT remodeling plays a crucial role in metabolic health, involving expansion mode, microenvironment, phenotype, and distribution. In individuals with MHO, WAT remodeling is beneficial, reducing ectopic fat deposition and insulin resistance (IR) through mechanisms like increased adipocyte hyperplasia, anti-inflammatory microenvironment, appropriate extracellular matrix (ECM) remodeling, appropriate vascularization, enhanced WAT browning, and subcutaneous adipose tissue (SWAT) deposition. Conversely, for those with MUO, WAT remodeling leads to ectopic fat deposition and IR, causing metabolic dysregulation. This process involves adipocyte hypertrophy, disrupted vascularization, heightened pro-inflammatory microenvironment, enhanced brown adipose tissue (BAT) whitening, and accumulation of visceral adipose tissue (VWAT) deposition. The review underscores the pivotal importance of intervening in WAT remodeling to hinder the transition from MHO to MUO. This insight is valuable for tailoring personalized and effective management strategies for patients with obesity in clinical practice.

Phenotyping obesity: A focus on metabolically healthy obesity and metabolically unhealthy normal weight.

Over the past 4 decades, research has shown that having a normal body weight does not automatically imply preserved metabolic health and a considerable number of lean individuals harbour metabolic abnormalities typically associated with obesity. Conversely, excess adiposity does not always equate with an abnormal metabolic profile. In fact, evidence exists for the presence of a metabolically unhealthy normal weight (MUHNW) and a metabolically healthy obese (MHO) phenotype. It has become increasingly recognised that different fat depots exert different effects on the metabolic profile of each individual by virtue of their location, structure and function, giving rise to these different body composition phenotypes. Furthermore, other factors have been implicated in the aetiopathogenesis of the body composition phenotypes, including genetics, ethnicity, age and lifestyle/behavioural factors. Even though to date both MHO and MUHNW have been widely investigated and documented in the literature, studies report different outcomes on long-term cardiometabolic morbidity and mortality. Future large-scale, observational and population-based studies are required for better profiling of these phenotypes as well as to further elucidate the pathophysiological role of the adipocyte in the onset of metabolic disorders to allow for better risk stratification and a personalised treatment paradigm.

Loss of CTRP10 results in female obesity with preserved metabolic health.

Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also show sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.

Differences in metabolic characteristics between Metabolically Healthy Obesity (MHO) and Metabolically Unhealthy Obesity (MUO) in weight reduction therapy.

Metabolically Healthy Obesity (MHO) is generally recognized as the absence of any metabolic disorders and cardiovascular diseases, including type 2 diabetes, dyslipidemia, and hypertension, in obese individuals; however, it is not clearly defined. Therefore, the present study investigated differences in metabolic characteristics between individuals with MHO and Metabolically Unhealthy Obesity (MUO) during weight reduction therapy. The key factors defining MHO and the importance of weight reduction therapy for MHO were also examined. Cohort data from the Japan Obesity and Metabolic Syndrome (JOMS) study were analyzed. Subjects were divided into the MHO (n = 25) and MUO (n = 120) groups. Prior to weight reduction therapy, serum adiponectin levels were significantly higher in the MHO group than in the MUO group. Serum adiponectin levels also negatively correlated with the area of subcutaneous adipose tissue (SAT) and Homeostasis model assessment (HOMA)-R in the MHO group, but not in the MUO group. Collectively, the present results suggest the importance of adiponectin for maintaining metabolic homeostasis in the MHO group. On the other hand, no significant differences were observed in inflammatory markers between the MHO and MUO groups, suggesting the presence of chronic inflammation in both groups. Furthermore, a positive correlation was noted between changes in serum cystatin C levels and waist circumference in the MHO group, which indicated that despite the absence of metabolic disorders, the MHO group exhibited anti-inflammatory responses during weight reduction therapy. These results underscore the significance of weight reduction even for individuals with MHO.

Adherence to the Mediterranean diet as a possible additional tool to be used for screening the metabolically unhealthy obesity (MUO) phenotype.

