Homeostasis, from the Greek words for "same" and "steady," refers to any process that organisms use to actively maintain fairly stable conditions necessary for survival. Fat storage homeostasis for example, ensures that during times of plenty the body’s inventory is increased, while in times of famine, stored fat is broken down to provide energy. In addition, an organism’s ability to sense different nutrient states can guide whether energetically costly processes like reproduction and immunity can be invested in under conditions of scarcity. This homeostatic behavior is coordinated by adipokines, signaling molecules released by fat cells to energy-store responsive neurons. The Rajan lab (Basic Sciences Division) is interested in the molecular mechanisms underlying this hormonal signaling between fat cells and the brain using the fruit fly as a model organism.
In previous work, the Rajan lab discovered how fat cells secrete the appropriate amount of fat hormones depending on nutrient state and uncovered a molecular mechanism that links dysfunctional calcium homeostasis to obesity. Specifically, they identified a mechanism coupling systemic energy sensing to adipokine secretion via intracellular calcium (Ca2+) signaling and found it to be evolutionarily conserved between Drosophila and humans. In a recent preprint , Drs Ava Brent and Akhila Rajan investigated the mechanism by which tonic adipokine information establishes baseline neuronal function. Dr Brent, a staff scientist in the Rajan lab explained the importance of the study: “Organisms maintain a steady-state amount of stored fat. Metabolic hormones that influence this steady-state (or ‘set-point’) are appreciated, but how they exert their effects to maintain this set-point remains unclear.”
In order to address this knowledge gap, the authors developed a work-stream that allowed them to visualize and quantify, within the fly brain, the number of synapses present in a particular fat-sensing neuronal circuit. “The process entailed genetically marking synapse contact points which included collecting images of those synapses via confocal microscopy, and employing image segmentation software to tag and quantify the number and size of each synapse contact point” explained Dr. Brent.
Using this pipeline, the authors investigated how the protein Unpaired 2 (Upd2), a Drosophila Leptin ortholog, regulates the extent of inhibitory tone provided by its target GABA neurons on the insulin producing cells (IPCs). In humans, the hormone leptin acts on receptors in the brain to inhibit hunger while insulin promotes the storage of nutrients. Together, leptin and insulin inform target neurons on energy stores. “We show that leptin and insulin function in directly opposing ways to determine the number of synaptic contacts made by fat-sensing neurons that control energy homeostasis, said Dr. Brent.
Since leptin and insulin in humans interact with one another, and these interactions are sometimes synergistic, sometimes antagonistic, the Drosophila provided a simpler model where leptin/insulin interactions are better defined. The authors were able to show that in Drosophila, the regulation of synapse number occurs when fat stores increase, but that homeostatic mechanisms are in place to restrict the activity of the pathways that promote fat storage. “These findings have implications for the set point theory of energy homeostasis, and suggest that exposure to prolonged surplus might disrupt the programs that keep the fat-sensing neuronal circuits under negative control,” explained Dr. Brent.
This is an important step towards understanding how animals sense and control nutrient surplus. In the future, the authors hope to understand how the fat-sensing neurons receive systemic hormonal signals. As Dr. Brent comments, “we want to know how hormones are packaged and released such that they can pass through the protective blood-brain barrier, and access their target neurons within.”
This study was made possible by grants from NIDDK, NIGMS, and New Development funds from Fred Hutch.
UW/Fred Hutch Cancer Consortium member Akhila Rajan contributed to this work.
Brent AE, Rajan A. 2019.Adipokines set neural tone by regulating synapse number. bioRxiv.