Cell Metabolism
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What Ignites UCP1?
Barbara Cannon1,* and Jan Nedergaard1
1Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
*Correspondence: barbara.cannon@su.se
https://doi.org/10.1016/j.cmet.2017.10.012
We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by
fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue
(Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced
in brown fat without intracellular lipolysis.
If you are only peripherally acquainted
with a scientific field, you can easily get
the impression that much more is known
than really is the case. These days, it is
generally accepted that brown adipose
tissue is found in adult humans and can
thus be seen as our most recently de-
tected organ. It is also generally acknowl-
edged that the possibility exists that by
keeping the tissue active, we might pro-
tect ourselves from obesity, by continu-
ously combusting excess food energy. It
is also well known that there is a specific
protein responsible for this, the so-called
uncoupling protein 1 (UCP1). However, if
challenged with the question of how
UCP1 produces the heat—and when—
you may think that, although these details
are not common knowledge, they must
certainly be known to specialists in
the field.
Surprisingly, this is not the case.
Although it is now more than 35 years
since Martin Klingenberg had the isolated
UCP1 protein in his hand (Lin and Klingen-
berg, 1980), it is still unclear how it actu-
ally uncouples. Although we say that it
transports ‘‘proton equivalents’’ over the
mitochondrial membrane, there is no gen-
eral agreement on how this occurs (Crich-
ton et al., 2017). In our opinion, UCP1 is
absolutely necessary for norepinephrine-
stimulated nonshivering thermogenesis:
brown fat cells without UCP1 do not pro-
duce heat, and animals without UCP1
gain extra body fat—in both cases,
despite the fact that the cells and tissue
still possess respiratory capacity, they
simply fail to burn without UCP1—but
we still do not really know how UCP1
uncouples.
Similarly, we do not know how the
activity of UCP1 is controlled. In the stan-
dard textbook version (Figure 1A), when-
ever heat is needed, the brown fat
cells are stimulated by norepinephrine
released from the sympathetic nerves
innervating the tissue. Within the cell,
UCP1 is basically inactive, being in its in-
hibited state due to binding of cytosolic
ATP and ADP (or GDP, which is routinely
used experimentally). The standard
model says that this inhibition will be
physiologically overcome by free fatty
acids that are released from intracellular
triglyceride droplets when the cells are
stimulated by norepinephrine, through
the activity of adipose tissue triglyceride
lipase (ATGL). Indeed, very many experi-
ments of many different types are consis-
tent with this model.
Thus, when Schreiber et al. (2017) and
Shin et al. (2017) started their investiga-
tions, published in this issue of Cell Meta-
bolism, this result would be anticipated
to be a ‘‘significance-of-the-sea-for-ship-
ping’’-story: although never really experi-
mentally proven, there would be no doubt
about the outcome. What the authors
did was eliminate the norepinephrine-
induced breakdown of lipid droplets spe-
cifically in the brown fat cells. Schreiber
et al. did this by generating mice that
lacked the ATGL itself in the brown fat
cells, while Shin et al. did it by generating
mice that lacked the ATGL-activating pro-
tein CGI-58 in the brown fat cells. In both
cases, the expected outcome would be
that nonshivering thermogenesis should
be not be there, as it should be fully
dependent on production of the free fatty
acids within the brown fat cells needed to
activate UCP1. However, surprisingly,
virtually nothing happened in this respect.
The most convincing experiments pre-
sented by the authors are the following.
They treated the mice with an agent
(CL-316 243) that specifically activates
Cell Metabolism 26, November 7, 2017 ª 2017 Elsevier Inc. 697
norepinephrine receptors of the beta3
subtype. The thermogenic response to
this agent is fully dependent on thermo-
genesis in brown adipose tissue. Unex-
pectedly, the response was the same or
almost the same in the mouse models
without brown fat lipolysis as in the con-
trol mice. Since there were no fatty acids
released within the tissue for combustion
in the mitochondria, the tissue instead
took up and burned fatty acids released
from white fat, a response that also oc-
curs normally when the tissue is stimu-
lated (Henkin et al., 2012). In cultured
brown fat cells, the critical experiment
(i.e., performed in the presence of serum
albumin) indicated that cells lacking lipol-
ysis still showed z50% stimulation of
respiration compared to control cells.
This should not have happened if
the UCP1 required local lipolysis for
activation.
It may be said that there have always
been certain issues that are difficult to
fully reconcile with the standard model.
For the activating effect of fatty acids,
there is an apparent lack of selectivity
and specificity. Fatty acids can uncouple
all types of mitochondria, but UCP1-con-
taining brown fat mitochondria are simply
more sensitive to fatty acids. Additionally,
even substances that are not very remi-
niscent of fatty acids can activate UCP1
(Shabalina et al., 2016). It may also seem
surprising that sufficiently high levels of
free fatty acids can ever be reached within
the brown fat cells, since the cells have
high levels of not only the general adipo-
cyte fatty acid-binding protein aP2
(FABP4), but also of the muscle-type fatty
acid-binding protein (FABP3). The model
also implies a competition between the
fatty acids and ATP, and although such
a competition can be shown functionally
 Cell Metabolism

