SCIeNTIFIC RePoRTS | 7: 16795 | DOI:10.1038/s41598-017-17148-w
Whitening and Impaired Glucose
Utilization of Brown Adipose Tissue
in a Rat Model of Type 2 Diabetes
, Paula Arias-Loza
, Nobuyuki Hayakawa
, Hiroshi Wakabayashi
, Xinyu Chen
, Tetsuya Shinaji
, Ken Herrmann
, Theo Pelzer
Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to
its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and
obesity, we aimed to investigate glucose utilization of BAT by
F-FDG PET imaging. Male Zucker
diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior
to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction
(ZDF-CR) group. Dynamic
F-FDG PET using a dedicated small animal PET system was performed under
F-FDG PET identied intense inter-scapular BAT glucose uptake
in all ZL control rats, while no focally increased
F-FDG uptake was detected in all ZDF-ND rats. Mild but
signicant improved BAT tracer uptake was identied after calorie restriction in diabetic rats (ZDF-CR).
The weight of BAT tissue and fat deposits were signicantly increased in ZDF-CR and ZDF-ND rats as
compared to ZL controls, while UCP-1 and mitochondrial concentrations were signicantly decreased.
Whitening and severely impaired insulin-stimulated glucose uptake in BAT was conrmed in a rat model
of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.
Obesity and its associated diseases, especially diabetes type 2, constitute one of the major public health concerns
in most developed societies
. Taking only energetics into account, treatment of obesity by reducing caloric intake
and increasing energy expenditure should be simple, however most patients fail to achieve or –more important-
maintain weight loss goals through diet and exercise alone
. erefore, pharmacologic and/or surgical treatment
options to support patients in the ght against excessive body weight are increasingly sought for. It is currently
known that body weight regulation goes beyond simple energetics and that other metabolic, behavioral, neuroen-
docrine, and autonomic responses play important roles in maintenance of the amount of fat reserves
Since its rediscovery in adult humans in the late 2000s, brown adipose tissue (BAT) has attracted a lot of atten-
tion as a potential target to combat obesity, and stimuli for its activation have been investigated in both animal
models and humans
. As part of the mechanisms of adaptive thermogenesis, BAT enables the release of energy
as heat instead of storage as energy molecules by dissociation of mitochondrial substrate oxidation from ATP
production, a phenomenon mediated by uncoupling protein 1 (UCP-1
), which is present in BAT, but not in
white adipose tissue (WAT).
Most recently, experimental murine studies reported that diet-induced obesity resulted in impaired glucose
tolerance, BAT functional hypoxia and subsequent structural “whitening” that eventually led to a functional shi
from thermogenesis toward lipid storage
. e loss of functional BAT in obesity might be consistent with the
lack of BAT response to both insulin and cold stimulation in obese adults
, whereas exposure to cold in young
Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany.
Department of Internal
Medicine I, Division of Cardiology, University Hospital Würzburg, Würzburg, Germany.
The Russell H Morgan
Department of Radiology and Radiological Science, Division of Nuclear Medicine, Baltimore, MD, United States.
Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany.
Department of Bio-
Medical Imaging, National Cerebral and Cardiovascular Center, Suita, Japan. Theo Pelzer and Takahiro Higuchi
contributed equally to this work. Correspondence and requests for materials should be addressed to T.H. (email:
Received: 23 May 2017
Accepted: 11 October 2017
Published: xx xx xxxx