Obesity is a result of dysfunctional energy homeostasis. Energy homeostasis enables maintenance of metabolic parameters, such as blood glucose and fat stores, within a permissible range. Maintenance of homeostasis requires communication between organs that sense nutritional status and those which integrate and respond to signals from sensors. A key ‘sensor’ of energy is the adipose tissue, which is composed of fat cells/adipocytes. Adipocytes communicate the total stored energy by secreting factors called adipokines. Adipokines signal to neural circuits in the central nervous system (CNS) that regulate food intake and energy expenditure, serving as ‘responders’ in the homeostatic loop.
Leptin is a primary adipokine that is released in proportion to the fat stores and impinges on CNS to regulate energy expenditure, appetite and physiological processes such as reproduction and immunity that occur only in high nutrition environments [you can learn more about this hormone and fat by listening to this NPR segment (click link)]. Improper Leptin signaling occurs in obese individuals. It is unclear why Leptin fails to signal effectively as fat stores increase.
We found that the hormone used by fruit flies to communicate information regarding its fat stores to its central nervous system is the same one humans (click link). Fruit flies are a premier model system with a wealth of techniques- from state-of-art genetic tricks to biochemical assays, and superb imaging tools including high resolution quantitative imaging. Using this model system, we will define how Leptin signaling works during 'normal' states. Then address how dysfunctional Leptin signaling occurs during chronic nutritional overload. Our ultimate goal is to understand how surplus signaling fails during 'over-nutrition'.
1. How do fat cells sense alterations in nutritional stores and regulate adipokine production?
2. How do the adipokines access the brain?
3. How fat sensing neurons respond to adipokines?
4. How over-nutrition causes ‘loss of plasticity’ in homeostasis?
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. Drosophila as a model for interorgan communication: lessons from studies on energy homeostasis. Developmental Cell 21, 29-31 (2011).
2 Rajan, A. & Perrimon, N. Of flies and men: insights on organismal metabolism from fruit flies. BMC Biol 11, 38 (2013).
3 Rajan, A*. & Perrimon, N*. Drosophila Cytokine Unpaired 2 Regulates Physiological Homeostasis by Remotely Controlling Insulin Secretion. Cell 151, 123-137 (2012). (* corresponding author)
4 Rajan A*, Housden, B.E., Wirtz-Peitz, F., Holderbaum, L., and Perrimon, N.** (2017). A mechanism coupling systemic energy sensing to adipokine secretion. Developmental Cell 43, 83-98 (2017). (* corresponding author & lead contact; ** corresponding author )
Our work is funded by the National Institutes of Health.
NIDDK: R00 DK101605 & NIGMS: R35 GM124593