Ghrelin concentration as an indicator of eating-disorder risk in obese women.

AIM: Eating disorders (EDs), disordered eating (DE) and obesity are thought to have overlapping aetiological processes. DE in obesity can jeopardize weight-loss results, and acyl ghrelin (AG) is a hormone that stimulates food intake and reward processes. The main study objective was to determine whether higher-than-expected concentrations of AG in common obesity are associated with DE symptoms. METHODS: The study population included 84 women, aged 20-55 years, free of established EDs: 55 were severely obese (OB) and 29 were of normal weight (NW). OB participants were stratified into two groups according to their median concentration of fasting AG distribution. The OB women with a high fasting plasma ghrelin concentration (HGC) were compared with both OB women with a low fasting plasma ghrelin concentration (LGC) and NW women. Participants were assessed by the Eating Disorder Inventory (EDI-2), Three-Factor Eating Questionnaire (TFEQ) and Hospital Anxiety and Depression Scale (HADS). Fasting glucose, insulin, leptin and ghrelin plasma concentrations were also quantified. RESULTS: Between the two AG groups of OB women, there was no statistical difference in either anthropometric or metabolic parameters, HADS, TFEQ or fasting hunger scores. However, the HGC group scored significantly higher than the LGC group on the drive-for-thinness subscale of EDI-2 (9.30±0.99 vs. 6.46±0.83, respectively; P=0.033). CONCLUSION: Results support the hypothesis of a potential relationship between fasting plasma AG concentrations and ED risk, regardless of mood and anxiety. AG may be considered a potential biomarker of vulnerability for developing EDs.

Associations between Plasmatic Polyunsaturated Fatty Acids Concentrations and Cognitive Status and Decline in Neurocognitive Disorders.

OBJECTIVE: To examine the association of plasmatic and erythrocyte concentrations polyunsaturated fatty acids (PUFA) with both cognitive status and decline. DESIGN: Longitudinal observational cohort study. SETTING: Memory Clinic of Lyon Sud university hospital. PARTICIPANTS: 140 patients, aged 60 and older, were referred to the memory clinic, and successively included in the cohort, between March 2010 and February 2014. MEASUREMENTS: Concentration of ω-3 PUFA (eicosapentaenoic: EPA and docosahexaenoic: DHA) and ω-6 PUFA (arachidonic: AA), were measured at baseline in plasma and in the erythrocytes membrane. Cognitive status was assessed using the mini mental state examination (MMSE), at baseline and every six months during follow-up. The median follow-up period was of 11,5 months. RESULTS: Compared to participants with minor neurocognitive disorders (MMSE≥24), participants with major neurocognitive disorders (NCD) had lower plasmatic concentrations of EPA and DHA (p<0.05) at baseline. Erythrocyte AA and DHA concentrations were significantly lower in patients with cognitive decline (defined as a ≥2 points loss of MMSE per year), while no difference in plasmatic concentrations was observed. CONCLUSIONS: Our study suggests that ω-3 PUFA plasma concentrations (mainly EPA and DHA) could be associated with cognitive status in older people. Moreover, in this exploratory study, lower erythrocyte PUFA concentrations (AA and DHA) were associated with accelerated decline and could be proposed as a surrogate marker for prediction of cognitive decline.

Plasma acyl-ghrelin increases after meal initiation: a new insight.

BACKGROUND/OBJECTIVES: Plasma ghrelin secretion over time in humans is characterized by pre-prandial increases and by post-prandial decreases all day long. However, some authors who measured ghrelin concentrations around meals showed a rise in plasma ghrelin concentration after meal initiation followed by the typical post-prandial decrease. In order to confirm this observation that has never been discussed, we described ghrelin profiles around four eating episodes in the morning in adult men. SUBJECTS/METHODS: Twenty normal-weight and 17 obese men were instructed to eat four fixed meals (706 kJ) 10 min long at 0800 h, 0900 h, 1000 h and 1100 h. Using frequent blood sampling, we determined plasma acyl-ghrelin concentrations around those eating episodes. Glucose, insulin and GLP-1 concentrations were also measured. RESULTS: The meals consumption induced a significant increase in plasma acyl-ghrelin concentrations 10 min after meal initiation (P<0.0001): +20.9±5.8 and +10.7±3.3 pg/ml in normal-weight and obese subjects for the first meal; +10.4±3.0 and +5.5±3.9 pg/ml in normal-weight and obese subjects for the second meal; +12.4±3.6 and +4.2±2.1 pg/ml in normal-weight and obese subjects for the third meal; and +4.4±4.1 and +3.3±2.61 pg/ml in normal-weight and obese subjects for the fourth meal. CONCLUSIONS: This study is the first to describe and discuss the post-meal initiation ghrelin increase. This finding is consistent in normal-weight and obese individuals.

