Aims/hypothesis Liraglutide 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). Methods In 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 enrollment 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 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days). 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 (fMRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Results Immunohistochemical 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 (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide −0.47 ± 0.18). 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/interpretation For 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 (3 mg) recently approved for obesity.

Purpose of review To 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 findings The 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 effectively 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 resistance. Thus, leptin administration has proven ineffective for inducing weight loss on its own but may be useful in combination with other therapies or for weight loss maintenance. Summary Leptin is not yet able to treat typical obesity, however, it is effective for reversing leptin deficiency-induced obesity and lipodystrophy. New mechanisms and pathways involved in leptin resistance are continuously discovered, while the development of new techniques and drug combinations which may improve leptin’s efficacy and safety regenerate the hope for its use as an effective treatment for typical obesity.

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.

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.

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We investigated the relationships between cerebral blood flow (CBF), cognitive and mobility decline in type 2 diabetes mellitus (T2DM) over a two-year period. Seventy-three participants (41 T2DM and 32 controls) were evaluated using volumetric CBF with arterial spin labeling (ASL) perfusion magnetic resonance imaging (pMRI) at baseline and at the two-year follow-up. Regions with significant CBF differences between T2DM participants and controls at baseline were detected using voxel-wise analysis. Correlation analysis was performed to investigate the association between regional CBF and cognitive or mobility performance over the two-year span. Compared to controls, participants with T2DM had decreased CBF in the resting state default mode, visual, and cerebellum networks. Greater decrease in longitudinal CBF values at these regions over a two-year span was associated with worse gait, memory and executive functions, and higher baseline insulin resistance and worse baseline cognitive performance. In T2DM, impairment of resting regional perfusion is closely related to worse cognitive and mobility performance. Insulin resistance may further contribute to regional perfusion deficit in T2DM.

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.

Objective: To investigate the effects of different coffee amounts on dietary intake and appetite feelings in normal-weight and overweight/obese individuals. Design and Methods: Thirty-three volunteers (16 normal-weight, 17 overweight/obese) participated in three trials: they consumed a standard breakfast along with 200 ml of either coffee with 3 or 6 mg caffeine/kg body weight (Coffee 3 and Coffee 6, respectively), or water. At fasting and at standard time points for the 3 h following breakfast/drink consumption participants recorded their appetite feelings on visual analogue scales. At 180 min, participants consumed an ad libitum meal and the next day they recalled their food intake during the experimental day. Results: A significant intervention effect was found for the energy intake of the ad libitum meal (P ¼ 0.05) and of the whole day (P ¼ 0.02) only in overweight/obese individuals. Specifically, Coffee 6 resulted in a reduced energy intake during the ad libitum meal compared to Coffee 3 (P ¼ 0.03) and in the total day compared to both water (P ¼ 0.04) and Coffee 3 (P ¼ 0.008). No effect was observed for the appetite feelings. Conclusions: A moderate coffee amount can effectively reduce energy intake in the following meal and in the total day compared to lower or no coffee intake in overweight/obese participants.