BACKGROUND: The terms metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) categorize subjects with obesity based on the presence or absence of cardio-metabolic risk factors. Detecting MUO phenotype is crucial due to the high risk of cardio-metabolic complications, requiring tailored and intensive follow-up. However, diagnosing MUO is time-consuming and costly. Thus, we aimed to investigate the role of Mediterranean diet (MD) in determining MHO/MUO phenotypes and whether adherence to MD could serve as an additional screening tool for MUO phenotype. METHODS: The study population of this cross-sectional observational study consisted of 275 subjects with obesity. We assessed their lifestyle habits (physical activity and smoking habits), anthropometric measurements (weight, height, waist circumference, body mass index), blood pressure, metabolic parameters, inflammatory marker (high sensitivity C reactive protein levels), adherence to MD (by PREvención con DIetaMEDiterránea (PREDIMED) questionnaire), and MHO/MUO phenotypes. RESULTS: The study included 275 individuals with obesity (256F/19M; 34.0 ± 10.5 years; BMI 38.3 ± 5.95 kg/m2). Among them, 114 (41.5%) exhibited MHO phenotype, while 161 (58.5%) had MUO phenotype. MHO phenotype exhibited favorable anthropometric and cardio-metabolic profiles, characterized by lower waist circumference (p < 0.001), BMI (p < 0.001), insulin resistance (p < 0.001), blood pressure (p < 0.001), inflammation (p < 0.001), and lipid levels (p < 0.001) compared to MUO phenotype. Notably, we found that MHO phenotype had higher adherence to MD (p < 0.001) and consumed more extra virgin olive oil (EVOO) (p < 0.001), vegetables (p < 0.001), fruits (p < 0.001), legumes (p = 0.001), fish (p < 0.001), wine (p = 0.008), and nuts (p = 0.001), while reporting lower intake of red/processed meats (p < 0.001), butter, cream, margarine (p = 0.008), soda drinks (p = 0.006), and commercial sweets (p = 0.002) compared to MUO phenotype. Adherence to MD (p < 0.001) and EVOO (p = 0.015) intake were identified as influential factors in determining the presence of MUO/MHO phenotypes. Furthermore, a PREDIMED score < 5 proved to be the most sensitive and specific cut-point value for predicting the presence of MUO phenotype (p < 0.001). CONCLUSION: High adherence to MD was associated with MHO phenotype. Moreover, we suggest that a specific cut-off of the PREDIMED score could be an indicator to discriminate patients with MUO/MHO phenotypes and therefore help in identifying patients at higher cardiovascular risk who will require specific dietary intervention.

Association of body mass index, metabolic health status and clinical outcomes in acute myocardial infarction patients: a national registry-based study.

Introduction: Obesity is an important risk factor for acute myocardial infarction (AMI), but the interplay between metabolic health and obesity on AMI mortality has been controversial. In this study, we aimed to elucidate the risk of short- and long-term all-cause mortality by obesity and metabolic health in AMI patients using data from a multi-ethnic national AMI registry. Methods: A total of 73,382 AMI patients from the national Singapore Myocardial Infarction Registry (SMIR) were included. These patients were classified into four groups based on the presence or absence of metabolic diseases, diabetes mellitus, hyperlipidaemia, and hypertension, and obesity: (1) metabolically-healthy-normal-weight (MHN); (2) metabolically-healthy-obese (MHO); (3) metabolically-unhealthy-normal-weight (MUN); and (4) metabolically-unhealthy-obese (MUO). Results: MHO patients had reduced unadjusted risk of all-cause in-hospital, 30-day, 1-year, 2-year, and 5-year mortality following the initial MI event. However, after adjusting for potential confounders, the protective effect from MHO on post-AMI mortality was lost. Furthermore, there was no reduced risk of recurrent MI or stroke within 1-year from onset of AMI by the MHO status. However, the risk of 1-year mortality was higher in female and Malay AMI patients with MHO compared to MHN even after adjusting for confounders. Conclusion: In AMI patients with or without metabolic diseases, the presence of obesity did not affect mortality. The exception to this finding were female and Malay MHO who had worse long-term AMI mortality outcomes when compared to MHN suggesting that the presence of obesity in female and Malay patients may confer worsened outcomes.

Metabolome Profiling and Pathway Analysis in Metabolically Healthy and Unhealthy Obesity among Chinese Adolescents Aged 11-18 Years.

The underlying mechanisms of the development of unhealthy metabolic phenotypes in obese children and adolescents remain unclear. We aimed to screen the metabolomes of individuals with the unhealthy obesity phenotype and identify the potential metabolic pathways that could regulate various metabolic profiles of obesity in Chinese adolescents. A total of 127 adolescents aged 11-18 years old from China were investigated using a cross-sectional study. The participants were classified as having metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) based on the presence/absence of metabolic abnormalities defined by metabolic syndrome (MetS) and body mass index (BMI). Serum-based metabolomic profiling using gas chromatography-mass spectrometry (GC-MS) was undertaken on 67 MHO and 60 MUO individuals. ROC analyses showed that palmitic acid, stearic acid, and phosphate could predict MUO, and that glycolic acid, alanine, 3-hydroxypropionic acid, and 2-hydroxypentanoic acid could predict MHO (all p < 0.05) from selected samples. Five metabolites predicted MUO, 12 metabolites predicted MHO in boys, and only two metabolites predicted MUO in girls. Moreover, several metabolic pathways may be relevant in distinguishing the MHO and MUO groups, including the fatty acid biosynthesis, fatty acid elongation in mitochondria, propanoate metabolism, glyoxylate and dicarboxylate metabolism, and fatty acid metabolism pathways. Similar results were observed for boys except for phenylalanine, tyrosine and tryptophan biosynthesis, which had a high impact [0.098]. The identified metabolites and pathways could be efficacious for investigating the underlying mechanisms of the development of different metabolic phenotypes in obese Chinese adolescents.

