Expanding the role of bitter taste receptor in extra oral tissues : TAS2R38 is expressed in human adipocytes

Increasing evidence indicates that taste receptors mediate a variety of functions in extra-oral tissues. The present study investigated the expression of bitter taste receptor TAS2R38 in human adipocytes, the possible link with genetic background and the role of TAS2R38 in cell delipidation and lipid accumulation rate in vitro. Subcutaneous (SAT) and visceral (VAT) adipose tissues were collected in 32 obese and 18 lean subjects. The TAS2R38 gene expression and protein content were examined in whole tissues, differentiated adipocytes and stroma-vascular fraction cells (SVF). The P49A SNP of TAS2R38 gene was determined in each collected sample. The effect of two bitter agonists (6-n-propylthiouracil and quinine) was tested. TAS2R38 mRNA was more expressed in SAT and VAT of obese than lean subjects and the expression/protein content was greater in mature adipocytes. The expression levels were not linked to P49A variants. In in vitro differentiated adipocytes, bitter agonists induced a significant delipidation. Incubation with 6-n-propylthiouracil induced an inhibition of lipid accumulation rate together with an increase in TAS2R38 and a decrease in genes involved in adipocyte differentiation. In conclusion, TAS2R38 is more expressed in adipocytes of obese than lean subjects and is involved in differentiation and delipidation processes

Differences in visceral fat and fat bacterial colonization between ulcerative colitis and Crohn's disease. An in vivo and in vitro study

Crohn's disease (CD) is notably characterized by the expansion of visceral fat with small adipocytes expressing a high proportion of anti-inflammatory genes. Conversely, visceral fat depots in ulcerative colitis (UC) patients have never been characterized. Our study aims were a) to compare adipocyte morphology and gene expression profile and bacterial translocation in omental (OM) and mesenteric (MES) adipose tissue of patients with UC and CD, and b) to investigate the effect of bacterial infection on adipocyte proliferation in vitro. Specimens of OM and MES were collected from 11 UC and 11 CD patients, processed and examined by light microscopy. Gene expression profiles were evaluated in adipocytes isolated from visceral adipose tissue using microarray and RTqPCR validations. Bacteria within adipose tissue were immuno-detected by confocal scanning laser microscopy. Adipocytes were incubated with Enterococcus faecalis and cells counted after 24 h. Morphology and molecular profile of OM and MES revealed that UC adipose tissue is less inflamed than CD adipose tissue. Genes linked to inflammation, bacterial response, chemotaxis and angiogenesis were down-regulated in adipocytes from UC compared to CD, whereas genes related to metallothioneins, apoptosis pathways and growth factor binding were up-regulated. A dense perinuclear positivity for Enterococcus faecalis was detected in visceral adipocytes from CD, whereas positivity was weak in UC. In vitro bacterial infection was associated with a five-fold increase in the proliferation rate of OM preadipocytes. Compared to UC, visceral adipose tissue from CD is more inflamed and more colonized by intestinal bacteria, which increase adipocyte proliferation. The influence of bacteria stored within adipocytes on the clinical course of IBD warrants further investigation

Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome

Somatostatin (SS) and dopamine (DA) receptors are widely expressed in neuroendocrine tumours that cause Cushing's Syndrome (CS). Increasing knowledge of specific subtype expression within these tumours and the ability to target these receptor subtypes with high-affinity compounds, has driven the search for new SS- or DA-based medical therapies for the various forms of CS. In Cushing's disease, corticotroph adenomas mainly express dopamine receptor subtype 2 (D2) and somatostatin receptor subtype 5 (sst5), whereas sst2is expressed at lower levels. Activation of these receptors can inhibit ACTH-release in primary cultured corticotroph adenomas and compounds that target either sst5(pasireotide, or SOM230) or D2(cabergoline) have shown significant efficacy in subsets of patients in recent clinical studies. Combination therapy, either by administration of both types of compounds separately or by treatment with novel somatostatin-dopamine chimeric molecules (e.g. BIM-23A760), appears to be a promising approach in this respect. In selected cases of Ectopic ACTH-producing Syndrome (EAS), the sst2-preferring compound octreotide is able to reduce cortisol levels effectively. A recent study showed that D2receptors are also significantly expressed in the majority of EAS and that cabergoline may decrease cortisol levels in subsets of these patients. In both normal adrenal tissue as well as in adrenal adenomas and carcinomas that cause CS, sst and DA receptor expression has been demonstrated. Although selected cases of adrenal CS may benefit from sst or DA-targeted treatment, its total contribution to the treatment of these patients is likely to be low as surgery is effective in most cases

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background Liraglutide 3\ub70 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3\ub70 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2\ub77 times longer with liraglutide than with placebo (95% CI 1\ub79 to 3\ub79, p<0\ub70001), corresponding with a hazard ratio of 0\ub721 (95% CI 0\ub713\u20130\ub734). Liraglutide induced greater weight loss than placebo at week 160 (\u20136\ub71 [SD 7\ub73] vs 121\ub79% [6\ub73]; estimated treatment difference 124\ub73%, 95% CI 124\ub79 to 123\ub77, p<0\ub70001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3\ub70 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark

Effect of short-term dietary intervention and probiotic mix supplementation on the gut microbiota of elderly obese women

