Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.

Morbidly obese, normoglycaemic and normotensive young women have increased HR and low HRV, indicating an abnormal cardiac autonomic function and representing a risk factor for adverse cardiovascular events. A decrease of HRV parameters is associated with a progressive increase of body FM. Other metabolic and hormonal factors, characterising obesity, do not show an independent influence on these HRV alterations.

The aim of the study was to evaluate the 3 years incidence of cardiometabolic risk factors, such as impaired fasting glucose, reduced high‐density lipoprotein (HDL)‐cholesterol, increased plasma triglycerides or blood pressure as well as impaired glucose tolerance in overweight or obese (ow/ob) and normal body weight (nbw) subjects metabolically normal at baseline. Subjects from the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) study were analyzed. We analyzed 284 nbw and 152 ow/ob subjects who, at baseline, did not show any of the above‐mentioned cardiometabolic risk factors. At 3 years, these parameters were re‐evaluated. Intima‐media thickness (IMT) of the common carotid artery (CCA) was echographically measured. At follow‐up, the incidence of one or more cardiometabolic risk factors was 57.2% in ow/ob vs. 31.7% in nbw (P < 0.0001). After adjustment for age, sex, menopause status, lifestyle parameters, insulin sensitivity, and fasting insulinemia, BMI remained significantly linked to the development of one or more cardiometabolic risk factors (P = 0.02). An increased BMI at follow‐up was significantly associated with the development of cardiometabolic alterations, in both nbw and ow/ob groups (P = 0.04). Ow/ob subjects who, at 3 years follow‐up, remained metabolically normal, showed a less favourable cardiometabolic profile, when compared to nbw counterparts. In ow/ob metabolically normal males and females, intima‐media of the common carotid at follow‐up was thicker than in nbw (P = 0.03 for males, P = 0.04 for females). In conclusion, metabolically normal obese subjects show a higher incidence of cardiometabolic risk factors, in a short follow‐up period. Weight gain is significantly associated with the development of these factors, in both nbw and ow/ob subjects.

Objectives: The objective of this study was to define metabolic normality and to investigate the cardiometabolic profile of metabolically normal obese. Design: Cross-sectional study conducted at 21 research centers in Europe. Subjects: Normal body weight (nbw, n ¼ 382) and overweight or obese (ow/ob, n ¼ 185) subjects free from metabolic syndrome and with normal glucose tolerance, were selected among the Relationship between Insulin Sensitivity and Cardiovascular Disease study participants. Main outcome measures: Insulin sensitivity was assessed by the clamp technique. On the basis of quartiles in nbw subjects, the limits of normal insulin sensitivity and of normal fasting insulinemia were established. Subjects with normal insulin sensitivity and fasting insulin were defined as metabolically normal. Results: Among ow/ob subjects, 11% were metabolically normal vs 37% among nbw, Po0.0001. Ow/ob subjects showed increased fasting insulin (P ¼ 0.0009), low-density lipoprotein cholesterol (LDL-cholesterol) (P ¼ 0.004), systolic (P ¼ 0.0007) and diastolic (P ¼ 0.001) blood pressure, as compared with nbw. When evaluating the contribution of body mass index (BMI), hyperinsulinemia and insulin resistance, BMI showed an isolated effect on high-density lipoprotein (P ¼ 0.007), high-sensitivity C-reactive protein (Po0.0001), systolic (P ¼ 0.002) and diastolic (P ¼ 0.008) blood pressures. BMI shared its influence with insulinemia on total cholesterol (P ¼ 0.04 and 0.003, respectively), LDL-cholesterol (P ¼ 0.003 and 0.006, respectively) and triglycerides (P ¼ 0.02 and 0.001, respectively). Conclusion: In obese subjects, fasting insulin should be taken into account in the definition of metabolic normality. Even when metabolically normal, obese subjects could be at increased risk for cardiometabolic diseases. Increased BMI, alone or with fasting insulin, is the major responsible for the less favorable cardio-metabolic profile.

In order to investigate the improvement of insulin resistance and cardiac autonomic function along massive weight loss, 12 obese women were evaluated before, and 3 and 12 months after Roux‐en‐Y gastric bypass. The 12‐month values were compared to those of BMI‐matched controls. Insulin sensitivity was assessed by euglycemic clamp and the cardiac autonomic function by the analysis of the Heart Rate Variability (HRV). After surgery, glucose uptake progressively increased from 4.3 ± 0.5 mg/kg lean body mass (LBM)/min preoperative (pre‐op) to 4.9 ± 0.5 and 7.0 ± 0.5, 3‐ and 12‐month postoperative (post‐op) (P = 0.04 and P = 0.006 vs. pre‐op), whereas the cardiac autonomic function showed a biphasic pattern. HRV values increased 3 months post‐op, and decreased at 12 months, thus indicating an early sympathetic withdrawal followed by a later reactivation (e.g., the standard deviation of the normal‐to‐normal intervals was 116 ± 7 ms in pre‐op, 161 ± 10 at 3 months, P = 0.008 vs. pre‐op, and 146 ± 15 at 12 months, P = 0.03 vs. pre‐op and P = 0.02 vs. 3 m). Insulin sensitivity was significantly related to body weight (P = 0.02), whereas the cardiac indexes were significantly linked to the profile of energy intake (e.g., HRV triangular index vs. energy intake P = 0.003). No significant relationship linked insulin sensitivity to the cardiac autonomic indexes. Insulin sensitivity and cardiac parameters of the 12‐month post‐op patients were similar to their matched controls. During massive weight loss, the cardiac autonomic deregulation and insulin resistance improved concomitantly but independently from each other. Our results suggest that the extent of the improvement is associated with the final body weight.