Molecular insights into the role of white adipose tissue in metabolically unhealthy normal weight and metabolically healthy obese individuals

The concept of heterogeneity among obese individuals in their risk for developing metabolic dysfunction and associated complications has been recognized for decades. At the origin of the heterogeneity idea is the acknowledgement that individuals with central obesity are more prone to developing type 2 diabetes and cardiovascular disease than those with peripheral obesity. There have been attempts to categorize subjects according to their metabolic health and degree of obesity giving rise to different obese and non-obese phenotypes that include metabolically unhealthy normal-weight (MUHNW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Individuals belonging to the MHO phenotype are obese according to their body mass index although exhibiting fewer or none metabolic anomalies such as type 2 diabetes, dyslipidemia, hypertension, and/or unfavorable inflammatory and fribinolytic profiles. However, some authors claim that MHO is only transient in nature. Additionally, the phenotype categorization is controversial as it lacks standardized definitions possibly blurring the distinction between obesity phenotypes and confounding the associations with health outcomes. To add to the discussion, the factors underlying the origin or protection from metabolic deterioration and cardiometabolic risk for these subclasses are being intensely investigated and several hypotheses have been put forward. In the present review, we compare the different definitions of obesity phenotypes and present several possible factors underlying them (adipose tissue distribution and cellularity, contaminant accumulation on the adipose tissue, dysbiosis and metabolic endotoxemia imposing on to the endocannabinoid tone and inflammasome, and nutrient intake and dietary patterns) having inflammatory activation at the center.

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Abstract 17843: Visceral Adipose Tissue Secretion of Adiponectin Decreases with Increased Body Mass Index

Circulation ◽

10.1161/circ.130.suppl_2.17843 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Lenore R Rengel ◽

Brittaney Obi ◽

Jon Gould ◽

Matthew Goldblatt ◽

Andrew Kastenmeier ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Metabolic Health ◽

Metabolically Healthy Obese ◽

Obese Subjects ◽

Healthy Obese ◽

Metabolically Healthy ◽

Visceral Adipose ◽

Subcutaneous Adipose

Introduction: Peripheral adiposity is associated with better metabolic health and higher plasma adiponectin (ADPN) levels. Since ADPN is secreted mainly by adipose tissue (AT), it is intriguing that higher visceral adipose tissue (VAT) is associated with lower ADPN levels and poor metabolic health. Hypothesis: We hypothesized that various AT depots differ in their ability to secrete ADPN. Methods: Paired AT samples (VAT and subcutaneous adipose tissue (SAT)) were collected from 19 subjects (10 women, 15 obese) undergoing elective abdominal surgery. The samples were cultured and the supernatant was collected after 24 hours. ADPN levels released into the supernatant from VAT and SAT were measured using multiplex methods. Subjects were defined as obese or non-obese (NO) based on BMI > or ≤ 30kg/m2 respectively. Obese subjects were further classified as metabolically unhealthy obese (MUO) or metabolically healthy obese (MHO) based on presence or absence of type 2 diabetes mellitus, hypertension, or cardiovascular disease at the time of surgery. Results: Mean ADPN secretion levels from SAT and VAT were similar in NO subjects (17.3 ± 3.4 vs. 9.8 ± 13.0 ng/mL/mg, p=0.5) whereas the mean ADPN secretion was lower from VAT among obese subjects (15.9 ± 0.8 vs. 4.5 ± 0.2 ng/mL/mg, p=0.0002). ADPN secretion decreased from VAT (r=-0.16) and increased from SAT (r=0.33) with increased BMI (Fig.1). When MHO and MUO were compared, ADPN secretion from VAT in MHO was reduced only slightly (16.1 ± 8.2 vs. 4.0 ± 2.0 ng/mL/mg, p=0.07) whereas ADPN secretion was significantly reduced in MUO (15.9 ± 5.3 vs. 4.7 ± 4.6 ng/mL/mg, p=0.003). Conclusions: Reduced ADPN secretion from VAT in subjects with increasing BMI may explain lower circulating ADPN levels in obese individuals. Higher ADPN production from SAT and the relatively preserved secretion of ADPN from VAT may explain metabolic health in some obese individuals. Futures studies will help identify factors that control ADPN secretion from AT.

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Do metabolically healthy obese individuals have the same mortality and morbidity risks as normal-weight metabolically healthy individuals?

Evidence-Based Practice ◽

10.1097/01.ebp.0000541945.10872.e1 ◽

2018 ◽

Vol 21 (1) ◽

pp. E7-E9

Author(s):

Christine Jacobs ◽

Sheran Fernando

Keyword(s):

Normal Weight ◽

Healthy Individuals ◽

Mortality And Morbidity ◽

Metabolically Healthy Obese ◽

Healthy Obese ◽

Metabolically Healthy ◽

Morbidity Risks

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Abstract 13508: Obesity Phenotype and the Risk of Hypertension and Type 2 Diabetes: Does Cardiorespiratory Fitness Matter?

