Download Quenching the thirst for hunger

Am J Physiol Endocrinol Metab 311: E950 –E951, 2016;
First published November 15, 2016; doi:10.1152/ajpendo.00358.2016.
Editorial
Quenching the thirst for hunger
Paul Lee
Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, Australia
Submitted 3 October 2016; accepted in final form 10 November 2016
Address for reprint requests and other correspondence: P. Lee, Garvan
Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, Australia 2010 (email: [email protected]).
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energy depletion, and Nan, the sensor for hypoosmolality, begs
the question whether hunger and thirst are coregulated by ISNs
through simultaneous AKH and osmolality sensing. This is
indeed the case, as illustrated by reciprocal water drinking and
sugar consumption in flies governed by starved and water-sated
states.
The intriguing studies cowiring hunger and thirst sensing to
behavioral sugar and water consumptive adaptations raise
many questions. First, how do identical neurons, the ISNs,
effect different consumptive behaviors simultaneously? Second, what is the evolutionary origin of coupled food/water
sensing? Finally, in a broader context, what are the implications of these findings to human disease states with perturbations in caloric and osmotic status, such as diabetes mellitus?
Insight into these questions could be drawn by dissecting
interactions between ISNs and systemic glucose/solute/hormone interactions. Although Jourjine and colleagues found no
effect of insulin alone on ISNs, insulin attenuated AKHstimulated ISN activation, thus signifying that ISN-mediated
water/food sensing is likely under multilevel hormonal influences, subsequently modulating drinking and feeding behavior.
In the survival hierarchy, water trumps food, and water is
required in all energy-utilizing biochemical processes. Moreover, glucose itself is a primary determinant of serum osmolality, and glycemic fluxes impact both AKH/insulin balance
and osmotic states. Although convergence of two mechanisms
within one neuronal center may confer an evolutionary vulnerability, coupling the two homeostatic drives within one locus
facilitates direct fine tuning to satisfy the two survival needs as
systemic energy/osmotic status fluctuates, at least in dipterans.
In rodents and humans, multiple and sometimes redundant
neuroendocrine circuits have evolved to maintain energy/water
homeostasis. ISNs in flies have perhaps provided a glimpse at
the origin of such homeostatic regulatory machinery in evolutionary history.
What can we learn from ISNs of flies to further our understanding of human health and disease? The hallmark of diabetes mellitus is hyperosmolar hyperglycemia. If a similar ISNlike coupling mechanism exists in humans, one would expect
low glucagon (the mammalian equivalent to AKH) from energy repletion and relative hyperosmolality induced by hyperglycemia to constitute an innate cap on appetite-driven weight
gain operated via ISNs. Insulin and its secretagogue (i.e.,
sulfonylurea) are traditional glucose-lowering therapies. Although efficacious, the drawback is weight gain, generally
attributed to an increase in appetite, albeit with poor understanding of the underlying mechanism. Through the lens of
ISNs, the balance between thirst vs. hunger would be expected
to gravitate toward food consumption, as osmolality falls
following pharmacological glucose lowering. In addition, sulfonylurea exhibits an antidiuretic effect, reducing free water
clearance (8). The net result is relative hypoosmolality that
could trigger an ISN-mediated orexigenic response. It is tempt-
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and water balance is fundamental to
survival across organisms. A recent study reveals a unique
neuroendocrine node in Drosophila that simultaneously surveys systemic caloric and osmotic fluctuations to fine-tune
food and water consumption, providing a new neuronal mechanistic insight on anti-diabetes therapeutics with dual glucose/
osmolality modulatory actions.
Deaths from starvation and dehydration are now rare in most
of the developed world. Even the word forthirst, meaning
‘dying of thirst’, has become obsolete English, although mortality from either was not uncommon only a century ago, and
strategies to overcome both are fundamental to survival across
animalia. On a physiological level, the hypothalamus plays an
integral part in energy and water homeostasis by sensing and
reacting to systemic signals of caloric and osmotic fluctuations.
However, little is known about the evolutionary footprint of
this survival-critical neuroendocrine circuitry. Now, Jourjine
and colleagues (5) report an energy and water homeostatic
coregulatory neuronal system in Drosophila that coordinates
food and water consumption juxtaposing at the interplay of a
hormone receptor and an ion channel.
