Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids?

OBJECTIVE: To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). METHODS: In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. RESULTS: Among completers (n = 87), body weight decreased in 35 patients (-9.1 ± 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 ± 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N-palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). CONCLUSION: Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL.

[Interdisciplinarity for obese patient global management]. / L'interdisciplinarité pour un traitement global du patient obèse.

Obesity is a chronic illness involving serious somatic comorbidities and psychological disorders. Furthermore, obese patients often suffer from personal and / or socio-cultural problems. Taken together these elements amount to a complex illness requiring comprehensive patient care and hence an interdisciplinary approach aimed at integrating and coordinating the interventions of the different health professionals. Through various initiatives, the Interdisciplinary group for the treatment of obesity (GITO) endeavours to apply and promote an interdisciplinary approach both in clinical practice and in the debate on the problems relating to obesity.

L'obésité est une maladie chronique compliquée par des comorbidités somatiques graves et par l'association à des troubles de la sphère psychologique. De plus, le patient obèse souffre souvent de problématiques d'ordre personnel et / ou socioculturel. L'interaction entre tous ces facteurs correspond au concept de maladie complexe, qui, très clairement, nécessite une prise en charge globale. Ceci implique un travail interdisciplinaire dont le but est d'intégrer et coordonner les actions des différents thérapeutes qui assurent le suivi du patient. Par le biais de différentes initiatives, le Groupe interdisciplinaire pour le traitement de l'obésité (GITO) s'efforce d'appliquer et de promouvoir les principes de l'interdisciplinarité aussi bien dans l'activité clinique que dans la réflexion sur les problématiques liées à l'obésité.

Involvement of dietary Fatty acids in multiple biological and psychological functions, in morbidly obese subjects.

BACKGROUND: Fatty acid (FA) profile is often altered, in morbidly obese subjects, both before and after bariatric surgery. We measured FA plasma levels before and 6 months after Roux-en-Y gastric bypass (RYGB), in order to evaluate their relationship with different biological and psychological parameters and the impact of RYGB on the FA plasma levels. METHODS: Thirty eight morbidly obese patients were investigated before RYGB, and 28 of them were reexamined 6 months postoperatively. Anxiety, depression, and quality of life were evaluated by validated questionnaires. Plasma FA (saturated, monounsaturated, polyunsaturated ω-6 and ω-3), vitamins A and E, fasting insulinemia, and high-sensitive C-reactive protein (hs-CRP) were measured. RESULTS: Before surgery, ω-3 polyunsaturated FA and vit A showed significant negative relationship with fasting insulinemia (γ-linolenic p = 0.03, eicosapentaenoic, vit A p = 0.01) and hs-CRP (eicosapentaenoic p = 0.03, vit A p = 0.02) and a positive link with HDL cholesterol (γ-linolenic p = 0.03, vit A p = 0.02). Depression score was significantly and negatively linked with palmitoleic (p = 0.03), γ-linolenic (p = 0.006), dihomo-γ-linolenic (p = 0.02), and α-linolenic (p = 0.03) acids. After surgery, FA and both vit A and E were significantly reduced. Vit A levels were below 2.4 µmol/l in 63 % of the patients, preoperatively, and in 79 % after surgery. Preoperative levels of linoleic acid were significantly related with the postoperative weight reduction (p = 0.0006). CONCLUSIONS: FA are involved in several biological and psychological functions. The RYGB-induced reduction of FA could have deleterious consequences on vitamin absorption, metabolism, and depression. Thus, the surveillance of FA levels is of primary importance both before and after RYGB.

Gastric bypass in morbid obese patients is associated with reduction in adipose tissue inflammation via N-oleoylethanolamide (OEA)-mediated pathways.

Paradoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation of the "endocannabinoid" system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.

[Reciprocal interactions between bariatric surgery and psychopathology]. / Queues interférences réciproques entre chirurgie bariatrique et psychopathologie?

In this article, the results of a bibliographic research concerning the interactions between bariatric surgery and psychopathologies are presented. In the preoperative phase, although not scientifically demonstrated, uncontrolled psychopathologies as well as the abuse of illicit substances are often considered as exclusion criteria for the intervention. From the psychological point of view, neither the existence of a "typical" profile, nor the presence of predictive factors have been demonstrated. However some "attitudes" or "personality traits" could influence the issue of the intervention. In the postoperative phase, the pre-existing psychopathologies transiently improve. On the other hand, alcohol and illicit substances abuse as well as suicide are increased.

[The endocannabinoid system in obesity]. / Le système endocannabinoïde dans l'obésité.

