Dataset Information

Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans.

ABSTRACT:

Objective

Glucagon-like peptide-1 (GLP-1) is released into the bloodstream after food intake. In addition to stimulating insulin release, it causes satiety and contributes to the termination of food intake. In this study, we investigated whether endogenous GLP-1 affects food-related brain activity and hunger.

Methods

Twenty-four volunteers (12 lean; 12 obese) underwent a 75 g oral glucose tolerance test that promotes GLP-1 secretion. Food cue-induced brain activity was assessed by functional magnetic resonance imaging and GLP-1 concentrations were measured before, 30, and 120 min after glucose intake.

Results

The significant increase in GLP-1 levels negatively correlated with a change in the food cue-induced brain activity in the orbitofrontal cortex, a major reward area. This association was independent of simultaneous alterations in insulin and glucose concentrations. The association was present in lean and overweight participants. By contrast, postprandial insulin changes were associated with orbitofrontal activations in lean individuals only.

Conclusions

The postprandial release of GLP-1 might alter reward processes in the orbitofrontal cortex and might thereby support the termination of food intake and reduce hunger. While obese persons showed brain insulin resistance, no GLP-1 resistance was observed. Our study provides novel insight into the central regulation of food intake by the incretin hormone GLP-1.

SUBMITTER: Heni M

PROVIDER: S-EPMC4731733 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans.

Heni Martin M Kullmann Stephanie S Gallwitz Baptist B Häring Hans-Ulrich HU Preissl Hubert H Fritsche Andreas A

Molecular metabolism 20150930 12

<h4>Objective</h4>Glucagon-like peptide-1 (GLP-1) is released into the bloodstream after food intake. In addition to stimulating insulin release, it causes satiety and contributes to the termination of food intake. In this study, we investigated whether endogenous GLP-1 affects food-related brain activity and hunger.<h4>Methods</h4>Twenty-four volunteers (12 lean; 12 obese) underwent a 75 g oral glucose tolerance test that promotes GLP-1 secretion. Food cue-induced brain activity was assessed by ...[more]

PMID: 26909313

Similar Datasets

Project description:ObjectiveTo regulate food intake, our brain constantly integrates external cues, such as the incentive value of a potential food reward, with internal state signals, such as hunger feelings. Incentive motivation refers to the processes that translate an expected reward into the effort spent to obtain the reward; the magnitude and probability of a reward involved in prompting motivated behaviour are encoded by the dopaminergic (DA) midbrain and its mesoaccumbens DA projections. This type of reward circuity is particularly sensitive to the metabolic state signalled by peripheral mediators, such as insulin or glucagon-like peptide 1 (GLP-1). While in rodents the modulatory effect of metabolic state signals on motivated behaviour is well documented, evidence of state-dependent modulation and the role of incentive motivation underlying overeating in humans is lacking.MethodsIn a randomised, placebo-controlled, crossover design, 21 lean (body mass index [BMI] < 25 kg/m2) and 16 obese (BMI³ 30 kg/m2) volunteer participants received either liraglutide as a GLP-1 analogue or placebo on two separate testing days. Incentive motivation was measured using a behavioural task in which participants were required to exert physical effort using a handgrip to win different amounts of food and monetary rewards. Hunger levels were measured using visual analogue scales; insulin, glucose, and systemic insulin resistance as assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) were quantified at baseline.ResultsIn this report, we demonstrate that incentive motivation increases with hunger in lean humans (F(1,42) = 5.31, p = 0.026, β = 0.19) independently of incentive type (food and non-food reward). This effect of hunger is not evident in obese humans (F(1,62) = 1.93, p = 0.17, β = -0.12). Motivational drive related to hunger is affected by peripheral insulin sensitivity (two-way interaction, F(1, 35) = 6.23, p = 0.017, β = -0.281). In humans with higher insulin sensitivity, hunger increases motivation, while poorer insulin sensitivity dampens the motivational effect of hunger. The GLP-1 analogue application blunts the interaction effect of hunger on motivation depending on insulin sensitivity (three-way interaction, F(1, 127) = 5.11, p = 0.026); no difference in motivated behaviour could be found between humans with normal or impaired insulin sensitivity under GLP-1 administration.ConclusionWe report a differential effect of hunger on motivation depending on insulin sensitivity. We further revealed the modulatory role of GLP-1 in adaptive, motivated behaviour in humans and its interaction with peripheral insulin sensitivity and hunger. Our results suggest that GLP-1 might restore dysregulated processes of midbrain DA function and hence motivational behaviour in insulin-resistant humans.

Project description:Aims/hypothesisInsulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic-euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans.MethodsAs part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25-35 kg/m2) previously underwent a two-step hyperinsulinaemic-euglycaemic clamp (using [6,6-2H2]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during high-insulin infusion [40 mU/(m2 × min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured.ResultsPlasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised β = 0.495, p < 0.001; TNF-α: standardised β = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised β = -0.206, p = 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity.Conclusions/interpretationWe demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.

Project description:BACKGROUND:Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS:Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS:With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION:Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION:ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Dataset Information

Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans.

Objective

Methods

Results

Conclusions

Publications

Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets