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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]). E950 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- 0193-1849/16 Copyright © 2016 the American Physiological Society http://www.ajpendo.org Downloaded from http://ajpendo.physiology.org/ by 10.220.33.1 on June 18, 2017 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. 1. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 8: 495–502, 2012. doi:10.1038/ nrendo.2011.243. 2. Grobe JL, Grobe CL, Beltz TG, Westphal SG, Morgan DA, Xu D, de Lange WJ, Li H, Sakai K, Thedens DR, Cassis LA, Rahmouni K, Mark AL, Johnson AK, Sigmund CD. The brain renin-angiotensin system controls divergent efferent mechanisms to regulate fluid and energy balance. Cell Metab 12: 431–442, 2010. doi:10.1016/j.cmet.2010.09.011. 3. Iadecola C. Astrocytes take center stage in salt sensing. Neuron 54: 3–5, 2007. doi:10.1016/j.neuron.2007.03.013. 4. Ingelfinger JR, Rosen CJ. Cardiac and Renovascular Complications in Type 2 Diabetes--Is There Hope? N Engl J Med 375: 380 –382, 2016. doi:10.1056/NEJMe1607413. 5. Jourjine N, Mullaney BC, Mann K, Scott K. Coupled sensing of hunger and thirst signals balances sugar and water consumption. Cell 166: 855– 866, 2016. doi:10.1016/j.cell.2016.06.046. 6. Kim J, Chung YD, Park DY, Choi S, Shin DW, Soh H, Lee HW, Son W, Yim J, Park CS, Kernan MJ, Kim C. A TRPV family ion channel required for hearing in Drosophila. Nature 424: 81–84, 2003. doi:10.1038/ nature01733. 7. Luft FC. Divergent effects of central and peripheral renin on body weight and metabolism. Cell Metab 12: 423–424, 2010. doi:10.1016/j.cmet.2010.10.009. 8. Reforzo-Membrives J, Moledo LI, Lanaro AE, Megías A. Antidiuretic effect of 1-propyl-3-p-chlorobenzene-sulfonylurea (chlorpropamide). J Clin Endocrinol Metab 28: 332–336, 1968. doi:10.1210/jcem-28-3-332. 9. Shimizu H, Watanabe E, Hiyama TY, Nagakura A, Fujikawa A, Okado H, Yanagawa Y, Obata K, Noda M. Glial Nax channels control lactate signaling to neurons for brain [Na⫹] sensing. Neuron 54: 59 –72, 2007. doi:10.1016/j.neuron.2007.03.014. AJP-Endocrinol Metab • doi:10.1152/ajpendo.00358.2016 • www.ajpendo.org Downloaded from http://ajpendo.physiology.org/ by 10.220.33.1 on June 18, 2017 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 E951