The endocannabinoid system is involved in the regulation of energy balance and metabolism. Endocannabinoids have central effects with raising appetite and hunger. On the other hand, different components of the endocannabinoid system are also found in peripheral organs and tissues and they could impact the lipid and glucose metabolism. Obesity is associated with an overactivity of the endocannabinoid system with increased both plasmatic and visceral adipose tissue levels. The amount of the intra-abdominal fat mass is an indicator of the peripheral endocannabinoid system dysregulation. Endocannabinoids-like molecules with more pronounced peripheral effects on lipids and glucose metabolism could be a new target of obesity treatment.

[Micronutrient deficiency in obesity]. / Déficiences micronutritionnelles chez les patients obèses.

Obesity is frequently associated with micronutrient deficiency due to unhealthy diet, lack of antioxidants and polyunsaturated fat on one side and abundance of saturated fat on the other side. The micronutrients play an important role in inflammation, metabolic syndrome and insulin resistance and could influence the weight loss. The screening of micronutrient deficiency should therefore be systematic in order to improve the management of obesity. This is of particular importance for bariatric surgery patients.

[Cardio-metabolic profile is influenced by modest modifications of body weight]. / Les modifications minimes du poids corporel influencent le profit cardio-métabolique.

Cardio-metabolic profile is influenced by modest modifications of body weight An increased body mass index (BMI) is associated with the metabolic syndrome (MS) and parameters composing it. There is a quasi linear relationship between BMI and number of MS components: an increase in BMI is associated with increasing number of cardio-metabolic alterations. This relationship exists not only in subjects with established obesity but also in those who are overweight or even have normal body weight. It has been also shown that a modest weight gain is associated with an increase in the number of MS components which, in turn, could contribute to the development of atherosclerosis. On the other hand, a modest weight loss is associated with decrease of MS components number and improvement of the cardio-metabolic profile.

From metabolic normality to cardiometabolic risk factors in subjects with obesity.

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.

The relationship between weight loss and psychosocial functioning among bariatric surgery patients.

BACKGROUND: Success after bariatric surgery should also reflect improvement in psychosocial functioning. The objective of this study was to assess the relationships between both mental health and eating disorders and weight loss in morbidly obese patients 2 years after gastric bypass. METHODS: Forty-three obese women (mean age, 39.3 +/- 1.4 years; mean body mass index, 44.7 +/- 0.4 kg/m2) were evaluated before and 1 and 2 years after gastric bypass. The Beck Depression Inventory and the Hospital Anxiety and Depression Scale were used for depression and anxiety evaluation and the Eating Disorder Inventory for eating disorder assessment. RESULTS: Decreases in depression (P <.01), anxiety (P <.05), and eating disorder (P <.01) scores were measured 2 years after surgery. Both excess weight loss and change in body mass index were associated with improvements in all measured psychologic outcomes 2 years after surgery. CONCLUSIONS: The importance of weight loss is in relation to mental health 2 years after bariatric surgery. Psychologic outcomes and eating disorders did not predict weight loss 2 years after gastric bypass. However, these factors improved significantly after weight loss.

Effect of obesity on growth-related oncogene factor-alpha, thrombopoietin, and tissue inhibitor metalloproteinase-1 serum levels.

We have recently identified several adipokines as oversecreted by omental adipose tissue (AT) of obese subjects: two chemokines (growth-related oncogene factor-alpha (GRO-alpha), macrophage inflammatory protein-1 beta (MIP-1 beta)), a tissue inhibitor of metalloproteinases-1 (TIMP-1), an interleukin-7 (IL-7) and a megakaryocytic growth-factor (thrombopoietin (TPO)). These adipokines are involved in insulin resistance and atherosclerosis. The objectives of this study were to determine whether the circulating levels of these adipokines were increased in obesity and to identify the responsible factors. A cross-sectional study including 32 lean (BMI (kg/m(2)) <25), 15 overweight (BMI: 25-29.9), 11 obese (BMI: 30-39.9), and 17 severely obese (BMI >40) age-matched women was carried out. Serum adipokine levels, insulin sensitivity, and substrate oxidation were measured by ELISA, euglycemic-hyperinsulinemic clamp, and indirect calorimetry, respectively. Circulating levels of GRO-alpha, TPO, and TIMP-1 were higher in obese and/or severely obese women than in lean ones (+30, 55, and 20%, respectively). Serum levels of these adipokines positively correlated with insulinemia or glycemia, and negatively with insulin sensitivity. TIMP-1 also positively correlated with blood pressure, and TPO with triglyceride levels. Multiple regression analysis showed that fat mass per se was an independent determinant of GRO-alpha, TPO, and TIMP-1 levels, suggesting that hypertrophied adipocytes and recruited macrophages in expanded AT mainly contribute to this hyperadipokinemia. Insulinemia, glycemia and resistance of glucose oxidation to insulin were additional predictors for TPO. Circulating GRO-alpha, TPO, and TIMP-1 levels are increased in obesity. This may be partially due to augmented adiposity per se and to hyperinsulinemia/insulin resistance. These high systemic levels may in turn worsen/promote insulin resistance and cardiovascular disease.

