INSIGHTS | PERSPECTIVES
Zachary A. Knight3
The sense of smell, or olfaction, allows animals to survey the chemical land- scape of the outside world and use this information to guide behavior. Olfactory cues are particularly im- portant for the regulation of feeding,
but how odor perception influences other
aspects of energy homeostasis remains
poorly understood. Recent work has begun
to uncover some of these connections, revealing an unexpected role for olfaction in
the control of metabolism and longevity.
The idea that olfaction and metabolism
could be connected goes back at least to
the work of Ivan Pavlov, who showed that
odors and other sensory cues associated
with food could trigger hormonal and
autonomic responses in anticipation of a
meal (1). These “cephalic phase” responses,
such as salivation and secretion of gastric
acid, are thought to help prepare the body
to accommodate the rapid influx of nutrients that occurs during eating. But how
chronic changes in odor exposure affect
metabolism has been less clear.
To address this question, a recent study
manipulated the olfactory system in the
mouse and measured the effect on energy
homeostasis (2). By ablating olfactory sensory neurons in adult mice, they generated
mice that had a reduced ability to smell.
These hyposmic mice exhibited normal
food intake and body weight on a regular
diet, but were resistant to obesity caused
by a high-fat diet. This leanness was due to
both reduced food intake and, surprisingly,
increased energy expenditure. Mechanistic
studies revealed that this enhanced energy
expenditure was caused by an increase in
the activity of brown adipose tissue, a specialized thermogenic organ that functions
to dissipate heat in mammals.
To test this idea further, the authors used
complementary manipulations to generate
mice with enhanced smelling ability. These
mice exhibited increased body weight in
the absence of any change in food intake
(2). Together, these observations reveal
that the olfactory system can regulate body
weight via direct effects on energy expen-
diture, rather than solely through changes
in food intake as has traditionally been as-
sumed. Other recent studies have also sug-
gested connections between olfaction and
metabolism, although the exact relation-
ship remains unclear (3, 4).
What are the implications of these findings? It is well established that metabolism
is a critical determinant of not only body
weight, but also aging. Thus, we might
predict that loss of smell could influence
life span, and this has indeed been demonstrated in invertebrates: Disrupting olfactory neuron function, either through
mutation or laser ablation, extends life
span in both worms and flies (5, 6). In
these simpler organisms, the smell of food
decreases life span, but only when the animals are calorie restricted (7). These data
support the idea that olfactory perception
may alter how an organism uses energy,
and suggest the intriguing possibility that
modulating smell could be a viable strategy for anti-aging interventions.
The mechanisms by which the olfactory system influences metabolism are
unknown, but one possibility is suggested
by the recent discovery that food odors
can regulate “hunger neurons” in the hypothalamus (8–10). These cells, known as
agouti-related protein (AgRP) neurons, are
activated by food deprivation, and their
activity powerfully influences food intake,
energy expenditure, and peripheral metabolism. Traditionally, AgRP neurons were
thought to be regulated exclusively by nutrients and hormones that circulate in the
blood, but it is now appreciated that these
cells also respond rapidly to sensory cues
associated with food. Indeed, the smell of
food alone can inhibit the AgRP neurons
of a hungry mouse within seconds (8–10).
How chronic disruption of this olfactory
input would affect physiology has not been
tested, but it is possible that such manipu-
Linking smell to
metabolism and aging
1Department of Cellular and Molecular Pharmacology,
University of California, San Francisco, San Francisco, CA
94158, USA. 2Buck Institute for Research on Aging, Novato,
CA 94945, USA. 3Department of Physiology, University of
California, San Francisco, San Francisco, CA 94158, USA.
The olfactory system can have direct effects
on energy homeostasis
cent of those that promote cell cycle transitions in proliferating cells. What remains
unclear, however, is how PLK1 and CDK1 coordinate the amplification, growth, and disengagement phases of centriole biogenesis.
In the future, it will be important to identify
the key targets of PLK1 and CDK1 and establish how phosphorylation of these substrates coordinates centriole amplification.
An additional area of investigation is
to examine the role that other CDK-cyclin
complexes play in multiciliogenesis. Given
that centriole duplication in cycling cells relies on the activity of CDK2 during S phase
of the cell cycle, it would not be surprising
if MCCs also use CDK2 activity to drive centriole amplification. In light of this, it would
be interesting to examine the role of cyclin
O, which can bind CDK2 and is specifically
expressed in MCCs, where it functions to
promote deuterosome formation and centriole amplification (8, 9). Interestingly,
cyclin O is encoded within a conserved
genomic locus that contains multiple key
regulators of MCC formation, including
the CDC20 paralog CDC20B. It is therefore
tempting to speculate that cyclin O and
CDC20B are specifically expressed in MCCs
to help regulate CDK activity and promote
differentiation. Recent studies have shown
that mutations in cyclin O and proteins that
specify MCC cell fate cause respiratory tract
disease by reducing the production of motile cilia (10, 11). A better understanding of
the molecular machinery that controls multiciliogenesis will therefore have important
implications for human health. j
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11. M.Boon etal., Nat.Commun. 5,4418(2014).
cells implement components
of the mitotic cell cycle
machinery to coordinate
events that are required for
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