The hormone used by fruit flies to communicate information regarding its fat stores to its central nervous system is the same one humans use to convey overall fat stores to brain circuits [you can learn more about this hormone and fat by listening to this NPR segment]. This important hormone is called Leptin is produced by human fat cells. Plugging back the human Leptin gene into the fly makes up for the lack of fly’s version of Leptin. This finding demonstrated that the fly system is a suitable model to investigate questions pertaining to energy imbalance, and that energy homeostasis studies in fruit flies have implications for human health.
While lack of Leptin leads to obesity, an oversupply of circulating Leptin, resulting from increased fat body fat, causes common obesity. This defect is termed "Leptin resistance", and the mechanisms that underlie it are poorly understood. Solving Leptin resistance will enable us to tackle common obesity and treat chronic metabolic disorders. Having now established a Leptin-like model in fruit flies positions us to investigate mechanisms underlying Leptin resistance, and other more basic questions pertaining to energy balance.
Emphasis will be on questions that are less tractable in mammalian model systems, such as: How does a fat cell sense systemic nutritional status? What cellular machinery orchestrates the appropriate release of hormones concomitant with nutrient stores? Does the mechanical properties of fat cells impact systemic energy balance? How are hormonal signals received by neural circuits and decoded to enact physiologic change in the entire organism?
Elucidate the cellular basis of adipokine secretion in response to alterations in lipid stores:
GRASP, a key unconventional secretion component, forms a nutrient sensitive compartment via which, Upd2, the ancestral leptin, is trafficked. Further, the GRASP compartment itself is regulated, by calcium, glycerol and sugar sensing kinases. Our immediate goal is to delineate how the GRASP complex, which is positioned on lipid droplets, integrates information from numerous nutrient signals and interacts with other endosomal components to release adipokines. We anticipate that these studies will provide an in depth molecular understanding of how hormonal signals are secreted in appropriate amounts based on the physiological status.
Examine the role of mechanical tension in fat cells for regulating the energy physiology:
Whether mechanical alterations in the fat cells, caused by changes in lipid levels, alters the cell biology of secretion remains uninvestigated. We will begin by testing how the genetic impairment of mechanotransduction genes, in the Drosophila fat cells, affects energy physiology. This will be done by spatio-temporally knocking down genes, involved in mechanical force sensing (Ex: integrins, talins, vinculin, RhoA) in the adult Drosophila fat cells and assessing their impact on metabolic parameters. Further, we will develop methods for quantifying mechanical tension in the Drosophila adult fat body by using tension sensor imaging. Our goal is to establish an in vivo system that will allow us to systematically probe how an adipose cells’ mechanobiology regulates systemic energy homeostasis.
Identify mechanisms by which adiposity signals affects molecular changes in neuronal groups:
How systemic signals such as hormones are received by neural circuits and decoded to enact physiologic change in the entire organism is another question which can be addressed using the system that we have established. Upd2 released by the fat body activates JAK/STAT signaling in GABAergic neurons. Similarly, Leptin functions in hypothalamic brain circuits, primarily by activation of STAT in GABAergic neurons. The mechanism(s) by which Leptin and Upd2 signaling affects GABAergic neuronal firing remain unknown and is crucial to understanding how Leptin resitance occurs. We performed a candidate based screen in GABAergic neurons in order to identify factors that mediate STAT signaling in GABA neurons. Nine of the candidate genes uncovered in our screen have roles in processes ranging from alcohol sensing and aggression to learning and memory. One of the drugs that FDA has approved for use in weight-loss, called topiramate, has been successfully used to treat alcohol addiction and is as a mood-stabilizer. However, the mechanism of action of this drug is completely unknown. Thus it is intriguing that our screen has identified genes in alcohol sensing and aggression, which also impact fat storage in flies. Future work at our lab, we will explore how these genes mechanistically regulate neuronal firing in an attempt to unravel the connection between fat storage and these other physiological processes.
We deploy an inter-disciplinary toolkit, using well-established techniques- such as fruit fly genetics, confocal imaging, lipid chromatography, mass spectrometry etc., in conjunction with emerging approaches that include high resolution electron microscopy, proximity mass spectrometry, and translating ribosomal affinity purification.
1 Rajan, A. & Perrimon, N. Of flies and men: insights on organismal metabolism from fruit flies.
BMC Biol 11, 38, doi:10.1186/1741-7007-11-38 (2013).
2 Rajan, A. & Perrimon, N. Drosophila as a model for interorgan communication: lessons from studies
on energy homeostasis. Dev Cell 21, 29-31, doi:10.1016/j.devcel.2011.06.034 (2011).
3 Rajan, A. & Perrimon, N. Drosophila Cytokine Unpaired 2 Regulates Physiological Homeostasis by
Remotely Controlling Insulin Secretion. Cell 151, 123-137, doi:10.1016/j.cell.2012.08.019 (2012).