SDRC Trainee Highlight
The SDRC is proud to highlight the research achievements of its trainees by presenting outstanding poster awards during its 4th Annual Frontiers in Diabetes Symposium.
Dr. Keren Ita Hilgendorf’s work focuses on understanding the function of a sensory organelle called the cilium on fat cell development and its role in metabolic diseases like obesity and diabetes. Explaining her focus on cilia, she says, “I have always been interested in understanding how key disease signaling pathways work on a molecular level. The primary cilium is an ancient and spatially distinct antenna-like protrusion that has emerged as a central sensory organelle of the cell. Patients with dysfunctional ciliary signaling present with a broad spectrum of clinical manifestations, including obesity and diabetes.” Her study provides a molecular framework to explain how the primary cilium regulates the formation of fat cells from fat cell precursors by identifying a novel ciliary receptor which is activated by omega-3 fatty acids, known to have anti-diabetic effects.
Dr. Hilgendorf used a mouse model which permitted visualization of cilia in fat tissue after the mice were fed a high-fat diet and showed that the ciliated fat precursor cells position themselves close to blood vessels and are thus able to quickly respond to changes in nutrient cues in the blood through proteins called receptors on the cilia. To identify signaling pathways involved in adipogenesis or the generation of fat cells from their precursors, Dr. Hilgendorf screened candidates in fat precursor cells grown in a dish enabling her to identify Ffar4, a novel free fatty acid ciliary receptor that responds to omega-3 fatty acids. Dr. Hilgendorf notes, “Human mutations in the Ffar4 gene have been linked to childhood obesity. Patients with dysfunctional ciliary signaling are obese and diabetic, and fat precursor cells isolated from obese humans are shortened and signaling-defective”, suggesting that she has identified a central pathway that has gone awry in obese and diabetic individuals. However, acknowledging that other signals likely also factor into the molecular dysfunction underlying obesity and diabetes, she notes “The integration of multiple ciliary signaling pathways may occur at the level of the primary cilium and we are actively pursuing this line of investigation”. Dr. Hilgendorf plans to use the SDRC poster prize money to attend the FASEB Cilia Conference this summer. She is a Research Scientist in SDRC member Dr. Peter Jackson’s group at Baxter Laboratories.
Research Scientist Dr. Owen Jiang and Postdoctoral scholar Dr. Yunshin Jung explore the mechanisms by which brown fat tissues provide metabolic benefits to the body. Brown fat is classically known for its heat generating capabilities which burns calories and contributes to weight loss. However, recent studies show that brown fat also secretes factors that help with blood sugar homeostasis. Drs. Jiang and Jung’s work identified one such secreted protein called Isthmin-1 (ISM1) which improves the ability of fat cells to take up glucose. “Initially, we were looking for secreted proteins that were both hormone-like and enriched in brown fat cells. This gave us 16 candidates, including Isthmin-1 which is expressed in brown fat”, they explained. Their subsequent analyses demonstrated that ISM1 induced glucose uptake by fat cells via an insulin-independent mechanism.
When mice fed with a high-fat diet are treated with ISM1, they display a long-term improvement in insulin sensitivity and glucose uptake. Interestingly, unlike insulin treatment, ISM1 treatment improves blood glucose levels without a concomitant increase in fat accumulation in peripheral tissues like the liver. Drs. Jiang and Jung found that ISM1 shuts down the molecular pathways that drive fat accumulation in the liver in these mice. The researchers are now developing even more sensitive assays to permit them to detect ISM1 in blood. “We have exciting preliminary data suggesting that our ISM1 assay can detect picogram levels of ISM1”, they note.
In terms of how their work is relevant to current and future therapeutic strategies combating diabetes and obesity, they are optimistic. “This could potentially become a recombinant protein therapy for patients with diabetes and insulin resistance”, they say. The power of ISM1 lies in the fact that although it activates a prominent signaling mechanism called the PI3K/AKT pathway in target cells which promotes glucose uptake, it does so without accumulating fat. The researchers plan to test the function of ISM1 in fat cell development and assess its role in human obesity in the future. Drs. Owen Jiang and Yunshin Jung are in Dr. Katrin Svensson’s group in the Department of Pathology at Stanford. They plan to use their SDRC poster prize money to cover travel expenses to conferences.
By
Harini Chakravarthy
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.