Download BRAIN GLUCOSE-SENSING: AGE- AND ENERGY

PROFESSOR DAVID SPANSWICK
A bioelectrical investigator
Professor David Spanswick is a prominent researcher in electrophysiology and neural systems. Here, he
discusses his research into the chemical and physiological components that regulate energy homeostasis
Dr Zane Andrews. My travels have certainly
been worthwhile and ultimately hold the key
to the commercial and clinical success of our
future research.
Why is it important for an organism to
maintain and control its energy balance?
Your biomedical career has led you all
over the world in the pursuit of scientific
discovery. How have your travels benefited
your research?
Travelling has been essential to the
development of my research. Having worked
extensively in North America, Japan and,
more recently, Australia, I have been trained
by, and collaborated with, some of the best
neuroscientists and physiologists in the world.
This has enabled me to establish neurosciencebased companies and labs in Canada, Australia
and the UK – and we are currently in the
process of setting one up in Southeast Asia.
Through a combination of academic and
commercial research, I have developed an
extensive, highly skilled and multidisciplinary
research team that interfaces between
industry and academia. More recently, my
move to Monash University, Australia, has
been incredibly rewarding and allows me to
collaborate with world-class scientists such as
Professors Michael Cowley, Iain Clarke, Mathew
Watt, Brian Oldfield and Mark Sleeman, and
20
INTERNATIONAL INNOVATION
Maintaining an energy balance is critical for
survival. It is achieved by matching food intake
and energy expenditure, and failure to maintain
this balance can be devastating. Excessive
food intake can ultimately manifest as obesity,
diabetes and other co-morbidities such as high
blood pressure and certain forms of cancer.
The other extreme is starvation and death.
To survive, animals have evolved systems
that maintain energy balance within narrow
limits and that adapt depending on their
external environment.
Which aspects of the brain are responsible
for maintaining energy balance?
The brain receives all manner of inputs,
including short-term meal-related signals.
For example, the hormone ghrelin – which
is released from the stomach when it is
empty – signals a state of hunger to the brain.
Conversely, following a meal, the hormones
GLP-1 and peptide YY signal the feeling of
satiety. The hormone leptin is just one of many
hormones released from fat cells and, together
with insulin, signals the levels of body adiposity.
Even more remarkably, certain individual nerve
cells integrate all of this information in the
form of electrical signals and codes and bring
about the appropriate changes in behaviour to
restore balance.
To what extent has a multidisciplinary approach
facilitated the success of your research?
This approach has been fundamental. As a
group comprising both commercial companies
and academia, we are relatively unusual in
that we have the ability to record bioelectrical
activity in the nervous system at every level:
from a single protein in a cell membrane to
the whole intact organism. Together with
our ability to relate electrophysiology to
changes at molecular, genetic, biochemical,
physiological and behavioural levels, this is
critical to cementing our understanding of
how neural systems in the brain, spinal cord
and periphery regulate aspects of normal
and abnormal behaviour. Without this
combination there is invariably no translation
to the clinical setting.
Our move to Monash University has allowed
our research to flourish and approach its full
potential. Indeed, with our electrophysiology
expertise complemented by the extensive
obesity-focused research at this institution,
my group is ideally positioned to translate our
research into clinical reality.
What are the next steps in translating your
research to the clinic?
To date, we have gathered sufficient
intelligence to establish two clinically relevant
series of experiments prior to pursuing clinical
proof of concept. First, we want to look at
a series of diet intervention strategies to
determine if it is possible to reverse the loss
of neural plasticity associated with obesity
and old age. Second, we will use the same
approach in combination with a therapeutic
drug-based strategy. Here, we will attempt
to identify the therapeutic window of
opportunity for a drug-based intervention, as
our current research indicates brain glucose
levels need to be controlled for maximal
therapeutic efficacy. Finally, we are aiming
to see what happens to the glucose-sensing
pro-opiomelancortin (POMC) plasticity during
rebound weight gain that frequently follows
‘crash diets’.
