Anna Gavrieli

GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial

Aims/hypothesisLiraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).MethodsIn 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17xa0days each (0.6xa0mg for 7xa0days, 1.2xa0mg for 7xa0days, and 1.8xa0mg for 3xa0days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.ResultsImmunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (pu2009<u20090.001; effect size: placebo 0.53u2009±u20090.24, liraglutide −0.47u2009±u20090.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.Conclusions/interpretationFor the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3xa0mg) recently approved for obesity.Trial registrationClinicalTrials.gov NCT01562678FundingThe study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Caffeinated Coffee Does Not Acutely Affect Energy Intake, Appetite, or Inflammation but Prevents Serum Cortisol Concentrations from Falling in Healthy Men

Our aim in this crossover study was to investigate the acute effects of caffeinated and decaffeinated coffee consumption on appetite feelings, energy intake, and appetite-, inflammation-, stress-, and glucose metabolism-related markers. Sixteen healthy men (age range, 21-39 y; BMI range, 19.7-28.6 kg/m(2)) received in a random order on 3 separate occasions a standard breakfast snack with 200 mL of either caffeinated coffee (3 mg caffeine/kg body weight), decaffeinated coffee, or water (control). Before intervention (-15 min) and at standard time points following breakfast consumption (0, 15, 30, 60, 90, 120, 150, and 180 min), participants recorded their appetite feelings and we collected blood samples for measurements of circulating glucose, insulin, cortisol, and appetite- and inflammation-related markers. At 180 min, participants consumed a meal ad libitum. The appetite-related ratings, the appetite plasma hormonal responses as well as the plasma glucose, serum insulin, and plasma and serum inflammatory marker responses did not show an overall intervention effect or a time x intervention interaction. Ad libitum energy intake did not differ among the 3 interventions. However, a significant intervention effect (P = 0.04) and a time x intervention interaction (P-interaction = 0.02) were found for serum cortisol; cortisol concentrations were significantly higher following the caffeinated coffee intervention, compared to control, at 60 min and thereafter. In conclusion, the usually consumed amount of caffeinated coffee does not have short-term effects on appetite, energy intake, glucose metabolism, and inflammatory markers, but it increases circulating cortisol concentrations in healthy men.

Leptin applications in 2015: what have we learned about leptin and obesity?

Purpose of reviewTo summarize previous and current advancements for leptin therapeutics, we described how leptin may be useful in leptin deficient states such as lipodystrophy, for which leptin was recently approved, and how it may be useful in the future for typical obesity. Recent findingsThe discovery of leptin in 1994 built the foundation for understanding the pathophysiology and treatment of obesity. Leptin therapy reverses morbid obesity related to congenital leptin deficiency and appears to possibly treat lipodystrophy, a finding which has led to the approval of leptin for the treatment of lipodystrophy in the USA and Japan. Typical obesity, on the other hand, is characterized by hyperleptinemia and leptin tolerance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but could possibly be useful in combination with other therapies or for weight loss maintenance. SummaryLeptin is not able to treat typical obesity; however, it is effective for reversing leptin deficiency-induced obesity and is possibly useful in lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, whereas the development of new techniques and drug combinations which may improve leptins efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity.

Effect of different amounts of coffee on dietary intake and appetite of normal‐weight and overweight/obese individuals

To investigate the effects of different coffee amounts on dietary intake and appetite feelings in normal‐weight and overweight/obese individuals.

Lorcaserin Administration Decreases Activation of Brain Centers in Response to Food Cues and These Emotion- and Salience-Related Changes Correlate With Weight Loss Effects: A 4-Week-Long Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

Lorcaserin is a serotonin 5-hydroxytryptamine 2c receptor agonist effective in treating obesity. Studies in rodents have shown that lorcaserin acts in the brain to exert its weight-reducing effects, but this has not yet been studied in humans. We performed a randomized, placebo-controlled, double-blind trial with 48 obese participants and used functional MRI to study the effects of lorcaserin on the brain. Subjects taking lorcaserin had decreased brain activations in the attention-related parietal and visual cortices in response to highly palatable food cues at 1 week in the fasting state and in the parietal cortex in response to any food cues at 4 weeks in the fed state. Decreases in emotion- and salience-related limbic activity, including the insula and amygdala, were attenuated at 4 weeks. Decreases in caloric intake, weight, and BMI correlated with activations in the amygdala, parietal, and visual cortices at baseline. These data suggest that lorcaserin exerts its weight-reducing effects by decreasing attention-related brain activations to food cues (parietal and visual cortices) and emotional and limbic activity (insula, amygdala). Results indicating that baseline activation of the amygdala relates to increased efficacy suggest that lorcaserin would be of particular benefit to emotional eaters.

Early life adversity and/or posttraumatic stress disorder severity are associated with poor diet quality, including consumption of trans fatty acids, and fewer hours of resting or sleeping in a US middle-aged population: A cross-sectional and prospective study