[Gut microbiota, responsible for our body weight?]. / La flore intestinale, responsable de notre poids?

Obesity is a multifactorial disease and often considered as an imbalance between energy intake and energy expenditure. However, the gut microbiota could have an impact on the development of excess body weight. According to the type of diet, this black box of the bowel could contribute to modifications of both the caloric extraction and the energy expenditure. The gut microbiota is linked with intermediary metabolism and inflammation, and could be involved in physiopathogenesis of type 1 and 2 diabetes, metabolic syndrome and obesity. Fiber enriched diet and Mediterranean type of diet could induce gut microbiota modifications with consecutive weight loss and improvement of both metabolic syndrome and diabetes.

[Enlarged waist circumference and cardiovascular risk factors]. / Périmètre abdominal augmenté et facteurs de risque cardiovasculaire.

Obesity is a recognized risk factor for cardiovascular diseases. As evaluated by body mass index (BMI), obesity is associated with increased morbidity and mortality due to chronic diseases, like type 2 diabetes, coronary artery disease and stroke. It has been shown that not only the quantity of the fat mass but also the fat mass distribution is important. Furthermore, the fat tissue deposition at visceral level, as measured by waist circumference, is a risk factor for cardio-metabolic diseases. The waist circumference is easy to measure and reflect the visceral adipose tissue which is a cardio-metabolic risk factor Abdominal fat accumulation induces a less favorable cardio-metabolic profile, even in normal body weight subjects with waist circumference within the normal range.

Low-grade chronic inflammation in the relationship between insulin sensitivity and cardiovascular disease (RISC) population: associations with insulin resistance and cardiometabolic risk profile.

OBJECTIVE: Low-grade chronic inflammation has been hypothesized to underlie the constellation of cardiometabolic risk factors, possibly by inducing insulin resistance. In the present study, we investigated associations between inflammation markers, insulin sensitivity (expressed as the ratio of the M value to the mean plasma insulin concentrations measured during the final 40 min of the clamp [M/I]), and a range of cardiometabolic risk factors in a large, healthy population. RESEARCH DESIGN AND METHODS: The Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort includes 1,326 nondiabetic European men and women, aged between 30 and 60 years. We measured cardiometabolic risk factors and performed a hyperinsulinemic-euglycemic clamp. We determined total white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) as markers of chronic inflammation. RESULTS: WBC and ESR were both strongly associated with M/I. WBC and ESR were further associated with a range of cardiometabolic risk factors. Associations between WBC and HDL cholesterol, triglycerides, heart rate, fasting C-peptide, and insulin and 2-h insulin in men and women and between WBC and 2-h glucose in women remained significant after adjustment for both M/I and waist circumference. Associations between ESR and HDL cholesterol, heart rate, fasting, and 2-h insulin in men and women and between ESR and fat mass in women remained significant after adjustment for M/I and waist circumference. CONCLUSIONS: This study showed that low-grade chronic inflammation is associated with the cardiometabolic risk profile of a healthy population. Insulin resistance, although strongly associated with inflammation, does not seem to play a large intermediary role.

Independent evolution of heart autonomic function and insulin sensitivity during weight loss.

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.

Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids?

Intra-myocellular triglycerides (IMTG) accumulate in the muscle of obese and endurance-trained (ET) humans and are considered a pathogenic factor in the development of insulin resistance, in the former. We postulate that this paradox may be associated with the peroxidation status of the IMTG. IMTG content was the same in the obese and ET subjects. The lipid peroxidation/IMTG ratio was 4.2-fold higher in the obese subjects. Hence, obesity results in an increased level of IMTG peroxidation while ET has a protective effect on IMTG peroxidation. This suggests a link between the lipid peroxidation/IMTG ratio and insulin resistance.

Progressive defect of insulin action on glycogen synthase in obesity and diabetes.

The purpose of the present work was to have a closer view on the changes in the regulation of glycogen synthase (GS) activity by insulin in relationship with the impairment of nonoxidative glucose disposal in human obesity. Obese patients with normal glucose tolerance (12), impaired glucose tolerance (11), diabetes (10), and lean control subjects (15) participated to the study. A euglycemic, hyperinsulinemic clamp was performed and associated with indirect calorimetry. Muscle needle biopsies were taken before and at the end of the 2-hour clamp for measurements of glycogen synthase fractional velocity and total activity. Total GS activity was significantly decreased (P <.05), while its percent activation by insulin was still normal in the obese glucose-tolerant group, and nonoxidative glucose disposal was decreased by 56% (P <.001) and glucose oxidation still normal. Total GS activity was decreased by about 50% (P <.01) and GS was unresponsive to insulin in the glucose-intolerant and diabetic groups. In conclusion, our data show that insulin-stimulated nonoxidative glucose disposal and total glycogen synthase are very early defects observed in obese patients.