Identification of Biomarkers Related to Metabolically Unhealthy Obesity in Korean Obese Adolescents: A Cross-Sectional Study.

BACKGROUND: The current study aimed to screen for relationships and different potential metabolic biomarkers involved between metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) in adolescents. METHODS: The study included 148 obese adolescents aged between 14 and 16. The study participants were divided into MUO and MHO groups based on the age-specific adolescent metabolic syndrome (MetS) criteria of the International Diabetes Federation. The current study was conducted to investigate the clinical and metabolic differences between the MHO and MUO groups. Multivariate analyses were conducted to investigate the metabolites as independent predictors for the odds ratio and the presence of the MetS. RESULTS: There were significant differences in the three acylcarnitines, five amino acids, glutamine/glutamate ratio, three biogenic amines, two glycerophospholipids, and the triglyceride-glucose index between the MUO group and those in the MHO group. Moreover, several metabolites were associated with the prevalence of MUO. Additionally, several metabolites were inversely correlated with MHO in the MUO group. CONCLUSIONS: In this study, the biomarkers found in this study have the potential to reflect the clinical outcomes of the MUO group. These biomarkers will lead to a better understanding of MetS in obese adolescents.

Metabolically Healthy Obesity: Are Interventions Useful?

PURPOSE OF REVIEW: This review aims to detail the current global research state of metabolically healthy obesogenesis with regard to metabolic factors, disease prevalence, comparisons to unhealthy obesity, and targeted interventions to reverse or delay progression from metabolically healthy to unhealthy obesity. RECENT FINDINGS: As a long-term condition with increased risk of cardiovascular, metabolic, and all-cause mortality risks, obesity threatens public health on a national level. The recent discovery of metabolically healthy obesity (MHO), a transitional condition during which obese persons carry comparatively lower health risks, has added to confusion about the true effect of visceral fat and subsequent long-term health risks. In this context, the evaluation of fat loss interventions, such as bariatric surgery, lifestyle changes (diet/exercise), and hormonal therapies require re-evaluation in light of evidence that progression to high-risk stages of obesity relies on metabolic status and that strategies to protect the metabolism may be useful in the prevention of metabolically unhealthy obesity. Typical calorie-based exercise and diet interventions have failed to reduce the prevalence of unhealthy obesity. Holistic lifestyle, psychological, hormonal, and pharmacological interventions for MHO, on the other hand, may at least prevent progression to metabolically unhealthy obesity.

Maternal hyperoxygenation during pregnancy as a tool in fetal disease diagnosis and treatment.

Maternal hyperoxygenation (MHO) consists of giving pregnant women (60% to 100%) oxygen through a facemask and using ultrasound assess or monitor the influence on fetal cardiovascular circulation. This review discusses the findings and the utility of acute and chronic MHO in various fetal diseases.

Israeli soldiers' intentions and actions toward seeking mental health help: Barriers and facilitators.

BACKGROUND: While military settings may increase psychological distress, soldiers frequently avoid seeking professional help. This study aimed to examine barriers and facilitators associated with intentions to seek help and actually seeking help from a mental health officer (MHO) and how these differ among soldiers who had sought help in the past and those who had not. METHOD: This cross-sectional study included 263 combat and noncombat soldiers. The Health Belief Model and the Help-Seeking Model were the theoretical framework used to map the potential variables associated with soldiers' decision to seek help. RESULTS: Stigma and administrative barriers were found to be significant barriers to both the intention to seek help and actually consulting an MHO. These findings were more definitive among combat soldiers. The belief in the effectiveness of mental health treatment was positively associated with the intention to seek help. Positive associations were found between well-being, perceived seriousness of one's condition, and belief in the effectiveness of mental health care and intention to seek MHO help. Distress and self-concealment were positively associated with actual consultation with an MHO. Public stigma about seeking help was associated with both the intention to seek mental health assistance and actually consulting an MHO. CONCLUSION: Military commanders should make an effort to make soldiers feel safe to seek mental health assistance by creating a supportive organizational atmosphere to reduce the stigma associated with mental health care.