Circulation ◽

10.1161/circ.130.suppl_2.13508 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Sae Young Jae ◽

Mercedes Carnethon ◽

Won Hah Park ◽

Bo Fernhall

Keyword(s):

Type 2 Diabetes ◽

Body Mass Index ◽

Cardiorespiratory Fitness ◽

Normal Weight ◽

Incident Hypertension ◽

Metabolically Healthy Obese ◽

Increased Risk ◽

Healthy Obese ◽

Metabolically Healthy

There is conflicting evidence regarding the association between metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUNW) with incident hypertension and type 2 diabetes. The role of cardiorespiratory fitness on these associations has not been fully explored. We tested the hypothesis that obesity phenotypes predict incident hypertension and type 2 diabetes, but cardiorespiratory fitness modifies these associations in a prospective study of apparently healthy men. 3800 men (mean age 48±6 yrs, range 20-76 yrs) participated in two health examinations during 1998-2009. All subjects were free of hypertension and type 2 diabetes at baseline examination. MHO was defined as obesity (body mass index ≥ 25 kg/m2) with no more than one metabolic abnormality, and MUNW was defined as body mass index < 23 kg/m2) with two or more abnormalities. Cardiorespiratory fitness was directly measured by peak oxygen uptake during a treadmill test. Incident hypertension and type 2 diabetes were defined as blood pressure ≥140/90mmHg and as ≥6.5% of HbA1c or ≥126mg/dl of fasting glucose at second examination, respectively. During an average follow-up of 5 years (1-12 yrs), there were 371 (9.8%) men incident hypertension and 170 (4.5%) men incident type 2 diabetes. MHO and MUNW were present in 844 (22%) and 249 (6.6%) men. Compared with metabolically healthy normal weight men, MHO and MUNW men were at increased risk for hypertension (relative risk (RR) =1.82, 95% Confidence Interval (CI): 1.29-2.56 and 1.75, 1.11-2.74) and type 2 diabetes (RR=3.68, 1.92-7.07 and 5.35, 2.61-10.94), respectively. These risks in MHO and MUNW men were still persisted with adjustment for confounder variables and cardiorespiratory fitness (hypertension=1.57, 1.05-2.34 and 1.59, 1.01-2.51; type 2 diabetes=3.35, 1.63-6.89 and 4.76, 2.32-9.77). Metabolically healthy obese or metabolically unhealthy normal weight men were at increased risk of hypertension and type 2 diabetes compared with metabolically healthy normal weight men. However, these associations were not attenuated by cardiorespiratory fitness or other confounder factors.

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Integrating Publicly Available Genome-Wide Association Data to Study the Genetic Basis of Metabolically Healthy Obese and Metabolically Obese but Normal-Weight Individuals

Diabetes ◽

10.2337/db14-1358 ◽

2014 ◽

Vol 63 (12) ◽

pp. 4004-4007 ◽

Cited By ~ 9

Author(s):

R. J. F. Loos

Keyword(s):

Genetic Basis ◽

Normal Weight ◽

Genome Wide Association ◽

Metabolically Healthy Obese ◽

Genome Wide ◽

Healthy Obese ◽

Metabolically Healthy ◽

Association Data

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Increased Heart Failure Risk in Normal-Weight People With Metabolic Syndrome Compared With Metabolically Healthy Obese Individuals

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2011.04.047 ◽

2011 ◽

Vol 58 (13) ◽

pp. 1343-1350 ◽

Cited By ~ 143

Author(s):

Christina Voulgari ◽

Nicholas Tentolouris ◽

Polychronis Dilaveris ◽

Dimitris Tousoulis ◽

Nicholas Katsilambros ◽

...

Keyword(s):

Heart Failure ◽

Metabolic Syndrome ◽

Normal Weight ◽

Metabolically Healthy Obese ◽

Failure Risk ◽

Healthy Obese ◽

Metabolically Healthy

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The high-fat diet induces myocardial fibrosis in the metabolically healthy obese minipigs—The role of ER stress and oxidative stress

Clinical Nutrition ◽

10.1016/j.clnu.2016.06.002 ◽

2017 ◽

Vol 36 (3) ◽

pp. 760-767 ◽

Cited By ~ 14

Author(s):

Sin-Jin Li ◽

Chia-Hsin Liu ◽

Hsien-Pin Chu ◽

Harry J. Mersmann ◽

Shih-Torng Ding ◽

...

Keyword(s):

Oxidative Stress ◽

Er Stress ◽

Myocardial Fibrosis ◽

High Fat Diet ◽

High Fat ◽

Metabolically Healthy Obese ◽

Healthy Obese ◽

Metabolically Healthy ◽

And Oxidative Stress

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Abstract MP81: Differences in Body Composition Between Metabolically Healthy Obese and Metabolically Abnormal Obese Phenotypes

Circulation ◽

10.1161/circ.127.suppl_12.amp81 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Sarah M Camhi ◽

Peter T Katzmarzyk

Keyword(s):