Accumulating literature is providing evidence that the gut microbiota is involved in metabolic disorders, but the question of how to effectively modulate it to restore homeostasis, especially in the elderly, is still under debate. In this study, we profiled the intestinal microbiota of 20 elderly obese women (EO) at the baseline (T0), after 15 days of hypocaloric Mediterranean diet administered as part of a nutritional-metabolic rehabilitation program for obesity (T1), and after a further 15 days of the same diet supplemented with a probiotic mix (T2). Fecal samples were characterized by Illumina MiSeq sequencing of the 16S rRNA gene. The EO microbiota showed the typical alterations found in obesity, namely, an increase in potential pro-inflammatory components (i.e., Collinsella) and a decrease in health-promoting, short-chain fatty acid producers (i.e., Lachnospiraceae and Ruminococcaceae members), with a tendency to reduced biodiversity. After 15 days of the rehabilitation program, weight decreased by (2.7 \ub1 1.5)% and the gut microbiota dysbiosis was partially reversed, with a decline of Collinsella and an increase in leanness-related taxa. During the next 15 days of diet and probiotics, weight dropped further by (1.2 \ub1 1.1)%, markers of oxidative stress improved, and Akkermansia, a mucin degrader with beneficial effects on host metabolism, increased significantly. These findings support the relevant role of a correct dietetic approach, even in the short term, to modulate the EO gut microbiota towards a metabolic health-related configuration, counteracting the increased risk of morbidity in these patients

Cardiovascular Risk Factors Associated With the Metabolically Healthy Obese (MHO) Phenotype Compared to the Metabolically Unhealthy Obese (MUO) Phenotype in Children

Background: In pediatric age the prevalence of obesity is high. Obese children who do not have other risk factors than excess weight have been defined as \u201cmetabolically healthy obese\u201d (MHO). Aim: The aim of this study is to evaluate, in a population of obese children, the prevalence of the MHO and \u201cmetabolically unhealthy obese\u201d (MUO) phenotype. Furthermore, we evaluated the distribution of Uric Acid, HOMA index and Waist-Height ratio (W-Hr) in the MHO and MUO sub-groups and the impact of these non-traditional risk factors on the probability to be MUO. Methods: In 1201 obese children and adolescents [54% males, age (\ub1SD) 11.9 (\ub13.0) years] weight, height, waist circumference, systolic (SBP) and diastolic (DBP) blood pressure, pubertal status, glucose, insulin, HDL cholesterol, triglycerides and Uric Acid serum values were assessed. MUO phenotype was defined as the presence of at least one of the following risk factors: SBP or DBP 65 90th percentile, glycaemia 65 100 mg/dl, HDL cholesterol &lt;40 mg/dl, triglycerides 65100 mg/dl (children &lt;10 years) or 65130 mg/dl (children 6510 years). A multivariate logistic regression analysis was used to estimate the association between MUO phenotype and non-traditional cardiovascular risk factors. Results: The prevalence of the MUO status was high (61%). MUO subjects were more often male, older and pubertal (p &lt; 0.001). The levels of the three non-traditional risk factors were significantly higher in MUO children compared to MHO children (p &lt; 0.001) and all of them were independent predictors of the fact of being MUO [OR 1.41 (95% CI 1.24\u20131.69); 1.15 (95% CI 1.06\u20131.23) and 1.03 (95% CI1.01\u20131.05) for Uric Acid, HOMA index and W-Hr, respectively]. About 15% of MHO subjects had serum Uric Acid, HOMA index and W-Hr values within the highest quartile of the study population. Conclusion: The prevalence of MUO subjects in a large pediatric population is high and serum Uric Acid, HOMA index and W-Hr values are independent predictors of the probability of being MUO. A non-negligible percentage of subjects MHO has high values of all three non-traditional risk factors

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Analysis of predictive equations for estimating resting energy expenditure in a large cohort of morbidly obese patients

The treatment of obesity requires creating an energy deficit through caloric restriction and physical activity. Energy needs are estimated assessing the resting energy expenditure (REE) that in the clinical practice is estimated using predictive equations. In the present cross sectional study, we compared, in a large cohort of morbidly obese patients, the accuracy of REE predictive equations recommended by current obesity guidelines [Harris-Benedict, WHO/FAO/ONU and Mifflin-St Jeor (MJ)] and/or developed for obese patients (Muller, Muller BC, Lazzer, Lazzer BC), focusing on the effect of comorbidities on the accuracy of the equations. Data on REE measured by indirect calorimetry and body composition were collected in 4,247 obese patients (69% women, mean age 48 \ub1 19 years, mean BMI 44 \ub1 7 Kg/m2) admitted to the Istituto Auxologico Italiano from 1999 to 2014. The performance of the equations was assessed in the whole cohort, in 4 groups with 0, 1, 2, or = 653 comorbidities and in a subgroup of 1,598 patients with 1 comorbidity (47.1% hypertension, 16.7% psychiatric disorders, 13.3% binge eating disorders, 6.1% endocrine disorders, 6.4% type 2 diabetes, 3.5% sleep apnoea, 3.1% dyslipidemia, 2.5% coronary disease). In the whole cohort of obese patients, as well as in each stratum of comorbidity number, the MJ equation had the highest performance for agreement measures and bias. The MJ equation had the best performance in obese patients with 653 comorbidities (accuracy of 61.1%, bias of -89.87) and in patients with type 2 diabetes and sleep apnoea (accuracy/bias 69%/-19.17 and 66%/-21.67 respectively), who also have the highest levels of measured REE. In conclusion, MJ equation should be preferred to other equations to estimate the energy needs of Caucasian morbidly obese patients when measurement of the REE cannot be performed. As even MJ equation does not precisely predict REE, it should be better to plan the diet intervention by measuring rather than estimating REE. Future studies focusing on the clinical differences that determine the high inter-individual variability of the precision of the REE predictive equations (e.g., on the organ-tissue metabolic rate), could help to develop predictive equations with a better performance