How do we know when to exert energy or to take it easy? Our brain receives signals indicating our nutrient levels and whether they are in surplus or decline. But how do our cells inform our brain about our nutrient state? This is a question Dr. Akhila Rajan, an Associate Professor in the Basic Sciences Division at Fred Hutchinson Cancer Center and her lab sought to answer. The Rajan lab started to dissect this question by turning to a model organism, the fruit fly, which to them is much more than a pest that hangs out in the kitchen. In fact, these tiny insects helped these researchers discover “an interconnectedness between starvation and satiety cellular mechanisms that have been previously overlooked,” said Dr. Kevin Kelly, a postdoc in the Rajan lab. These findings were published recently in Current Biology.
Despite the difference in size, fruit flies share many conserved signaling pathways with humans. For example, ubiquitin-like proteins Atg8 in flies and LC3 in humans function similarly during nutrient deprivation. Both proteins mediate fusion between two types of vesicles—autophagosomes that engulf intracellular material and lysosomes that house enzymes that can recycle any material by breaking it down into smaller units. This process enables proteins, DNA, RNA, carbohydrates and lipids to be reused in the metabolic pathway of the cell. “Atg8/LC3 are critical during times of starvation,” explained Dr. Kelly. “When resources are scarce Atg8 is activated in order to "self-eat" and maintain critical cell functions.” But what happens under conditions of surplus? The Rajan group stumbled upon a system that revealed which factors are needed to notify the brain of nutrient surplus.
Their research has revealed that Atg8 in fly cells and LC3 in human cells, regulates Upd2 and Leptin secretion, respectively by mediating loading of these molecules into vesicles and release from adipocytes, explained Drs. Kelly and Rajan. Upd2/Leptin is “a key fat-brain surplus satiety signal,” added Dr. Rajan, suggesting that these factors might connect the nutrient sensors in cells to the brain. They discovered this mechanism by studying an interesting fly mutant. “We show that mutations that retain the fly Leptin within fat cells, because it cannot access Atg8/LC3, change the overall feeding behavior of flies, making them want to eat more,” stated Dr. Rajan. This mutant also “exhibited a "superpower" - increased survival under conditions of starvation,” shared Dr. Aditi Madan, a staff scientist in the Rajan lab. “We believe Leptin plays roles beyond a signaling molecule and may impact gene regulation in fat cells. Thus, when Leptin is retained in the fat, it switches certain genes on/off, that help the animal survive better in the face of scarcity.” Excitingly, this work reveals an under-explored role of these ubiquitin-like proteins, Atg8 and LC3, to load Upd2/Leptin into vesicles and secrete them from adipocytes to signal nutrient surplus conditions.
“Our investigations raise fundamental questions that will stimulate future investigations,” shared Dr. Rajan. “For instance, Atg8/LC3’s family proteins have a special ability to fuse with membranes, hence does Atg8/LC3-mediated Leptin release allow it to cross the blood brain barrier to reach the brain?” Answering this fundamental question will help to understand this connection between nutrient sensing and fat-brain signaling. Additionally, “this study beautifully demonstrates the evolutionary conservation of fat-to-brain signaling circuits between flies and humans,” shared Dr. Madan. Therefore, “Drosophila [fruit fly] serves as an excellent model for screens” such as those that “help pinpoint exact molecules/pathways that Leptin impinges upon under different metabolic/pathological states. Information gleaned from upcoming studies will shed light on potential drug targets for metabolic disorders in humans” such as obesity and anorexia. Dr. Rajan concluded by highlighting the “superb, shared resources facilities including the proteomics, genomics and cellular imaging facilities that are supported by the Cancer Consortium Collaborations.”
The spotlighted research was funded by the National Institutes of Health, Fred Hutchinson Cancer Center, NSF, and Helen Hay Whitney Foundation.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Akhila Rajan contributed to this work.
Madan A, Kelly KP, Bahk P, Sullivan CE, Poling ME, Brent AE, Alassaf M, Dubrulle J, Rajan A. 2024. Atg8/LC3 controls systemic nutrient surplus signaling in flies and humans. Curr Biol. S0960-9822(24)00757-7.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.