In a recent paper, Jourjine et al. (5) set out the goal to
identify novel regulators of hunger and thirst in flies. Crossinterrogation of brain region-specific gene inhibition in experimentally induced food- and water-seeking flies identified a set
of neurons and a cation channel, neither with known roles in
energy/fluid homeostasis, actually modulate sugar and water
consumption in cooperation. The authors named the neurons in
the subesophageal zone (SEZ) that stimulate feeding behavior
the interoceptive SEZ neurons (ISNs), while the cation channel
located in the SEZ was identified as the Nanchung (Nan)
protein, first described a decade ago for its role in chordotonal
mechanotransduction (6). Mining ISN coexpression data in
hormone receptor-Gal4 flies pinpointed adipokinetic hormone
(AKH), a hunger-sensing peptide, to be one afferent signal of
ISNs. Nan SEZ neurons, on the other hand, fire directly in
response to a decrease in hemolymph osmolality.
These findings paved the way for a series of ISN- and
Nan-focused experiments proceeding in the parallel universes
of food and water investigative neuroscience, at least initially,
but the two worlds eventually overlapped out of remarkable
scientific serendipity: AKH receptor-expressing and osmosensitive Nan SEZ neurons are, in fact, the same neurons, and
ISNs responded equally to osmolality and AKH changes.
The authors then examined AKH and Nan action within
ISNs. In vitro, direct exposure to AKH or hypoosmotic fluid
stimulates ISNs activity; in vivo, ISNs firing heightened in
starved flies with high AKH as well as in mutant flies with Nan
knockdown. Opposing ISN modulation by AKH, the signal of
MAINTENANCE OF ENERGY
Editorial
QUENCHING THE THIRST FOR HUNGER
hormone-channel neurosensor, poised for further experimentations in rodents/humans.
Overall, this exciting study by Jourjine and colleagues uncovers a neuroendocrine center capable of juggling water and
caloric needs by integrating hunger/water satiety signals. Coupling of energy/osmolality sensing centrally illuminates pathophysiology and therapeutic responses in human disease states
characterized by caloric and water balance disturbances. By
unveiling a previously underappreciated layer of neuronal
input to satiety control from osmotic status, this unexpected
insight from Drosophila opens avenues in therapeutics research, exploring interactive manipulation of energy and solute/water balance, centrally and peripherally, in our ongoing
combat against diabetes/obesity.
ACKNOWLEDGMENTS
Paul Lee is supported by an Australian National Health Medical Research
Council (NHMRC) Career Development Fellowship (APP1111944).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
P.L. prepared figure, drafted manuscript, edited and revised manuscript, and
approved final version of manuscript.
REFERENCES
Fig. 1. A clinical perspective on hunger/thirst-coupled sensing in Drosophila.
The interoceptive subesophageal zone neurons (ISNs) are specialized sensors in
Drosophila capable of simultaneously sensing systemic energy and water balance
through input from adipokinetic hormone (AKH) and osmolality sensing by Nan
ion channel, respectively. High AKH (signifying energy depletion) and low
osmolality both drive feeding behavior through ISN activation, while high osmolality promotes water drinking by repressing ISNs. This ancient conserved loop
coupling energy/osmolality sensing may underlie appetite stimulation during
glucose-lowering therapies in humans that also reduce osmolality, such as insulin
and sulfonylurea. Conversely, treatments that reduce glucose but induce osmotic
diuresis, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors could lessen
ISN-mediated orexigenic response, limiting weight gain.
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ing to speculate whether ISN-like neurophysiology, should it
exist in humans, could potentially explain, at least partly, the
long-recognized weight gain phenomenon observed during insulin/sulfonylurea treatment. In contrast, the new class of oral
hypoglycemic agents, sodium-glucose cotransporter 2 (SGLT2)
inhibitors, reduce glucose by inducing glycosuria, which is accompanied by osmotic diuresis (1). The lack of hyperphagia
despite caloric loss upon SGLT2 inhibitor therapy has puzzled
many but could hypothetically be a result of repressed ISNmeditated hunger signal from relative hyper-osmolality (Fig. 1).
Conceptually, the corollary of these implications may also
be applicable to weight loss benefits associated with reninangiotensin-aldosterone (RAA) antagonism. While various
central mechanisms have been postulated (2, 7), weight reduction from RAA blockade could potentially emanate from augmented osmolality lessening ISNs’ hunger signal. Emerging
evidence is spotlighting astrocytes as salt sensors (3, 9) and
kidney as a diabetes treatment target (4). ISN neurophysiology
in Drosophila sheds new light on how water/solute homeostasis could wire to energy balance through an ancient coupled
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