Neurohormonal & Behavioral Correlates of Obesity and Weight Loss
| Status: | Completed |
|---|---|
| Conditions: | Obesity Weight Loss |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 9/26/2018 |
| Start Date: | February 2011 |
| End Date: | January 15, 2013 |
Obesity has reached epidemic levels in the United States, and is on the rise in many
industrialized nations. The rate of recidivism for long-term weight loss is substantial and
presents a critical problem given the importance of obesity as a modifiable risk factor for
diseases like type 2 diabetes. Further, the comorbidity of depression with diseases like
obesity, type 2 diabetes, and cardiovascular disease suggest that there may be an underlying
shared biology for diseases of metabolic dysfunction and emotional dysregulation. The shared
biology of these diseases may actually promote the precipitation and exacerbation of comorbid
conditions, impacting the success of treatment. Endogenous opioid systems regulate a number
of physiological and psychological processes including mood, energy management, and reward.
Endogenous opioid µ-receptor-mediated reward processing is thought to be involved both in the
short-term control of eating and hedonic food consumption, based on data in animal models.
The present proposal will examine the function of the µ-opioid receptor (MOR) system in lean
and obese human volunteers following an overnight fast and the change in µ-opioid receptor
occupancy (i.e., endogenous opioid release) following the consumption of a standardized meal
using PET imaging with the µ-selective radiotracer [11C]carfentanil. The obese individuals
will be retested in the fasting and fed state following a 15% weight loss with a Very Low
Calorie Diet. Further, the investigators will evaluate the function of the MOR system within
the context of the individual's metabolic and psychological profile including aspects of mood
and inhibitory control. This information will provide the neurobiological bases to develop
novel avenues of intervention based on individual variations in central mechanisms associated
with motivational systems and appetite and their potential role in weight regain.
The investigators hypothesize that overeating in chronically obese individuals will be
associated with a dysregulation of MOR system function, manifested by reductions in baseline
MOR availability (binding potential, BP) in limbic and reward circuitry, and lower release of
endogenous opioids after a standard meal, compared to lean volunteers. The latter is observed
as acute reductions in the BP measure after meal ingestion.
industrialized nations. The rate of recidivism for long-term weight loss is substantial and
presents a critical problem given the importance of obesity as a modifiable risk factor for
diseases like type 2 diabetes. Further, the comorbidity of depression with diseases like
obesity, type 2 diabetes, and cardiovascular disease suggest that there may be an underlying
shared biology for diseases of metabolic dysfunction and emotional dysregulation. The shared
biology of these diseases may actually promote the precipitation and exacerbation of comorbid
conditions, impacting the success of treatment. Endogenous opioid systems regulate a number
of physiological and psychological processes including mood, energy management, and reward.
Endogenous opioid µ-receptor-mediated reward processing is thought to be involved both in the
short-term control of eating and hedonic food consumption, based on data in animal models.
The present proposal will examine the function of the µ-opioid receptor (MOR) system in lean
and obese human volunteers following an overnight fast and the change in µ-opioid receptor
occupancy (i.e., endogenous opioid release) following the consumption of a standardized meal
using PET imaging with the µ-selective radiotracer [11C]carfentanil. The obese individuals
will be retested in the fasting and fed state following a 15% weight loss with a Very Low
Calorie Diet. Further, the investigators will evaluate the function of the MOR system within
the context of the individual's metabolic and psychological profile including aspects of mood
and inhibitory control. This information will provide the neurobiological bases to develop
novel avenues of intervention based on individual variations in central mechanisms associated
with motivational systems and appetite and their potential role in weight regain.
The investigators hypothesize that overeating in chronically obese individuals will be
associated with a dysregulation of MOR system function, manifested by reductions in baseline
MOR availability (binding potential, BP) in limbic and reward circuitry, and lower release of
endogenous opioids after a standard meal, compared to lean volunteers. The latter is observed
as acute reductions in the BP measure after meal ingestion.
Neuroimaging Study. Male and Female volunteers will be recruited from the Investigational
Weight Management Clinic (IWMC) at the University of Michigan for this study. All
neuropsychological instruments will be collected in lean and obese individuals at baseline,
and between 4-6-months. Obese individuals will undergo 4 PET scans: 1) at baseline following
an overnight fast; 2) at baseline following consumption of an Ensure shake; 3) after at least
a15% reduction in body weight following an overnight fast; 4) and following consumption of an
Ensure shake at the post-weight loss time point. Lean individuals will undergo the two scans
at baseline after fasting and post-Ensure shake consumption. All lean subjects will consume
their normal diets prior to the initial scanning. The obese subjects will undergo their
second set of scans, post-weight loss, while still consuming the HMR diet.