Association between metabolic overweight/obesity phenotypes and readmission risk in patients with lung cancer: A retrospective cohort study.

Background: Increased body mass index (BMI) and metabolic abnormalities are controversial prognostic factors of lung cancer. However, the relationship between metabolic overweight/obesity phenotypes and hospital readmission in patients with lung cancer is rarely reported. Methods: We established a retrospective cohort using the United States (US) Nationwide Readmissions Database (NRD). We included adult patients diagnosed with lung cancer from January 1, 2018 to November 30, 2018 and excluded patients combined with other cancers, pregnancy, died during hospitalization, low body weight, and those with missing data. The cohort was observed for hospital readmission until December 31, 2018. We defined and distinguished four metabolic overweight/obesity phenotypes: metabolically healthy with normal weight (MHNW), metabolically unhealthy with normal weight (MUNW), metabolically healthy with overweight or obesity (MHO), and metabolically unhealthy with overweight or obesity (MUO). The relationship between metabolic overweight/obesity phenotypes and 30-day readmission risk was assessed by multivariable Cox regression analysis. Findings: Of the 115,393 patients included from the NRD 2018 (MHNW [58214, 50.4%], MUNW [44980, 39.0%], MHO [5044, 4.4%], and MUO [7155, 6.2%]), patients with the phenotype MUNW (6531, 14.5%), MHO (771, 15.3%), and MUO (1155, 16.1%) had a higher readmission rate compared to those with MHNW (7901, 13.6%). Compared with patients with the MHNW phenotype, those with the MUNW (hazard ratio [HR], 1.10; 95% CI, 1.06-1.14), MHO (HR, 1.15; 95% CI, 1.07-1.24), and MUO (HR, 1.28; 95% CI, 1.20-1.36) phenotypes had a higher risk of readmission, especially in men, those without surgical intervention, or those aged >60 years. In women, similar results with respect to readmission were observed in people aged >60 years (MUNW [HR, 1.07; 95% CI, 1.01-1.13], MHO [HR, 1.19; 95% CI, 1.06-1.35], and MUO [HR, 1.28; 95% CI, 1.16-1.41]). We also found increased costs for 30-day readmission in patients with MHO (OR, 1.18; 95% CI, 1.07-1.29) and MUO (OR, 1.11; 95% CI, 1.02-1.20). Interpretation: Increased BMI and metabolic abnormalities are independently associated with higher readmission risks in patients with lung cancer, whereas increased BMI also increases the readmission costs. Follow-up and intervention method targeting increased BMI and metabolic abnormalities should be considered for patients with lung cancer. Funding: The National Key Research and Development Program of China (2017YFC1309800).

Quality of life and emergency preparedness of MHO staff: role of psychological capital and perceived organizational support.

PURPOSE: Enhancing the initiative and enthusiasm of emergency preparedness behaviors among Medical and Health Organization (MHO) staff is an effective measure to prevent and reduce losses from emergencies. In this study, emergency preparedness behavioral intentions were divided into noncooperative behavioral intentions (EPNCBI) and cooperative behavioral intentions (EPCBI) to discuss the impact brought by quality of life (QoL). The mediating effects of psychological capital (PsyCap) and perceived organizational support (POS) were also considered. DESIGN/METHODOLOGY/APPROACH: A web-based questionnaire was used for MHO staff in China, and a structural equation analysis of the data collected from 243 participants was conducted to test the hypotheses. FINDINGS: The empirical results reveal that: (1) QoL had a positive effect on EPNCBI, PsyCap and POS; (2) PsyCap had a positive effect on EPNCBI and EPCBI; (3) POS had a positive effect on PsyCap and EPCBI; (4) PsyCap mediated the relationship between QoL and EPNCBI, and the relationship between POS and EPNCBI; (5) PsyCap and POS mediated the relationship between QoL and EPCBI. PRACTICAL IMPLICATIONS: Improving MHO staff's QoL is an effective way to enhance positive behavioral outcomes. Furthermore, these findings could provide managers with valuable insight focusing their limited resources on enhancing the emergency preparedness of MHO staff by reinforcing the level of PsyCap and POS. ORIGINALITY/VALUE: This study provides important updated considerations for the application of positive psychology in the field of emergency preparedness.

The Interaction Between Dietary Total Antioxidant Capacity and MC4R Gene and HOMA-IR in Metabolically Healthy and Unhealthy Overweight and Obese Women.

