The adipokine profile of metabolically benign obese and at-risk normal weight postmenopausal women: the Women's Health Initiative Observational Study.

OBJECTIVE: Nearly, a third of obese individuals, termed metabolically benign obese, have a low burden of adiposity-related cardiometabolic abnormalities, whereas a substantial proportion of normal-weight individuals possess risk factors. METHODS: In cross-sectional analyses of 699 normal weight and 1,294 overweight/obese postmenopausal women enrolled in a nested case-control stroke study ancillary to the Women's Health Initiative Observational Study, we compared levels of adiponectin, leptin, and resistin among metabolically benign normal weight, at-risk normal weight, metabolically benign obese, and at-risk obese women using components of the ATP III definition of the metabolic syndrome (metabolically benign: ≤1 of the four components; at-risk phenotype: ≥2 components or diabetes). RESULTS: Overall, 382/699 normal-weight women (54.6%) and 328/1,194 overweight/obese women (27.5%) were metabolically benign. Among normal-weight women, at-risk women had higher leptin and lower adiponectin levels compared to metabolically benign women; multivariate-adjusted odds ratios were significant for having leptin (OR: 2.51; 95% CI: 1.28-5.01) and resistin (1.46; 1.03-2.07) in the top tertile and adiponectin in the bottom tertile (2.64; 1.81-3.84). Compared to metabolically benign overweight/obese women, at-risk obese women had higher odds of having leptin in the top tertile (1.62; 1.24-2.12) and adiponectin in the bottom tertile (2.78; 2.04-3.77). CONCLUSIONS: Overall, metabolically benign overweight/obese women had an intermediate adipokine profile (between at-risk obese and metabolically benign normal-weight women), whereas at-risk normal-weight women had a less favorable profile compared to metabolically benign normal-weight women. As adiponectin was the only adipokine independent of BMI, it may be most likely to have a role in the etiological pathway of these phenotypes.

Ectopic fat and adipokines in metabolically benign overweight/obese women: the Kronos Early Estrogen Prevention Study.

OBJECTIVE: It is unclear why despite a comparable cardiometabolic risk profile, "metabolically benign" overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals. DESIGN AND METHODS: In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined "metabolically benign" with ≤ 1, and "at-risk" with ≥2 components of the metabolic syndrome. RESULTS: Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62-5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94). CONCLUSIONS: Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state.

Incident cardiovascular disease events in metabolically benign obese individuals.

Nearly one-third of obese individuals are classified as metabolically benign; however whether this subgroup is at a lower risk of cardiovascular disease (CVD) is unclear. Using pooled data from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies, we assessed incident CVD (coronary heart disease and stroke) using three definitions of the metabolically benign phenotype: (i) the ATP-III metabolic syndrome definition (≤2 of the ATP-III components, excluding abdominal obesity (ii) the expanded ATP-III definition (≤1 of: any ATP-III components, insulin resistance (IR), or systemic inflammation), and (iii) the IR-based definition (sex-specific lowest quartile of the HOMA(IR) distribution). The sample included 6,106 normal weight, 7,115 overweight, and 4,323 obese participants. Among obese, 27.0%, 18.1%, and 20.4% were metabolically benign by the three definitions, respectively. The CVD incidence rates (mean follow-up 11.8 years) were 7.1, 5.8, and 8.4 per 1,000 person-years in metabolically benign obese via the three definitions, respectively, compared to 14.3, 13.8, and 13.3 in at-risk obese, and 7.5, 6.7, and 8.2 in metabolically benign normal weight participants. Multivariable-adjusted hazard ratios of incident CVD in metabolically benign obese compared to their at-risk obese counterparts were 0.59 (95% CI 0.47-0.73), 0.52 (0.39-0.68), and 0.71 (0.57-0.90), respectively; and 1.24 (0.99-1.57), 1.16 (0.86-1.56), and 1.28 (1.01-1.62) compared to metabolically benign normal weight individuals. Only 28.7% of obese participants classified as metabolically benign by at least one definition were "metabolically benign" by all three definitions. Despite similar CVD risk estimates, the three definitions identified different subgroups of the obese population, perhaps suggesting distinct etiologies.

Empirical derivation to improve the definition of the metabolic syndrome in the evaluation of cardiovascular disease risk.

OBJECTIVE: To examine whether a quantitatively derived metabolic syndrome definition predicts incident cardiovascular disease (CVD) events better than do existing definitions. RESEARCH DESIGN AND METHODS: Data were pooled from the Atherosclerosis Risk in Communities, Cardiovascular Health, and Framingham Offspring studies (n = 20,581). Incident coronary heart disease and stroke events were ascertained over 9 years. RESULTS: The sensitivity for incident CVD events was higher and the specificity lower for the empirically derived versus the Adult Treatment Panel (ATP) III, International Diabetes Federation (IDF), or Harmonized metabolic syndrome definitions (sensitivity/specificity 0.65/0.53 vs. 0.53/0.63, 0.51/0.66, and 0.64/0.56, respectively), resulting in no overall improvement in discrimination. Multivariable-adjusted hazard ratios for incident CVD events were similar across definitions and were 1.7 (95% CI 1.6-1.9) for ATP III, 1.8 (1.6-2.0) for IDF, 1.9 (1.7-2.0) for Harmonized, and 1.7 (1.6-1.9) for the empirically derived definition. CONCLUSIONS: Empirical derivation of the metabolic syndrome definition did not improve CVD discrimination or risk prediction.

High-molecular-weight adiponectin and incident ischemic stroke in postmenopausal women: a Women's Health Initiative Study.

BACKGROUND AND PURPOSE: Although low levels of adiponectin are associated with coronary heart disease and cardiovascular disease risk factors, it is unclear whether adiponectin levels are related to the risk of developing ischemic stroke. METHODS: We examined the relationship between baseline high-molecular-weight (HMW) adiponectin levels and incident ischemic stroke in postmenopausal women using data and specimens from the Hormones and Biomarkers Predicting Stroke Study, a case-control study nested within the Women's Health Initiative Observational Study. Included were 855 incident ischemic stroke cases and 855 control subjects matched for age, race-ethnicity, date of entry into the cohort, and follow-up time. ORs of incident ischemic stroke associated with baseline HMW adiponectin levels were calculated using conditional logistic regression modeling adjusting for body mass index, type 2 diabetes, hypertension, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, physical activity, C-reactive protein, and aspirin use. RESULTS: Lower levels of HMW adiponectin were significantly associated with type 2 diabetes, hypertension, higher body mass index, waist circumference, glucose, and insulin levels and lower high-density lipoprotein cholesterol levels. The distribution of incident stroke cases by HMW adiponectin quartiles was 49.9%, 50.5%, 50.7%, and 48.9%, respectively (P=0.96). Multivariable-adjusted ORs of stroke associated with the top 3 quartiles of HMW adiponectin versus the first quartile were 0.99 (95% CI, 0.71 to 1.37), 1.37 (0.99 to 1.91), and 1.25 (0.88 to 1.79), respectively (P trend=0.14). CONCLUSIONS: Despite moderate associations between HMW adiponectin and cardiovascular disease risk factors, we found no evidence of an association between HMW adiponectin levels and incident ischemic stroke in these postmenopausal women.