Risk Factors ◽

Body Composition ◽

Adipose Tissue ◽

Bone Mineral ◽

Fat Mass ◽

Lean Mass ◽

Cardiometabolic Risk ◽

Metabolically Healthy Obese ◽

Healthy Obese ◽

Metabolically Healthy

Purpose: Studies of body composition between metabolically healthy obese (MHO) and metabolically abnormal obese (OA) cardiometabolic profiles have been limited to mostly small sample sizes and postmenopausal women. Thus, the purpose is to determine whether measures of body composition differ between MHO and OA using men and women across a wide age range. Methods: The sample included 395 obese (≥30 kg/m 2 ) adults (66% women; 62% white, 38% African American) from the Pennington Center Longitudinal Study, 18-68 years of age (mean±SD: 40.6±13.2). Adults were classified as OA (≥2 cardiometabolic risk factors: blood pressure ≥130/85 mmHg; triglycerides ≥150 mg/dL, high density lipoprotein cholesterol men <40, women <50 mg/dL; fasting glucose ≥100 mg/dL) or MHO (<2 cardiometabolic risk factors). Whole-body bone mineral density (BMD; g/cm 2 ), bone mineral content (BMC; kg), percent body fat (%), fat mass (kg), lean mass (kg) and trunk adipose tissue mass (kg) were measured with dual-energy x-ray absorptiometry. Visceral (VAT; cm 2 ), subcutaneous (SAT; cm 2 ), and total abdominal adipose tissue (TAT; cm 2 ) were measured with computed tomography. Non-normally distributed variables were log transformed for analysis (lean mass, VAT, BMD and BMC) but means were reverse-transformed for presentation of results. Gender-specific general linear regression models (men: n=136; women: n=259) were used to determine differences in body composition between MHO (men: n=57; women n=153) and OA (men: n=79; women n=106) controlling for age, race, smoking status, and menopause status (in women). Results: In men, OA had greater fat mass (OA vs. MHO mean±SE; p-value for difference: 31.4±1.2 vs. 28.6±1.2 kg; p=0.02) and greater trunk adipose tissue (16.5±0.7 vs. 14.3±0.8 kg; p=0.002) compared with MHO, but no significant differences between MHO and OA profiles for BMD, BMC, % fat, lean mass, VAT, SAT, or TAT. Women with OA profiles had greater lean mass (54.4±1.0 vs. 51.5±1.0 kg; p<0.0001), greater VAT (119.4±1.1 vs. 95.7±1.1 cm 2 ; p<0.0001) and greater trunk adipose tissue (18.0±0.5 vs. 17.1±0.5 kg; p=0.03) when compared with MHO women, with no significant differences between MHO and OA for BMD, BMC, % fat, fat mass, SAT or TAT. Conclusion: OA and MHO cardiometabolic profiles are characterized by differences in body composition that vary by gender. Men have differences in overall and trunk adipose tissue while women have differences in lean mass and centralized fat (VAT and trunk). Future studies should confirm these results in different race and age groups.

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Abstract 163: The Prevalence of the Metabolically Healthy Obese Phenotype in an Aging Population and its Association with Subclinical Cardiovascular Disease: The Brazilian Study on Healthy Aging

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a163 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Lara L Roberson ◽

Shozab A Siddiqui ◽

Michael J Blaha ◽

Arthur A Agatston ◽

Roger S Blumenthal ◽

...

Keyword(s):

Cardiovascular Disease ◽

Waist Circumference ◽

Healthy Aging ◽

Subclinical Atherosclerosis ◽

Aging Population ◽

Normal Weight ◽

Metabolically Healthy Obese ◽

Subclinical Cardiovascular Disease ◽

Healthy Obese ◽

Metabolically Healthy

BACKGROUND Obese and overweight individuals have been shown to be at higher risk of CVD events than normal weight individuals. Current literature has elucidated a new phenotype, Metabolically Healthy Obese (MHO), with risks of CVD similar to that of normal weight individuals. Few studies have examined the MHO phenotype in an aging population, especially in association with subclinical cardiovascular disease. METHODS The cross sectional study population consisted of 208 individuals (79% Female), age 80 and older (mean age 84±4, range 80-102). Anthropometrics & biochemical parameters were measured. The Adult Treatment Panel definition of metabolic syndrome (MetS), excluding waist circumference, criteria was used to define metabolically healthy (<3 MetS components) versus unhealthy. A combination of BMI and waist circumference were used to define normal weight and overweight/obese. Multidetector-row cardiac CT for coronary artery calcium score (CACS) was used to detect subclinical atherosclerosis. High reactive C reactive protein (hs-CRP) was measured to assess degree of underlying inflammation. RESULTS The prevalence of MHO defined by BMI≥25 kg/m2 &/or waist circumference >88cm in women, >102cm in men & having 3mg/dl, Uric Acid >6 mg/dl (p=NS). Gender, total cholesterol, HDL, LDL, triglycerides, and SBP was significantly associated with MHO (p<0.05). CONCLUSIONS Our results suggest that the MHO phenotype is still seen in octogenarians, but at lower rates than in the general population suggesting MHO may not simply be an intermediary stage, driven by length of spent in the obese state. Those with this phenotype tended to have lower triglycerides, higher HDL, and lower body fat % than their metabolically at risk obese counterparts (p<0.05), however, degree of subclinical CVD was not different. Further studies are needed to explore the related risk of CVD among MHO octogenarians.

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