Neuroimaging Measures. Two PET studies with [11C]carfentanil (a selective µ-opioid receptor
radiotracer) will be acquired for each lean volunteer and 4 PET studies with [11C]carfentanil
will be acquired for obese individuals. Structural and functional MRI will be acquired for
obese individuals before and after weight loss, and for lean individuals at baseline for
co-registration and anatomical standardization of the PET data and activation response to
visual stimuli. After their completion, the following data will be used for statistical
analyses: 1) Baseline µ-opioid receptor availability in vivo (binding potential, BPND) in
lean and obese individuals following an overnight fast. 2) µ-opioid system activation after
consuming 500 kcal (16fl oz, 18% protein, 14% CHO, 25% fat) of Ensure shake (fed) in lean and
obese individuals as measured by acute reductions in BPND. 3) Baseline MOR BPND in obese
individuals who have lost ≥15% of their body weight over 4-6 months (fasting), following an
overnight fast. 4) µ-opioid system activation in obese individuals who have lost ≥15% of
their body weight after consuming 250 kcal of Ensure shake (fed).
PET Acquisition. Briefly, [11C]carfentanil a selective and specific µ-opioid receptor
radioligand, is administered at tracer doses using a bolus/continuous infusion protocol to
achieve rapid steady-states between specific and non-specific binding regions (5-7 min
post-tracer administration). Twenty-eight frames will be acquired over 70 minutes with an
increasing duration (30 sec to 5 min). Two scans will be acquired twice each: A baseline,
without challenges, and a scan following consumption of an Ensure shake. Subsequently,
dynamic image data for the receptor scans is transformed, on a voxel-by-voxel basis, into
parametric maps, and co-registered to each other. These include, 1) a tracer transport
measure (K1 ratio, proportional to cerebral blood flow; tracer transport = blood flow x
tracer extraction), and receptor-related measures, (BPND), during 2) baseline scans, and 3)
following shake consumption. The reduction in BPND from baseline to post-shake consumption
represents a measure of endogenous opioid system activation following shake consumption
(related to the occupancy and ligand-receptor interactions by the endogenous ligand). These
parametric images are calculated using a modified Logan graphical analysis, with the
occipital cortex as the reference region. PET images are then co-registered to the T1 MRI
structural, anatomical image, affine transformed and warped to standard Montreal Neurological
Institute (MNI) stereotactic space using mutual information algorithms. The baseline scan, in
the fasted state, will precede the post-consumption scan due to time constraints, and to
avoid carry-over effects from active (fed) to baseline (fasted) states. Both PET scans will
be performed on the same day to reduce travel time for the subjects and hence experimental
burden.
Clinical Measures Psychobehavioral measures to be acquired during the imaging studies
include: The Positive and Negative Affect Scale, Profile of Mood Scales, State portion of the
Spielberg Anxiety Inventory, and a visual analog scale (VAS) for appetite and palatability
will be administered before and after each experiment. These measures will assess emotional
state and appetite for correlative purposes with changes in neuroreceptor and circulating
hormone levels during performance of the studies. The MINI International Neuropsychiatric
Interview (MINI600), Inventory of Depressive Symptomatology (IDS-SR), EuroQol measure of
health outcome, Trait portion of the Anxiety Inventory, and NEO Personality Inventory will be
obtained prior to scanning for secondary analyses (e.g. relationship between imaging measures
and "stable" traits).
Weight Management Clinic (IWMC) at the University of Michigan for this study. All
neuropsychological instruments will be collected in lean and obese individuals at baseline,
and between 4-6-months. Obese individuals will undergo 4 PET scans: 1) at baseline following
an overnight fast; 2) at baseline following consumption of an Ensure shake; 3) after at least
a15% reduction in body weight following an overnight fast; 4) and following consumption of an
Ensure shake at the post-weight loss time point. Lean individuals will undergo the two scans
at baseline after fasting and post-Ensure shake consumption. All lean subjects will consume
their normal diets prior to the initial scanning. The obese subjects will undergo their
second set of scans, post-weight loss, while still consuming the HMR diet.
