Circadian Brown Adipose Tissue Metabolism

Overview

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.

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.