We hypothesize that: 1) Post-ingestion nutrient signals trigger striatal dopamine release, which may be disturbed (decreased) in obese individuals and thereby contribute to pathological feeding behavior. 2) Post-ingestion nutrient signals affect…
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The effect of intragastric infusion of nutrients on:
- Brain activity assessed as the induced change in fMRI signal and resting state brain connectivity measured with fMRI.
- Striatal dopamine response, measured as the change in D2/D3R binding potential of IBZM assessed by SPECT.
The effect of intragastric infusion of nutrients on:
- Glucoregulatory and gut hormone release
- Objective scores of hunger and satiety during a buffet test meal after the infusion of the nutrients.
- Subjective (VAS) scores of hunger and satiety
- Neuropsychological functioning and feeding behaviour characteristics assessed by questionnaires and tasks
Rationale: The worldwide obesity epidemic is a major health burden. Obesity is caused by disturbed feeding behaviour, leading to overconsumption of high-calorie and highly palatable food. Feeding behaviour is regulated by a complex interplay of the homeostatic and hedonic systems, and influenced by peripheral inputs. Recent evidence suggests that ingested nutrients trigger gut-to-brain signals that stimulate central (brain) dopamine release. Changes in post-ingestion nutrient signals may be involved in the development of the pathological (habitual/compulsive) feeding behaviour in obese humans. However, the mechanism of nutrient-triggered dopamine release and its potential role in obesity remain to be elucidated. Gaining more insight in post-ingestion nutrient signalling is necessary to develop new therapeutic options to restore disturbed feeding behaviour in obesity.
Objective: To study the effects of post-ingestion nutrients on brain activity and brain dopaminergic responses in lean subjects, and in obese subjects before and after diet-induced weight loss.
Study design: Single-blind randomized cross-over study
Study population: Lean (BMI 20-25 kg/m2) and obese (BMI >30 kg/m2) men and (postmenopausal) women aged 50-75 years (n = 30 per group)
Main study parameters/endpoints:
Differences in brain fMRI signal and differences in striatal dopamine release (measured as D2/3 receptor binding potential (D2/3R-BP) in response to intragastric infusion of fat and glucose, between lean and obese subjects (before and after diet-induced weight loss). Correlations between gut-derived hormones and measured brain responses.
We hypothesize that:
1) Post-ingestion nutrient signals trigger striatal dopamine release, which may be disturbed (decreased) in obese individuals and thereby contribute to pathological feeding behavior.
2) Post-ingestion nutrient signals affect brain activity in brain regions involved in the regulation of food intake/feeding behavior and this effect will differ between lean and obese individuals: we expect obese individuals to show reduced post-ingestion nutrient signal-induced inhibition of brain activity in regions involved in homeostatic control of food intake, and reduced activation of brain areas involved in reward.
3) Diet-induced weight loss will change (increase) the dopaminergic response in the striatum to post-ingestion nutrient signals.
4) Diet-induced weight loss will improve the brain activity response to post-ingestion nutrient signals in obesity.
5) The effects of post-ingestion nutrient signals will depend on the type of macronutrient
- 1 Training session
- 3 fMRI sessions (water, glucose, lipid; random order)
- 2 SPECT sessions (one with glucose, one with intralipid; random order)
- Baseline: 1 training session, 3 fMRI sessions, 1 SPECT session (either with intralipid or glucose)
- During the diet: several visits to assess progress of weight loss
- Following the 3 month hypocaloric diet: 3 fMRI sessions, 1 SPECT session (intralipid or glucose)
Intra-gastric infusion of:
- 250 ml water
- 250 ml intralipid 20%
- 250 ml glucose 50%
Hypocaloric diet intervention: 3 months, aim to lose 10% of total bodyweight.
- Ability to provide informed consent;
- Age: 50-70 years
- Females: postmenopausal (history, amenorrhoea, elevated FSH)
- BMI: 20-25kg/m2 for lean subjects, >30kg/m2 for obese subjects
- For obese subjects: insulin resistance, defined as fasting insulin >74 pmol/l
- Stable weight (i.e. <10% change) for 3 months prior to study inclusion
- Use of any medication except for those related to treatment of components of the metabolic syndrome (not including insulin, oral glucose lowering drugs, alpha- and beta-blockers)
- Any actual medical condition except for treated hypothyroidism and the metabolic syndrome
- History of any psychiatric disorder, neurological disorders, eating disorders (anorexia, binge eating, bulimia), alcohol abuse or upper gastrointestinal tract surgery/abnormalities.
- Shift work
- Intensive sports (>3/week)
- Restrained eaters
- XTC, cannabis, amphetamine or cocaine abuse
- Alcohol abuse (>3 units/day)
- Occupational radiation exposure
- Contraindication for MRI
- Lactose/gluten intolerance
- Soya oil, egg or peanut allergy
- Childhood onset of obesity (<4 years)
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