PROFESSOR DAVID SPANSWICK
Balancing brain glucose
Researchers based in the Department of Physiology at Monash
University, Australia, are engaging in collaborative and multidisciplinary
research with the goal of understanding how glucose-sensing neurons
could contribute to fighting the global obesity epidemic
OBESITY IS AN epidemic of enormous
proportions that has overtaken many parts of
the world. Defined as abnormal or excessive
fat accumulation that may impair health, it is
a highly visible threat in both developed and
developing countries, with cases affecting both
genders, and all age and socioeconomic groups.
The condition puts individuals at increased risk
of many conditions, including cardiovascular
disease, diabetes mellitus, hypertension, stroke
and certain types of cancer; consequently,
it represents a major public health burden.
Alarmingly, worldwide obesity has almost
doubled since 1980 and this percentage is
continuing to rise.
This is unsurprising given the increasing
abundance of energy-rich food supplies,
meaning that it can be challenging for many
individuals to avoid gaining weight. However,
maintaining a healthy body weight contributes
to a person’s mental and physical wellbeing,
and is therefore of great importance. A healthy
weight is achieved by balancing food intake with
energy expenditure – yet the mechanisms that
monitor and regulate this equilibrium are highly
complex, involving the central nervous system
and a series of interactive and overlapping neural
and nutrient-sensing pathways. The brain plays
a central role in controlling energy homeostasis,
with nerve cells and circuits detecting changes in
energy status. This information is then converted
into electrical signals and codes, consequently
triggering behavioural changes that help to
restore balance.
UNDERSTANDING ENERGY BALANCE
Professor David Spanswick, based in the
Department of Physiology at Monash
University, Australia, is fascinated by the
mechanisms that underpin energy homeostasis
in organisms. With a research background in
neurophysiology, he has worked internationally
and lectured in some of the world’s top
universities. Working with a multidisciplinary
team of collaborators, Spanswick is primarily
attempting to understand how nerve cells
interpret the enormous volume of hormonal
and nutrient signals they receive, and how
their function changes as a result of factors
including ageing, obesity, food deprivation and
diet. “By understanding the physiology and
pathophysiology associated with the function
of these nerve cells, we hope to contribute key
intelligence to help in the design of therapeutic
and preventive strategies that target obesity,”
he outlines.
Spanswick’s research has emerged from a
significant body of work that is dedicated
to exploring the pathways and mechanisms
by which the brain controls food intake and
energy expenditure. The past two decades have
seen detailed studies on the respective roles
of the hypothalamus, brainstem and spinal
cord in governing food intake and metabolism.
More recently, scientists have paid increasing
attention to the roles of reward pathways
and the midbrain dopaminergic system. As
established areas of addiction and substance
abuse research, they also seem to underpin
various food reward-based behaviours. “It
is undoubtedly the integrated activity of
these different neural circuits that ultimately
controls behaviour,” Spanswick asserts. “For
instance, aspects of the hypothalamus target
the reward pathways and there are reciprocal
connections between hypothalamic and
brainstem centres.”
A novel method
One of the most pivotal moments in Spanswick’s research occurred
several years ago, when he challenged three scientists in one of his
companies – Neurosolutions – to determine the normal levels of brain
glucose associated with health, obesity and ageing.
The technical demand of this experiment was exponential, yet these scientists successfully mimicked the
environment of the brain in a dish, manipulating it in functionally meaningful ways. Not only did this enable
them to establish glucose levels in the brain, but it also allowed them to ascertain the correlation between
brain and blood glucose levels in real-time. Since this landmark moment, the scientists have focused on
profiling the levels of fatty acids, lipids and hormones in both the blood and the cerebrospinal fluid they have
collected, mapping the correlations between both. Crucially, these methods have completely revolutionised
the team’s strategies by introducing cutting-edge tests that establish functionally meaningful changes in the
levels of glucose and other nutrients.
WWW.INTERNATIONALINNOVATION.COM
21
INTELLIGENCE
BRAIN GLUCOSE-SENSING: AGEAND ENERGY-STATUS-DEPENDENT
PLASTICITY OF FUNCTION-SPECIFIC
PRO-OPIOMELANOCORTIN (POMC)
GLUCOSE-SENSING NEURONS IN
THE ARCUATE NUCLEUS OF THE
HYPOTHALAMUS
OBJECTIVES
To address questions relating to the
mechanisms by which aspects of the brain
and spinal cord orchestrate behavioural
responses to disturbances in energy levels,
and to identify and isolate the component
parts at the single cell and neural brain
circuit level that underpin this behaviour.
