New insights on the role of the endocannabinoid system in the regulation of energy balance.

Within the past 15 years, the endocannabinoid system (ECS) has emerged as a lipid signaling system critically involved in the regulation of energy balance, as it exerts a regulatory control on every aspect related to the search, the intake, the metabolism and the storage of calories. An overactive endocannabinoid cannabinoid type 1 (CB1) receptor signaling promotes the development of obesity, insulin resistance and dyslipidemia, representing a valuable pharmacotherapeutic target for obesity and metabolic disorders. However, because of the psychiatric side effects, the first generation of brain-penetrant CB1 receptor blockers developed as antiobesity treatment were removed from the European market in late 2008. Since then, recent studies have identified new mechanisms of action of the ECS in energy balance and metabolism, as well as novel ways of targeting the system that may be efficacious for the treatment of obesity and metabolic disorders. These aspects will be especially highlighted in this review.

[Obesities: What's new in 2016?] / Obésités : quoi de neuf en 2016 ?

Since 1997, the World Health Organisation considered obesity, defined as an excess of fat mass, as a disease. Many plans have been set up to fight against obesity in industrialised countries. However, the prevalence of obesity is still increasing. The goal of this paper is to report some of the major scientific publications in terms of epidemiology, physiopathology or therapeutic in the field of obersity mainly published during year 2015-2016 or presented at ENDO meeting 2016.

Maintenance of energy expenditure on high-protein vs. high-carbohydrate diets at a constant body weight may prevent a positive energy balance.

BACKGROUND & AIMS: Relatively high-protein diets are effective for body weight loss, and subsequent weight maintenance, yet it remains to be shown whether these diets would prevent a positive energy balance. Therefore, high-protein diet studies at a constant body weight are necessary. The objective was to determine fullness, energy expenditure, and macronutrient balances on a high-protein low-carbohydrate (HPLC) diet compared with a high-carbohydrate low-protein (HCLP) diet at a constant body weight, and to assess whether effects are transient or sustained after 12 weeks. METHODS: A randomized parallel study was performed in 14 men and 18 women [mean ± SD age: 24 ± 5 y; BMI (in kg/m(2)): 22.8 ± 2.0] on diets containing 30/35/35 (HPLC) or 5/60/35 (HCLP) % of energy from protein/carbohydrate/fat. RESULTS: Significant interactions between dietary intervention and time on total energy expenditure (TEE) (P = 0.013), sleeping metabolic rate (SMR) (P = 0.040), and diet-induced thermogenesis (DIT) (P = 0.027) appeared from baseline to wk 12. TEE was maintained in the HPLC diet group, while it significantly decreased throughout the intervention period in the HCLP diet group (wk 1: P = 0.002; wk 12: P = 0.001). Energy balance was maintained in the HPLC diet group, and became positive in the HCLP diet group at wk 12 (P = 0.008). Protein balance varied directly according to the amount of protein in the diet, and diverged significantly between the diets (P = 0.001). Fullness ratings were significantly higher in the HPLC vs. the HCLP diet group at wk 1 (P = 0.034), but not at wk 12. CONCLUSIONS: Maintenance of energy expenditure on HPLC vs. HCLP diets at a constant body weight may prevent development of a positive energy balance, despite transiently higher fullness. The study was registered on clinicaltrials.gov with Identifier: NCT01551238.

Early changes in respiratory quotient and resting energy expenditure predict later weight changes in patients treated for poorly controlled type 2 diabetes.

AIM: This study looked at whether early changes in resting energy expenditure (REE) and respiratory quotient (RQ) are correlated with later weight changes in patients with type 2 diabetes (T2D) being treated with insulin or GLP-1 analogues, or diet. METHODS: A total of 67 patients (age: 57 ± 9 years; BMI: 33.7 ± 5.0 kg/m(2); HbA1c: 9.9 ± 1.5%) began taking an insulin analogue at bedtime (INS, n=28; initial dose: 0.2 IU/kg) or a GLP-1 analogue (GLP-1, n=23), or only a dietary intervention (diet, n=16; restricted carbohydrates and calories). Their respiratory exchanges were monitored on days 0, 1 and 2 before breakfast. RESULTS: Two days after starting the bedtime insulin analogue, fasting glycaemia improved (INS: -65 ± 41 mg/dL; GLP-1: -29 ± 48 mg/dL; diet: -31 ± 46 mg/dL; P<0.05), REE decreased (INS: -162 ± 241 kcal/24h; GLP-1: 0 ± 141 kcal/24h; diet: -41 ± 154 kcal/24h; P<0.05) and RQ increased (from 0.76 ± 0.04 to 0.80 ± 0.04; P<0.01), whereas only RQ decreased with diet (from 0.79 ± 0.05 to 0.76 ± 0.04; P<0.05) and remained unchanged with GLP-1 (P<0.005 for ΔRQ across treatments). Only 33 patients attended the scheduled examination three months later. HbA1c improved (INS, n=16: -1.7 ± 1.4%; GLP-1, n=12: -2.1 ± 1.4%; diet, n=5: -1.7 ± 2.8%; NS), while weight changes differed (INS: +1.5 ± 4.3 kg; GLP-1: -2.8 ± 2.8 kg; diet: -2.2 ± 2.7 kg; P<0.005). After three months, weight changes correlated with early changes in REE (r=-0.37, P<0.05) and RQ (r=+0.43, P<0.01), and remained correlated when both changes were included in a multivariate regression analysis (r=0.58, P<0.005). CONCLUSION: In poorly controlled patients with T2D and two days after the introduction of a bedtime insulin analogue, REE decreased by -9% while RQ increased by +5%, pointing to a reduction of lipid oxidation. These changes were predictive of later weight gain.

Simultaneous postprandial deregulation of the orexigenic endocannabinoid anandamide and the anorexigenic peptide YY in obesity.

BACKGROUND: The endocannabinoid system is a potential pharmacotherapy target for obesity. However, the role of this system in human food intake regulation is currently unknown. METHODS: To test whether circulating endocannabinoids might functionally respond to food intake and verify whether these orexigenic signals are deregulated in obesity alongside with anorexigenic ones, we measured plasma anandamide (AEA), 2-arachidonoylglycerol (2-AG) and peptide YY (PYY) changes in response to a meal in 12 normal-weight and 12 non-diabetic, insulin-resistant obese individuals. RESULTS: Both normal-weight and obese subjects had a significant preprandial AEA peak. Postprandially, AEA levels significantly decreased in normal-weight, whereas no significant changes were observed in obese subjects. Similarly, PYY levels significantly increased in normal-weight subjects only. No meal-related changes were found for 2-AG. Postprandial AEA and PYY changes inversely correlated with waist circumference, and independently explained 20.7 and 21.3% of waist variance. Multiple regression analysis showed that postprandial AEA and PYY changes explained 34% of waist variance, with 8.2% of the variance commonly explained. CONCLUSION: These findings suggest that AEA might be a physiological meal initiator in humans and furthermore show that postprandially AEA and PYY are concomitantly deregulated in obesity.

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

OBJECTIVE: Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. METHODS: Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. RESULTS: Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. CONCLUSIONS: Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.