Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite-and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebocontrolled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite-and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.The global rise in obesity and type 2 diabetes (T2DM) prevalence is a major public health problem (1,2). It has been hypothesized that excessive eating due to changes in central nervous system (CNS) satiety and reward responses to food underlies the development of obesity and T2DM, comparable to the role for altered CNS responses in drug addiction (3). Several studies in obese individuals have demonstrated increased CNS responses to visual food cues in areas involved in appetite and reward processing (insula, amygdala, orbitofrontal cortex [OFC], and striatum) (4-6), and this increased CNS food-cue responsiveness predicts future weight gain (7). The mechanisms underlying these alterations in CNS responses to food cues are not clear, but multiple metabolic and hormonal factors seem to be involved (8-10).Food ingestion activates the secretion of several gutderived mediators, including the incretin hormone GLP-1. GLP-1 stimulates meal-related insulin secretion, inhibits glucagon release, and delays gastric emptying, mechanisms that all contribute to its glucometabolic effects (11). In addition, several observations suggest that GLP-1 has a role in the regulation of food intake. Systemic administration of GLP-1 reduced food intake in rodent and human studies (12), and blocking the GLP-1 receptor with

The delivery of nutrients to the gastrointestinal tract after food ingestion activates the secretion of several gut-derived mediators, including the incretin hormone glucagon-like peptide 1 (GLP-1). GLP-1 receptor agonists (GLP-1RA), such as exenatide and liraglutide, are currently employed successfully in the treatment of patients with type 2 diabetes mellitus. GLP-1RA improve glycaemic control and stimulate satiety, leading to reductions in food intake and body weight. Besides gastric distension and peripheral vagal nerve activation, GLP-1RA induce satiety by influencing brain regions involved in the regulation of feeding, and several routes of action have been proposed. This review summarises the evidence for a physiological role of GLP-1 in the central regulation of feeding behaviour and the different routes of action involved. Also, we provide an overview of presently available data on pharmacological stimulation of GLP-1 pathways leading to alterations in CNS activity, reductions in food intake and weight loss.

Our findings show that GLP-1 receptor activation decreases anticipatory food reward, which may reduce cravings for food and increases consummatory food reward, which may prevent overeating.

Aims/hypothesisThe central nervous system (CNS) is a major player in the regulation of food intake. The gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have an important role in this regulation by relaying information about nutritional status to the CNS. We hypothesised that endogenous GLP-1 has effects on CNS reward and satiety circuits.MethodsThis was a randomised, crossover, placebo-controlled intervention study, performed in a university medical centre in the Netherlands. We included patients with type 2 diabetes and healthy lean control subjects. Individuals were eligible if they were 40–65 years. Inclusion criteria for the healthy lean individuals included a BMI <25 kg/m2 and normoglycaemia. Inclusion criteria for the patients with type 2 diabetes included BMI >26 kg/m2, HbA1c levels between 42 and 69 mmol/mol (6.0–8.5%) and treatment for diabetes with only oral glucose-lowering agents. We assessed CNS activation, defined as blood oxygen level dependent (BOLD) signal, in response to food pictures in obese patients with type 2 diabetes (n = 20) and healthy lean individuals (n = 20) using functional magnetic resonance imaging (fMRI). fMRI was performed in the fasted state and after meal intake on two occasions, once during infusion of the GLP-1 receptor antagonist exendin 9-39, which was administered to block actions of endogenous GLP-1, and on the other occasion during saline (placebo) infusion. Participants were blinded for the type of infusion. The order of infusion was determined by block randomisation. The primary outcome was the difference in BOLD signal, i.e. in CNS activation, in predefined regions in the CNS in response to viewing food pictures.ResultsAll patients were included in the analyses. Patients with type 2 diabetes showed increased CNS activation in CNS areas involved in the regulation of feeding (insula, amygdala and orbitofrontal cortex) in response to food pictures compared with lean individuals (p ≤ 0.04). Meal intake reduced activation in the insula in response to food pictures in both groups (p ≤ 0.05), but this was more pronounced in patients with type 2 diabetes. Blocking actions of endogenous GLP-1 significantly prevented meal-induced reductions in bilateral insula activation in response to food pictures in patients with type 2 diabetes (p ≤ 0.03).Conclusions/interpretationOur findings support the hypothesis that endogenous GLP-1 is involved in postprandial satiating effects in the CNS of obese patients with type 2 diabetes.Trial registration: ClinicalTrials.gov NCT 01363609Funding The study was funded in part by a grant from Novo Nordisk.

Type 2 diabetes mellitus (T2DM) is characterized by obesity, hyperglycemia and insulin resistance. Both T2DM and obesity are associated with cerebral complications, including an increased risk of cognitive impairment and dementia, however the underlying mechanisms are largely unknown. In the current study, we aimed to determine the relative contributions of obesity and the presence of T2DM to altered white matter structure. We used diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) to measure white matter integrity and volume in obese T2DM patients without micro- or macrovascular complications, age- gender- and BMI-matched normoglycemic obese subjects and age- and gender-matched normoglycemic lean subjects. We found that obese T2DM patients compared with lean subjects had lower axial diffusivity (in the right corticospinal tract, right inferior fronto-occipital tract, right superior longitudinal fasciculus and right forceps major) and reduced white matter volume (in the right inferior parietal lobe and the left external capsule region). In normoglycemic obese compared with lean subjects axial diffusivity as well as white matter volume tended to be reduced, whereas there were no significant differences between normoglycemic obese subjects and T2DM patients. Decreased white matter integrity and volume were univariately related to higher age, being male, higher BMI, HbA1C and fasting glucose and insulin levels. However, multivariate analyses demonstrated that only BMI was independently related to white matter integrity, and age, gender and BMI to white matter volume loss. Our data indicate that obese T2DM patients have reduced white matter integrity and volume, but that this is largely explained by BMI, rather than T2DM per se.