KEY COLLABORATORS
MONITORING ELECTRICAL ACTIVITY
One of the main elements of Spanswick’s
research focuses on the role of glucose-sensing
neurons in controlling energy balance. After
detecting changes in the levels of glucose,
these cells cause behavioural changes such as
modifications in food intake or metabolism,
which in turn maintain or restore glucose to
normal levels. Additionally, it is thought that
glucose-sensing neurons are able to detect
other signals regarding changes to food intake
or energy metabolism. These include specific
hormones that are released when the stomach
is full or empty, as well as hormones that carry
information about the body’s fat stores.
CONTACT
Pro-opiomelancortin (POMC) neurons are
some of the most well-studied glucose-sensing
cells. Indeed, they have a vital role in helping to
maintain energy balance; mutations in POMC
neurons and their target receptors are known
to contribute to some of the most common
forms of human monogenic obesity. “It is
only relatively recently that we have begun to
recognise that POMC cells do not constitute
a single functional population,” Spanswick
discloses. “Rather, there are clear, functionspecific subgroups, most likely related to the
ultimate target organs that they innervate and
the associated different behavioural outcomes.”
David Spanswick
Professor of Neuroscience
Using electrophysiology to monitor the
electrical activity and excitability of POMC
Professor Michael Cowley; Professor
Brian Oldfield; Professor Matt Watt;
Professor Iain Clarke; Professor Mark
Sleeman; Dr Zane Andrews, Monash
University, Australia
Dr Leo Renaud
University of Ottawa, Canada
FUNDING
National Health and Medical Research
Council, Australia
Department of Physiology
Monash University
Building 13F
Clayton Campus
Wellington Road
Victoria, 3800
Australia
nerve cells in real-time, Spanswick and his
colleagues have shown that POMC cells can
help to change activities and drive behaviours
that restore the levels of glucose in the body.
In their experiments, they found that POMC
cells were much less sensitive to glucose in
both fed and high-fat diet models. Crucially,
unlike their healthy counterparts, when these
models were fasted the POMC cells failed
to adapt and change sensitivity: “These data
indicate dysfunction of the glucose-sensing
POMC neural networks in terms of obesity and
old age, with the failure of this system critical
to the development of diabetes and the failure
to regulate glucose levels,” discloses Spanswick.
FORGING AHEAD
These findings have been made possible by the
multidisciplinary and highly technical nature
of the research conducted by Spanswick and
his academic and commercial colleagues
throughout the world. Looking ahead, the
hope is that this talented and unique group
of researchers will continue to forge deeper
insights into the chemical and physiological
mechanisms that underlie energy homeostasis.
Such insights will eventually be used to devise
innovative pharmacological and diet-related
interventions that effectively target obesity
and related metabolic diseases. Additionally,
the researchers are also planning to design
preventive diet-based strategies that promote
healthy ageing.
Obesity in numbers
In 2008, the World
Health Organization
(WHO) estimated
that more than
1.4 billion adults
were overweight
T +61 3 9902 4307
E [email protected]
http://bit.yl/1tfhdpV
SOCIAL MEDIA
Some 65% of the world’s population live
in countries
where
overweight
and obesity
kills more
people than
underweight
http://linkd.in/1yXkgFF
DAVID SPANSWICK gained his MSc and
PhD at the University of Birmingham,
UK. Since then he has held positions at
universities in Japan, Canada and, most
recently, at Monash University in Australia.
Spanswick has founded three spin-off
companies – Pacific Discovery Services,
Australia; Neurosolutions Ltd, UK; and
Cerebrasol, UK and Canada. In addition to
his research activities, Spanswick performs
undergraduate teaching and supervises
postgraduate research in his laboratory.
In 2011, more
than 40 million
children under
the age of five were
overweight
At least 2.8 million adults
die each year as a result of
being overweight or obese
It has been estimated that overweight and obesity are responsible for:
44% of the
diabetes burden
23% of the ischaemic
heart disease burden
7-41% of certain
cancer burdens
22
INTERNATIONAL INNOVATION