Circadian Brown Adipose Tissue Metabolism
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 45 |
| Updated: | 4/21/2016 |
| Start Date: | March 2014 |
| End Date: | April 2015 |
A Pilot Study to Investigate Circadian Variations in Brown Adipose Tissue Metabolism in Healthy Volunteers.
Brown adipose tissue is poorly understood fat that can metabolize glucose in order to
generate heat. Since activated brown fat has a high metabolic rate, it is of great interest
as a potential target to combat obesity. However, the signaling and control of brown fat
metabolism is poorly understood. Because brown fat uses glucose as its energy source, brown
fat metabolism can be imaged with PET/CT using the positron emitting glucose analog F-18
FDG. We have recently shown in mice a striking circadian variation in brown fat metabolism
as evidenced by changes in FDG uptake. In this study we endeavor to generate pilot data on a
potential circadian variation in brown fat activation in healthy humans.
generate heat. Since activated brown fat has a high metabolic rate, it is of great interest
as a potential target to combat obesity. However, the signaling and control of brown fat
metabolism is poorly understood. Because brown fat uses glucose as its energy source, brown
fat metabolism can be imaged with PET/CT using the positron emitting glucose analog F-18
FDG. We have recently shown in mice a striking circadian variation in brown fat metabolism
as evidenced by changes in FDG uptake. In this study we endeavor to generate pilot data on a
potential circadian variation in brown fat activation in healthy humans.
Brown adipose tissue is a form of fat that is able to metabolize glucose in order to
generate heat. When active, it can convert a great deal of glucose into thermal energy.
Activation of brown fat could potentially help to combat obesity by increasing the basal
metabolic rate. However, activation and signaling of brown fat is poorly understood. In a
mouse model, we have recently shown that there is significant circadian variation in brown
fat activation and have also discovered the gene that is responsible for the circadian
changes (Gerhart-Hines et al, Nature 2013). Specifically, we have shown that in wild type
mice, brown fat activation is high at night and low during the day. Whether human brown fat
activation has a circadian component is currently unknown. Showing that brown fat activation
in humans is subject to similar circadian rhythms as in mice would be an important step in
understanding the signaling of activation and may help to elucidate potential strategies to
control activation. Positron emission tomography/computed tomography (PET/CT) is a hybrid
imaging modality that allows imaging positron emitting isotopes such as fluorine-18 (F-18)
along with anatomic imaging using x-rays. The physiologic information from the PET component
is co-registered with the anatomic information from the CT component, permitting accurate
localization and quantification of physiologic processes. The most common clinically used
positron emitting radiopharmaceutical is F-18 fluorodeoxyglucose (FDG). It is a glucose
analog which is taken up by glucose transporters and phosphorylated to FDG-6P by hexokinase.
However, isomerase, the next enzyme in the glycolytic pathway, is inactive on FDG-6P and so
it is largely trapped in the cell. Therefore, FDG PET/CT gives a map of relative amount of
glucose uptake and phosphorylation over the interval from injection to scan. Activated brown
fat has robust FDG uptake with very intense signal seen. Therefore, FDG PET/CT can be used
both to determine whether a person has activated brown fat at the time of the scan as well
as to quantify the overall level of metabolism in the fat. Our primary objective is to
gather pilot data on the potential presence of circadian variations in brown fat uptake in
young, healthy, lean male volunteers. We plan to do this by performing two FDG PET/CT scans
12 hours apart while the patient remains in a temperature and diet controlled environment
leading up to both scans. Our primary hypothesis is that brown fat activity will be higher
during the day than at night (as human and mouse circadian rhythms are reversed). We will
also pair measurement of cortisol with the FDG injections as cortisol levels provide
valuable independent information on the circadian rhythm.
generate heat. When active, it can convert a great deal of glucose into thermal energy.
Activation of brown fat could potentially help to combat obesity by increasing the basal
metabolic rate. However, activation and signaling of brown fat is poorly understood. In a
mouse model, we have recently shown that there is significant circadian variation in brown
fat activation and have also discovered the gene that is responsible for the circadian
changes (Gerhart-Hines et al, Nature 2013). Specifically, we have shown that in wild type
mice, brown fat activation is high at night and low during the day. Whether human brown fat
activation has a circadian component is currently unknown. Showing that brown fat activation
in humans is subject to similar circadian rhythms as in mice would be an important step in
understanding the signaling of activation and may help to elucidate potential strategies to
control activation. Positron emission tomography/computed tomography (PET/CT) is a hybrid
imaging modality that allows imaging positron emitting isotopes such as fluorine-18 (F-18)
along with anatomic imaging using x-rays. The physiologic information from the PET component
is co-registered with the anatomic information from the CT component, permitting accurate
localization and quantification of physiologic processes. The most common clinically used
positron emitting radiopharmaceutical is F-18 fluorodeoxyglucose (FDG). It is a glucose
analog which is taken up by glucose transporters and phosphorylated to FDG-6P by hexokinase.
However, isomerase, the next enzyme in the glycolytic pathway, is inactive on FDG-6P and so
it is largely trapped in the cell. Therefore, FDG PET/CT gives a map of relative amount of
glucose uptake and phosphorylation over the interval from injection to scan. Activated brown
fat has robust FDG uptake with very intense signal seen. Therefore, FDG PET/CT can be used
both to determine whether a person has activated brown fat at the time of the scan as well
as to quantify the overall level of metabolism in the fat. Our primary objective is to
gather pilot data on the potential presence of circadian variations in brown fat uptake in
young, healthy, lean male volunteers. We plan to do this by performing two FDG PET/CT scans
12 hours apart while the patient remains in a temperature and diet controlled environment
leading up to both scans. Our primary hypothesis is that brown fat activity will be higher
during the day than at night (as human and mouse circadian rhythms are reversed). We will
also pair measurement of cortisol with the FDG injections as cortisol levels provide
valuable independent information on the circadian rhythm.
Inclusion Criteria:
- At least 18 years of age and less than 45 years of age
- Able and willing to provide informed consent
- Male gender
- Capable of complying with study procedures and able to lie still in the PET/CT
scanner for up to 40 minutes continuously
- Normal fasting glucose (less than 100 mg/dl)
- No evidence of significant concurrent illness
- Follow typical sleep/wake cycle of generally asleep at night and awake during the day
Exclusion Criteria:
- Prior surgery or radiation to the head, neck, or upper chest (except surgeries such
as tonsillectomy/adenoidectomy/tympanostomy that would not be expected, in the
judgement of the investigator, to have disrupted the adipose tissue in the neck or
the upper chest)
- Active addiction or illicit drug abuse
- BMI greater than 25
- Employment in the night shift/3rd shift
- Unable to remain in the Clinical and Translational Research Center (CTRC) for entire
24 hour period.
- Unable or unwilling to maintain peripheral intravenous access for up to 24 hours
- Abnormal liver or kidney function (serum creatinine or transaminase levels greater
than 1.5 ULN)
- Subject has any other condition or personal circumstance that, in the judgement of
the investigator, might interfere with the collection of complete, high quality data
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