BACKGROUNDnEarly life adversity (ELA) and post-traumatic stress disorder (PTSD) are associated with poorer psychological and physical health. Potential underlying mechanisms and mediators remain to be elucidated, and the lifestyle habits and characteristics of individuals with ELA and/or PTSD have not been fully explored. We investigated whether the presence of ELA and/or PTSD are associated with nutrition, physical activity, resting and sleeping and smoking.nnnMETHODSnA cross-sectional sample of 151 males and females (age: 45.6±3.5 years, BMI: 30.0±7.1 kg/m(2)) underwent anthropometric measurements, as well as detailed questionnaires for dietary assessment, physical activity, resting and sleeping, smoking habits and psychosocial assessments. A prospective follow-up visit of 49 individuals was performed 2.5 years later and the same outcomes were assessed. ELA and PTSD were evaluated as predictors, in addition to a variable assessing the combined presence/severity of ELA-PTSD. Data were analyzed using analysis of covariance after adjusting for several socioeconomic, psychosocial and anthropometric characteristics.nnnRESULTSnIndividuals with higher ELA or PTSD severity were found to have a poorer diet quality (DASH score: p=0.006 and p=0.003, respectively; aHEI-2010 score: ELA p=0.009), including further consumption of trans fatty acids (ELA p=0.003); the differences were significantly attenuated null after adjusting mainly for education or income and/or race. Further, individuals with higher ELA severity reported less hours of resting and sleeping (p=0.043) compared to those with zero/lower ELA severity, and the difference remained significant in the fully adjusted model indicating independence from potential confounders. When ELA and PTSD were combined, an additive effect was observed on resting and sleeping (p=0.001); results remained significant in the fully adjusted model. They also consumed more energy from trans fatty acids (p=0.017) tended to smoke more (p=0.008), and have less physical activity (PTSD p=0.024) compared to those with no or lower ELA and PTSD severity. Adjustments for sociodemographic factors and/or BMI rendered results of the above lifestyle parameters non-significant. The analysis of the prospective data showed similar trends to the cross-sectional analysis, further supporting the conclusions, although statistical significance of results was lower due to the lower number of participants.nnnCONCLUSIONnFewer hours of resting and sleeping and poorer diet quality are linked to ELA and/or PTSD, indicating that these pathways might underlie the development of several metabolic abnormalities in individuals with ELA and/or PTSD. Differences in terms of diet quality are significantly attenuated by race and/or education and/or income, whereas differences in other lifestyle habits of individuals with and without ELA and/or PTSD, such as physical activity, are mostly explained by confounding sociodemographic variables and/or body mass index.

Gender and body mass index modify the effect of increasing amounts of caffeinated coffee on postprandial glucose and insulin concentrations; a randomized, controlled, clinical trial

OBJECTIVEnTo examine the effects of different coffee amounts on blood glucose and insulin concentrations of healthy volunteers, and to assess potential effect modification by sex and body mass index category.nnnMATERIALS/METHODSnThirty-three volunteers [16 ♀/17 ♂, 16 normal-weight and 17 overweight/obese, 27.3 ± 7.2 (19-44) y] took part in this randomized, crossover study. Ιn the morning of each experimental day volunteers received a standardized meal along with 200 mL of water or instant coffee containing either 3 or 6 mg of caffeine/kg body weight. Blood samples were obtained and analyzed for glucose and insulin concentrations in the fasting state, immediately after meal/drink consumption and at standard time points for the next 3h thereafter.nnnRESULTSnCoffee delayed the rise of insulin in response to the standardized meal and the fall of glucose concentrations from its maximum levels in the entire study sample. Glucose incremental area under the curve (IAUC) was significantly different between interventions (P=.009) with both coffee amounts inducing a greater area compared to water. Secondary, subgroup analysis at the nominal level showed that this might be more evident among females (PIAUC=.05) and overweight/obese participants (PIAUC=.03). Furthermore, coffee, mainly the 6 mg dose, could be lowering insulin concentrations the first 30 min after its consumption compared to water in men and overweight/obese participants.nnnCONCLUSIONSnCoffee exerts an acute effect on postprandial glucose and insulin concentrations. This effect may be modified by sex and overweight/obese status. Future research is necessary to elucidate underlying mechanisms.

A Novel Approach for Increasing Fruit Consumption in Children

Despite the well-documented health benefits of fruits and vegetables and the public health campaigns promoting their consumption, childrens intake is below the recommended levels. A randomized controlled trial for evaluating the effectiveness of a school-based intervention for increasing childrens fruit intake, with the teacher being the exposure model, was designed. Two hundred eighteen elementary school students (aged 9 years) in Cyprus were randomly assigned into two 1-year intervention groups, the Educational Material group (EDUC) (n=59) and the Exposure group (EXPO) (n=67), or a control group (n=58). Childrens dietary intake was assessed through 2-day dietary records before the intervention began (October 2008), at the end of the intervention (June 2009), and at 1-year follow-up (June 2010). Students in the EDUC group received a weekly educational program for increasing awareness and improving skills regarding fruit preparation/consumption and students in the EXPO group were exposed to the consumption of a fruit on a daily basis by their teacher. The control group members received no intervention. Repeated measures analysis of variance was used to evaluate the group effect and the time×group interaction. Higher fruit intake was reported by the children in the EXPO and the EDUC groups compared with the control group at the end of the intervention: a statistically significant group effect was found (P<0.001). At 1-year follow-up, results remained significant only for the children in the EXPO group (P<0.001). Exposure to fruit consumption by schoolteachers may be a more effective way for improving fruit intake of children compared with traditional educational approaches.

Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss

Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.

White matter microstructure and cognitive decline in metabolic syndrome: a review of diffusion tensor imaging

Metabolic syndrome is a cluster of cardiovascular risk factors defined by the presence of abdominal obesity, glucose intolerance, hypertension and/or dyslipidemia. It is a major public health epidemic worldwide, and a known risk factor for the development of cognitive dysfunction and dementia. Several studies have demonstrated a positive association between the presence of metabolic syndrome and worse cognitive outcomes, however, evidence of brain structure pathology is limited. Diffusion tensor imaging has offered new opportunities to detect microstructural white matter changes in metabolic syndrome, and a possibility to detect associations between functional and structural abnormalities. This review analyzes the impact of metabolic syndrome on white matter microstructural integrity, brain structure abnormalities and their relationship to cognitive function. Each of the metabolic syndrome components exerts a specific signature of white matter microstructural abnormalities. Metabolic syndrome and its components exert both additive/synergistic, as well as, independent effects on brain microstructure thus accelerating brain aging and cognitive decline.