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Figure 1. Possible Models of Regulation of UCP1-Mediated Heat Production

(A) The standard model for regulation of heat production downstream of the release of fatty acids from lipid droplets in the brown fat cells. Norepinephrine (NE)
released from the sympathetic nervous system binds to beta3-adrenergic receptors that, via activation of CGI-58, lead to activation of adipose tissue triglyceride
lipase (ATGL). The released free fatty acids (FFAs) are combusted in the mitochondria, but some of them directly activate uncoupling protein 1 (UCP1), which is
innately inhibited by cytosolic purine nucleotides such as ATP. The data presented by Schreiber et al. (2017) and Shin et al. (2017) indicate that alternative models
may be necessary.
(B) In one such model, external fatty acids released from white adipose tissue are both substrates for thermogenesis and activators of UCP1 (but the acute
significance of the nervous system is then lost).
(C) In another such model, it is necessary to postulate the existence of an NE-induced non-fatty-acid ‘‘activator’’ that activates UCP1 to allow it to uncouple so that
external fatty acids can be combusted for thermogenesis.

(Shabalina et al., 2004), fatty acids do not
experimentally compete away the inhibi-
tory ATP (Rial et al., 1983). Still, the stan-
dard model has maintained that it is the
released fatty acids from the intracellular
lipid droplets that activate UCP1.
The observations of Schreiber et al. and
Shin et al. may now be added to these
issues. There may obviously be trivial ex-
planations for the outcome. Thus, to
immediately fully abandon the idea that
activation of UCP1 is mediated via in-
creases in fatty acids released from intra-
cellular lipolysis is probably somewhat
premature. It could be suggested that
there may still be some fatty acid produc-
tion in the brown fat cells from other
lipases, despite the elimination of the
ATGL activity. The authors have docu-
mented that there is no glycerol release
from the brown fat cells that lack ATGL
activity, but that does not fully guarantee
that there is no lipolysis. Indeed, brown
fat cells have unusually high levels of glyc-
erol kinase, and this means that released
glycerol from the breakdown of triglycer-
ides may escape detection and lipolysis
may thus not have been fully absent.
Furthermore, we cannot be absolutely
certain that the heat production still origi-
nates from UCP1 activity—although it
would be surprising to observe UCP1-in-
dependent heat production of this magni-
tude in this situation since it has not been
unequivocally observed in any physiolog-
ical situation.
Thus, we are principally left with two
possibilities. In one (Figure 1B), the fatty
acids released from the white fat reach
such levels in the blood that they enter
the brown fat cells and directly activate
UCP1. We have known for a long time
that it is possible to activate thermogene-
sis by adding high amounts of fatty acids
from the outside to brown fat cells
(Prusiner et al., 1968) and that this ther-
mogenesis is UCP1 dependent, but func-
tionally this model seems illogical: the
sympathetic innervation of the tissue
loses its meaning. This would mean that
there could be situations in which brown
fat thermogenesis would be activated via
nervous stimulation of white adipose tis-
sue—a very costly process, as this could
turn on thermogenesis during starvation,
and the model is incompatible with the
demonstrated necessity of a nervous
supply to the tissue for thermogenesis
to occur.
The alternative is that there is some-
thing there we do not know about: a direct
activator of UCP1 (Figure 1C), originating
directly from beta-receptor stimulation.
Ideas of such activators have been
around even longer than UCP1 itself has
been known, but none have been inde-
pendently confirmed. We may thus be at
a point where the absence of the ex-
pected experimental outcome places
challenges on our ingenuity to clarify the
pathway for activation of thermogenesis:
what ignites UCP1?
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