Introduction: The current prevalence of the metabolically healthy obesity is about 3%. Genetic and nutrition are influencers of such phenotypes. The main goal of this study was to assess the interaction between Dietary Total Antioxidant Capacity (DTAC) and the genotypes of MC4R and Insulin resistance in metabolically healthy/unhealthy overweight and obese women in Iran. Material And Methods: This cross-sectional study was conducted on 237 overweight-obese women with a mean age of 36. The value of Dietary total antioxidant capacity (DTAC) was calculated using the following indices: Total reactive antioxidant potential (TRAP), Trolox equivalent antioxidant capacity (TEAC), and ferric reducing ability of plasma (FRAP). The Metabolic health status was evaluated using the Karelis criteria. Melanocortin 4 receptor single nucleotide polymorphisms were determined by the restriction fragment length polymorphism (PCR-RFLP) method. Also, insulin resistance was evaluated through homeostasis model assessment (HOMA). Result: Our data noted that 72.96% of participants presented Unhealthy Metabolically and 26.94% Healthy Metabolically including 33.5% of the total had T/T genotype, 23.8% had the C/T genotype, and 42.5% had the C/C genotype (P = .05). A linear regression model test showed that the probability of metabolically healthy obesity was significantly higher in patients with the T/C genotype. The test value was statistically significant (95% CI: 0.000-0.001; P = .056, ß = 0). No statistically significant relation was observed between study parameters and DTAC values. HOMA-Index was higher in all unhealthy subjects significantly. Conclusions: The findings indicated that there are significant associations between genotypes of rs1333048 SNP and DTAC. The C/C genotype subjects with higher DTAC had a better lipid profile and were metabolically healthier.

Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21.

The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.

Serum proteome profiling reveals differentially expressed proteins between subjects with metabolically healthy obesity and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading risk factor for common chronic liver disease and is often regarded as a prevalent metabolic disorder tightly associated with obesity. However, the existence of metabolically healthy obesity (MHO) indicates that some important factors may participate in protecting individuals with MHO free of NAFLD, even with excessive adiposity. To explore factors independent of obesity that may be involved in the occurrence of NAFLD, we performed an iTRAQ-based proteomic study to identify proteins differentially expressed in serum between NAFLD and MHO subjects. Compared with the MHO group, ten proteins were upregulated and five were downregulated significantly in the NAFLD group. Gene Ontology analysis indicated significant changes in the immune response and triglyceride metabolism-related pathways between MHO and NAFLD. We further validated three candidates markedly dysregulated in NAFLD by Western blotting and ELISA, including two upregulated proteins (afamin and apolipoprotein H) and one downregulated protein (apolipoprotein C-1). Detection of serum apolipoprotein H levels in a large-scale cohort with MHO and different stages of NAFLD indicated that apolipoprotein H may be a potential blood biomarker for distinguishing NAFLD from MHO and an independent risk factor for predicting NAFLD.

The Association Between Metabolic Status and Risk of Cancer Among Patients With Obesity: Metabolically Healthy Obesity vs. Metabolically Unhealthy Obesity.

Background: Controversial evidence about the association between cancer risk and metabolic status among individuals with obesity has been reported, but pooled data remain absent. This study aims to present pooled data comparing cancer risk between patients with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Methods: The current study systematically searched pieces of literature on January 4, 2021, of prospective cohorts that compare the incidence of cancer between MHO and MUO. The quality of included studies was assessed using Newcastle-Ottawa scale, and publication bias was evaluated using funnel plots. Results: Eleven high-quality studies were eventually selected. Quantitative analysis indicates that a lower cancer incidence exists for MHO phenotype than that for MUO (odds ratio [OR], 0.71; 95% confidential interval [CI], 0.61-0.84). Consistent outcomes are presented by subgroup analyses, which are grouped by cohort region (western population: [OR, 0.84; 95% CI, 0.75-0.93]; Asian population: [OR, 0.64; 95% CI, 0.54-0.77]); definition of metabolic unhealthiness (≥3 metabolic abnormalities: [OR, 0.62; 95% CI, 0.54-0.71]; ≥1 metabolic abnormality: [OR, 0.76; 95% CI, 0.62-0.94]); and definition of obesity (body mass index (BMI), ≥30 kg/m2: [OR, 0.84; 95% CI, 0.73-0.98]; BMI, ≥25 kg/m2: [OR, 0.53; 95% CI, 0.52-0.55]). Conclusion: In conclusion, this study suggests a reduced cancer risk for MHO compared to MUO regardless of population heterogeneity, or the definitions of obesity and metabolic status.