Endogenous GLP‐1 alters postprandial functional connectivity between homeostatic and reward‐related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy

Meyer‐Gerspach, Anne Christin; Ly, Huynh Giao; Borgwardt, Stefan; Dupont, Patrick; Beglinger, Christoph; Oudenhove, Lukas Van; Wölnerhanssen, Bettina K.

doi:10.1111/dom.13369

Cited by 18 publications

(10 citation statements)

References 41 publications

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“…With our exploratory fMRI sub-study, we were not able to reinforce this hypothesis. Specifically, we did not observe altered resting state functional connectivity between homeostatic and reward-related brain areas on GLP-1 RA, as previously showed in healthy volunteers by Meyer-Gerspach et al (37).…”

Section: Discussionsupporting

confidence: 88%

“…Functional connectivity of three key regions of the reward network (left accumbens, right accumbens, midbrain) and the hypothalamus (see supplementary figure S9) with the rest of the brain was assessed during the resting-state session (37). In patients, the main effect of treatment on functional connectivity values was tested with the hypothesis that functional connectivity between those core regions and other regions of the reward network would be altered on dulaglutide, as compared to placebo (37). Similarly, functional connectivity of those regions was compared between patients under placebo and controls.…”

Section: Discussionmentioning

confidence: 99%

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A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

Winzeler¹,

Sailer²,

Coynel³

et al. 2021

Journal of Clinical Investigation

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Background Primary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide-1 (GLP-1) reduces appetite and food intake. In experimental models, they also play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia. MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover-trial, 34 patients with primary polydipsia received weekly dulaglutide (Trulicity®) 1.5mg and placebo (0.9% sodium chloride). During the last treatment week, patients attended an 8-hour evaluation visit with free water access. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI. Findings Patients on dulaglutide reduced fluid intake by 490ml [95%-CI -780, -199], p=0.002, from 2950ml [95% CI 2435, 3465] on placebo to 2460ml [95% CI 1946, 2475] on dulaglutide (model estimates), corresponding to a relative reduction of 17%. 24-hour urinary output was reduced by -943ml [95%-CI -1473, -413], p=0.001. Thirst perception in response to beverage pictures was higher in patients with primary polydipsia versus controls and lower on dulaglutide versus placebo, but functional activity was similar between groups and treatments.Interpretation GLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

Winzeler¹,

Sailer²,

Coynel³

et al. 2021

Journal of Clinical Investigation

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“…Both PYY and GLP-1 levels are elevated in the postprandial state following bariatric surgery ( 44 ), while fasting ghrelin levels have been shown to decline postoperatively ( 45 ). ten Kulve et al ( 46 ) reported that the GLP-1 analog exenatide promotes hypothalamic activity in humans and hypothalamic connectivity with the rest of the brain, and Meyer-Gerspach et al ( 47 ) extended this to the action of endogenous GLP-1, revealing that administration of the GLP-1 receptor antagonist exendin(9-39) disrupted functional connectivity between homeostatic (hypothalamus) and reward-related (OFC) brain regions. More recently, another study by ten Kulve et al ( 48 ) showed that in 10 obese females undergoing RYGB, activation was reduced in the caudate nucleus in response to food and that this was interrupted after RYGB with GLP-1R blockade.…”

Section: Discussionmentioning

confidence: 99%

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study

et al. 2021

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OBJECTIVE Weight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference. RESEARCH DESIGN AND METHODS Sixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups. RESULTS We show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1 ) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2 ) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3 ) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD. CONCLUSIONS Taken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.

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“…The literature on resting‐state functional connectivity alterations in response to GLP‐1 receptor blockade is scarce. One study in males showed that blocking GLP‐1 receptors after ingestion of a glucose load resulted in increased connectivity with the amygdala and orbitofrontal cortex, but lower connectivity with the caudate nucleus compared with ingestion of a glucose load without GLP‐1 receptor blockade 9 . Bariatric surgery has also been shown to affect intrinsic functional connectivity, albeit literature reporting this is scarce.…”

Section: Introductionmentioning

confidence: 99%

Cerebral effects of glucagon‐like peptide‐1 receptor blockade before and after Roux‐en‐Y gastric bypass surgery in obese women: A proof‐of‐concept resting‐state functional MRI study

Duinkerken

Bernardes

Bloemendaal

et al. 2020

Diabetes Obesity Metabolism

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Aim To assess the effects of Roux‐en‐Y gastric bypass surgery (RYGB)‐related changes in glucagon‐like peptide‐1 (GLP‐1) on cerebral resting‐state functioning in obese women. Materials and Methods In nine obese females aged 40‐54 years in the fasted state, we studied the effects of RYGB and GLP‐1 on five a priori selected networks implicated in food‐ and reward‐related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). Results Before surgery, GLP‐1 receptor blockade (using exendin9‐39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP‐1 receptor blockade had a larger effect on connectivity in this region than GLP‐1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. Conclusions These findings suggest GLP‐1 involvement in resting‐state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP‐1–induced changes in resting‐state connectivity in RYGB‐mediated weight loss and appetite control.

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Endogenous GLP‐1 alters postprandial functional connectivity between homeostatic and reward‐related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy

Abstract: This pilot trial provides preliminary experimental evidence that glucose-induced endogenous GLP-1 affects central regulation of appetite by modulating rsFC in homeostatic and reward-related brain regions in healthy lean male participants in a GLP-1 receptor-mediated fashion.

Cited by 18 publications

References 41 publications

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study

Cerebral effects of glucagon‐like peptide‐1 receptor blockade before and after Roux‐en‐Y gastric bypass surgery in obese women: A proof‐of‐concept resting‐state functional MRI study

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