Nicotinic acid effects on insulin sensitivity and hepatic lipid metabolism: an in vivo to in vitro study.

Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan(®) on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan(®) (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan(®) treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri-glyceride production rate was markedly reduced after Niaspan(®) (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05) in the Niaspan(®) condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan(®) treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.

Regulation of energy metabolism and mitochondrial function in skeletal muscle during lipid overfeeding in healthy men.

CONTEXT/OBJECTIVE: The aim of this study was to evaluate the regulation of the fuel partitioning and energy metabolism in skeletal muscle during lipid overfeeding in healthy men. Design/Participants/Intervention: Thirty-nine healthy volunteers were overfed for 56 days with a high-fat diet (3180 kJ/d). Energy metabolism (indirect calorimetry) was characterized in the fasting state and during a test meal before and at the end of the diet. Skeletal muscle biopsies were taken at day 0 and day 56. MAIN OUTCOME MEASURES: Change in gene expression, mitochondrial respiration, nicotinamide adenine dinucleotide (NAD(+)) content, and acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle was measured. RESULTS: Overfeeding increased body weight (+2.6 kg) and fat mass concomitantly with a shift in the use of substrates as energy fuel toward preferential oxidation of carbohydrates instead of lipids. Changes in lipid metabolic gene expression supported this observation, with a reduction in pyruvate dehydrogenase kinase 4 expression that could be the consequences of decreased NAD(+) concentration and reduced deacetylase activity of the sirtuins, as supported by hyperacetylation of PGC-1α after overfeeding. Interestingly, this reduction of the sirtuin PGC-1α pathway was associated with increased mitochondrial gene expression and higher respiration rate under these conditions. CONCLUSION: Adaptation to lipid overfeeding and regulation of fuel partitioning in human muscle appear to rely on a dissociation between the regulatory functions of the sirtuin-PGC-1α pathway on fatty acid oxidation and on mitochondrial regulation. This may facilitate lipid storage during a period of positive energy balance while maintaining mitochondrial functions and oxidative capacities.

[Validation of pharmaceutical quality of a [6,6-(2)H(2)]-glucose parenteral solution used for insulin-resistance measurement during human clinical trials]. / Validation de la qualité pharmaceutique de préparations de [6,6-(2)H(2)]-glucose en solution aqueuse administrées par voie parentérale pour la mesure de l'insulino-résistance dans le cadre d'essais cliniques.

INTRODUCTION: Deuterated glucose ([6,6-(2)H(2)]-glucose) is a stable isotopic tracer administered parenterally in healthy volunteers, obese or diabetic patients in clinical trial to study glucose metabolism during euglycemic hyperinsulinemic clamps. In accordance with the Health Authorities on drug safety, we evaluated the pharmaceutical quality of this preparation for biomedical research with a stability study. METHODS: After pharmaceutical qualification of the raw material, the [6,6-(2)H(2)]-glucose was dissolved in water for injection, then sterile, filtered under positive pressure of nitrogen and then autoclaved. Two batch products (500mg/10mL and 2g/15mL) were sampled to evaluate glucose alteration, isotope shift, limpidity, apyrogenicity and sterility at regular intervals for 2 years. Deuterated glucose solutions were stored in the dark, at +2°C+8°C, in type II glass bottles. RESULTS: Neither significant decrease of glucose concentration nor pH variation were observed for 2 years. The 5-hydroxymethylfurfural concentration was below the human harmful levels, attesting a non-generation of metabolites during autoclaving. Isotopic enrichment higher than 99% reflected the stability of deuterated label on the 6-carbon of glucose molecules. The non-visible particle concentration below the minimal permissible concentration tolerated by the European Pharmacopoeia and the absence of bacterial endotoxin and bacterial growth attested limpidity, apyrogenicity and sterility of the [6,6-(2)H(2)]-glucose solutions. CONCLUSION: After the 2-year study, 500mg/10mL and 2g/15mL deuterated glucose solutions stored in the dark at +2°C+8°C were stable in aqueous solution, allowing to ensure safety administration for human clinical trials using euglycemic hyperinsulinemic clamps.