Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Department of Molecular and Integrative Physiology, University of Michigan Medical
School, Ann Arbor, MI, USA.
International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of
MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
Department of Respiratory Medicine,
Key Site of National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China.
Fudan University, Shanghai, China.
Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
Medical Scientist Training Program, University of Michigan, Ann Arbor,
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Department of Pharmacology, University of Michigan, Ann Arbor,
Division of Hematology–Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
Department of Cell and
Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
Present address: Department of Chemistry, Center for Behavioral Neuroscience,
American University, Washington, D.C., USA.
Present address: Division of Hematology–Oncology, Department of Medicine and Abramson Family Cancer
Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. *e-mail: email@example.com
he serious metabolic complications closely associated with
obesity emphasize the urgency to develop counteracting
strategies. It has recently been reported that beige-like ther
mogenic adipocytes are present in human adults
and that the acti-
vation of these thermogenic fat cells increases energy expenditure
and improves metabolic health in humans
. Whereas the regula-
tion of white and classical brown fat cells has been investigated for
decades, many aspects of the beige adipocyte function are still yet
to be elucidated.
Previous studies of the regulation of thermogenic fat cells in
vivo have mainly been focused on signaling through the β -adren
. Here we demonstrate that expression of CHRNA2,
a subunit of the nicotinic acetylcholine receptor (nAChR) family,
is upregulated during beiging and that it specifically functions in
beige fat cells from subcutaneous adipose depots. The nAChRs
belong to a large superfamily of ligand-gated ion channels that are
expressed throughout both the central and the peripheral nervous
systems, as well as in non-neuronal cell populations
. At an indi-
vidual-cell-level resolution, we observed that CHRNA2-mediated
signaling specifically occurred in Ucp1-expressing beige fat cells
within subcutaneous culture, but not in either white or brown fat
cells. Calcium imaging assays further revealed that primary fat cells
from the human subcutaneous depot, but not those from the peri
renal depot, responded to stimulation with a CHRNA2 agonist, sug-
gesting that this beige-selective response was conserved in humans.
We identified acetylcholine-producing immune cells within the
subcutaneous fat depot that communicated with beige fat cells
via CHRNA2 through paracrine signaling. Additionally, Chrna2-
knockout (hereafter referred to as Chrna2 KO) mice had a com
promised response to cold, specifically in beige fat, and impaired
metabolic homeostasis after dietary challenges. Our results iden
tify CHRNA2 as a functional beige-selective marker and suggest
that this immune–adipose interaction through acetylcholine and
CHRNA2 may lead to novel druggable targets to treat human obe
sity and the metabolic syndrome.
Chrna2 is induced in subcutaneous adipocytes during the pro-
cess of beiging. Rosiglitazone (Rosi), a thiazolidinedione (TZD)
that acts as a peroxisome proliferator-activated receptor (PPAR)-γ
agonist, has been shown to induce the activation of thermogenic fat
(‘browning’) in vitro and in vivo
. Thus, to investigate which sig-
naling pathways activate beige adipocytes, we performed a micro-
array analysis with RNA samples from fully differentiated primary
An immune-beige adipocyte communication via
nicotinic acetylcholine receptor signaling
, Hui Yu
, Jianke Gong
, Juan Jiang
, Xiaona Qiao
, Eric Perkey
, Dong-il Kim
Margo P. Emont
, Alexander G. Zestos
, Jung-Sun Cho
, Jianfeng Liu
, Robert T. Kennedy
, X. Z. Shawn Xu
and Jun Wu
Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against
hypothermia and obesity. Prior reports indicate that beige-like adipocytes exist in adult humans and that they may present
novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of
activated beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced
in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regu-
lated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive
beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this sig-
naling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised
the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and
associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo had detrimental consequences.
Our results reveal a beige-selective immune–adipose interaction mediated through CHRNA2 and identify a novel function of
nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to coun-
teract human obesity.
NATURE MEDICINE | VOL 24 | JUNE 2018 | 814–822 | www.nature.com/naturemedicine
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.