Neuroimaging Measures. Two PET studies with [11C]carfentanil (a selective µ-opioid receptor
radiotracer) will be acquired for each lean volunteer and 4 PET studies with [11C]carfentanil
will be acquired for obese individuals. Structural and functional MRI will be acquired for
obese individuals before and after weight loss, and for lean individuals at baseline for
co-registration and anatomical standardization of the PET data and activation response to
visual stimuli. After their completion, the following data will be used for statistical
analyses: 1) Baseline µ-opioid receptor availability in vivo (binding potential, BPND) in
lean and obese individuals following an overnight fast. 2) µ-opioid system activation after
consuming 500 kcal (16fl oz, 18% protein, 14% CHO, 25% fat) of Ensure shake (fed) in lean and
obese individuals as measured by acute reductions in BPND. 3) Baseline MOR BPND in obese
individuals who have lost ≥15% of their body weight over 4-6 months (fasting), following an
overnight fast. 4) µ-opioid system activation in obese individuals who have lost ≥15% of
their body weight after consuming 250 kcal of Ensure shake (fed).
PET Acquisition. Briefly, [11C]carfentanil a selective and specific µ-opioid receptor
radioligand, is administered at tracer doses using a bolus/continuous infusion protocol to
achieve rapid steady-states between specific and non-specific binding regions (5-7 min
post-tracer administration). Twenty-eight frames will be acquired over 70 minutes with an
increasing duration (30 sec to 5 min). Two scans will be acquired twice each: A baseline,
without challenges, and a scan following consumption of an Ensure shake. Subsequently,
dynamic image data for the receptor scans is transformed, on a voxel-by-voxel basis, into
parametric maps, and co-registered to each other. These include, 1) a tracer transport
measure (K1 ratio, proportional to cerebral blood flow; tracer transport = blood flow x
tracer extraction), and receptor-related measures, (BPND), during 2) baseline scans, and 3)
following shake consumption. The reduction in BPND from baseline to post-shake consumption
represents a measure of endogenous opioid system activation following shake consumption
(related to the occupancy and ligand-receptor interactions by the endogenous ligand). These
parametric images are calculated using a modified Logan graphical analysis, with the
occipital cortex as the reference region. PET images are then co-registered to the T1 MRI
structural, anatomical image, affine transformed and warped to standard Montreal Neurological
Institute (MNI) stereotactic space using mutual information algorithms. The baseline scan, in
the fasted state, will precede the post-consumption scan due to time constraints, and to
avoid carry-over effects from active (fed) to baseline (fasted) states. Both PET scans will
be performed on the same day to reduce travel time for the subjects and hence experimental
burden.
Clinical Measures Psychobehavioral measures to be acquired during the imaging studies
include: The Positive and Negative Affect Scale, Profile of Mood Scales, State portion of the
Spielberg Anxiety Inventory, and a visual analog scale (VAS) for appetite and palatability
will be administered before and after each experiment. These measures will assess emotional
state and appetite for correlative purposes with changes in neuroreceptor and circulating
hormone levels during performance of the studies. The MINI International Neuropsychiatric
Interview (MINI600), Inventory of Depressive Symptomatology (IDS-SR), EuroQol measure of
health outcome, Trait portion of the Anxiety Inventory, and NEO Personality Inventory will be
obtained prior to scanning for secondary analyses (e.g. relationship between imaging measures
and "stable" traits).
Inclusion Criteria:
- Obese population defined as BMI > 30 kg/m2.
- Lean population BMI < 28 but > 17 kg/m2.
- Able and willing to provide written informed consent for the trial.
- Right handed
- age >/= 18 years
Exclusion Criteria:
- Evidence of inherited disorders of lipid metabolism.
- History of Cancer within the last 5 years except for minor skin cancers
- Human immunodeficiency virus (HIV) antibody positive.
- Patients with solid organ transplants.
- Positive pregnancy screen in Women
- Uncontrolled thyroid disease
- Unstable angina or NY heart association class II failure or above
- Gastrointestinal disease specifically GI motility disorders
- Unstable neuropsychiatric disease including major depression/anxiety, eating disorder
such as bulimia or anorexia
- End stage renal or hepatic disease
- Autoimmune disorders (e.g. SLE)
- Body weight fluctuation of more than 5 kg in the previous 3 months
- Prior bariatric surgery
- A history or current alcohol/substance abuse, or opoid abuse/use and change in smoking
habits or cessation in the past 6 months.
- Any medical condition, which in the opinion of the investigator would make the patient
unsuitable for recruitment, or could interfere with the patient participating in or
completing the protocol.
- Unwilling or unable to consent for the study.
- > 300 lbs (gantry table limit).
- having a waist diameter <53 cm (due to fMRI bore diameter)
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