The study, which was published in Cell Metabolism on January 4, 2022, shows that a hormone called FGF1 regulates blood glucose by inhibiting fat breakdown (lipolysis). Like insulin, FGF1 controls blood glucose by inhibiting lipolysis, but the two hormones do so in different ways. Importantly, this difference could enable FGF1 to be used to safely and successfully lower blood glucose in people who suffer from insulin resistance.

“Finding a second hormone that suppresses lipolysis and lowers glucose is a scientific breakthrough,” says co-senior author and Professor Ronald Evans, holder of the March of Dimes Chair in Molecular and Developmental Biology. “We have identified a new player in regulating fat lipolysis that will help us understand how energy stores are managed in the body.”

When we eat, energy-rich fats and glucose enter the bloodstream. Insulin normally shuttles these nutrients to cells in muscles and fat tissue, where they are either used immediately or stored for later use. In people with insulin resistance, glucose is not efficiently removed from the blood, and higher lipolysis increases the fatty acid levels. These extra fatty acids accelerate glucose production from the liver, compounding the already high glucose levels. Moreover, fatty acids accumulate in organs, exacerbating the insulin resistance — characteristics of diabetes and obesity.

Previously, the lab showed that injecting FGF1 dramatically lowered blood glucose in mice and that chronic FGF1 treatment relieved insulin resistance. But how it worked remained a mystery.

In the current work, the team investigated the mechanisms behind these phenomena and how they were linked. First, they showed that FGF1 suppresses lipolysis, as insulin does. Then they showed that FGF1 regulates the production of glucose in the liver, as insulin does. These similarities led the group to wonder if FGF1 and insulin use the same signaling (communication) pathways to regulate blood glucose.

It was already known that insulin suppresses lipolysis through PDE3B, an enzyme that initiates a signaling pathway, so the team tested a full array of similar enzymes, with PDE3B at the top of their list. They were surprised to find that FGF1 uses a different pathway — PDE4.

“This mechanism is basically a second loop, with all the advantages of a parallel pathway. In insulin resistance, insulin signaling is impaired. However, with a different signaling cascade, if one is not working, the other can. That way you still have the control of lipolysis and blood glucose regulation,” says first author Gencer Sancar, a postdoctoral researcher in the Evans lab.

Finding the PDE4 pathway opens new opportunities for drug discovery and basic research focused on high blood glucose (hyperglycemia) and insulin resistance. The scientists are eager to investigate the possibility of modifying FGF1 to improve PDE4 activity. Another route is targeting multiple points in the signaling pathway before PDE4 is activated.

“The unique ability of FGF1 to induce sustained glucose lowering in insulin-resistant diabetic mice is a promising therapeutic route for diabetic patients. We hope that understanding this pathway will lead to better treatments for diabetic patients,” says co-senior author Michael Downes, a senior staff scientist in the Evans lab. “Now that we’ve got a new pathway, we can figure out its role in energy homeostasis in the body and how to manipulate it.”

Other authors included Sihao Liu, Emanuel Gasser, Jacqueline G. Alvarez, Christopher Moutos, Kyeongkyu Kim, Yuhao Wang, Timothy F. Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett Collins, Emma Tilley, Matthew J. Kolar, Ruth T. Yu, Annette R. Atkins and Alan Saghatelian of Salk; Tim van Zutphen, Theo H. van Dijk and Johan W. Jonker of the University of Groningen, in the Netherlands.

The research was supported by the National Institutes of Health, the Nomis Foundation, the March of Dimes, Deutsche Forschungsgemeinschaft (DFG), Netherlands Organization for Scientific Research, the European Foundation for the Study of Diabetes and the Swiss National Science Foundation.

“The nanoparticle we developed is a powerful new delivery system for genome editing in vascular endothelial cells, and could be used to treat many diseases, including acute respiratory distress syndrome from severe COVID-19,” said senior author Dr. Zhao from Lurie Children’s. “With this nanoparticle we can introduce genes to inhibit vascular injury and/or promote vascular repair, correct gene mutations and turn genes on or off to restore normal function. It also allows us to edit multiple genes at the same time. This is an important advance for treating any disease caused by endothelial dysfunction.”

Endothelial dysfunction is at the root of many diseases, such as coronary artery disease, stroke, bronchopulmonary dysplasia and pulmonary artery hypertension. Dr. Zhao explained that genome editing in endothelial cells could even treat cancers by cutting off the blood supply to the tumor or blocking cancer metastasis.

At this stage, Dr. Zhao and colleagues achieved excellent results in a mouse model. The nanoparticle carrying CRISPR/Cas9 plasmid DNA was introduced via a one-time IV injection and required a few days to be effective. Preclinical testing will be necessary before clinical trials can begin.

“Our nanoparticle delivery system for genome editing and transgene expression also is a huge advance for cardiovascular research,” added Dr. Zhao.

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Materials provided by Ann & Robert H. Lurie Children’s Hospital of Chicago. Note: Content may be edited for style and length.

The field of self-repairing materials is rapidly expanding, and what used to be science fiction might soon become reality, thanks to Technion — Israel Institute of Technology scientists who developed eco-friendly nanocrystal semiconductors capable of self-healing. Their findings, recently published in Advanced Functional Materials, describe the process, in which a group of materials called double perovskites display self-healing properties after being damaged by the radiation of an electron beam. The perovskites, first discovered in 1839, have recently garnered scientists’ attention due to unique electro-optical characteristics that make them highly efficient in energy conversion, despite inexpensive production. A special effort has been put into the use of lead-based perovskites in highly efficient solar cells.

The Technion research group of Professor Yehonadav Bekenstein from the Faculty of Material Sciences and Engineering and the Solid-State Institute at the Technion is searching for green alternatives to the toxic lead and engineering lead-free perovskites. The team specializes in the synthesis of nano-scale crystals of new materials. By controlling the crystals’ composition, shape, and size, they change the material’s physical properties.

Nanocrystals are the smallest material particles that remain naturally stable. Their size makes certain properties more pronounced and enables research approaches that would be impossible on larger crystals, such as imaging using electron microscopy to see how atoms in the materials move. This was, in fact, the method that enabled the discovery of self-repair in the lead-free perovskites.

The perovskite nanoparticles were produced in Prof. Bekenstein’s lab using a short, simple process that involves heating the material to 100°C for a few minutes. When Ph.D. students Sasha Khalfin and Noam Veber examined the particles using a transmission electron microscope, they discovered the exciting phenomenon. The high voltage electron beam used by this type of microscope caused faults and holes in the nanocrystals. The researchers were then able to explore how these holes interact with the material surrounding them and move and transform within it.

They saw that the holes moved freely within the nanocrystal, but avoided its edges. The researchers developed a code that analyzed dozens of videos made using the electron microscope to understand the movement dynamics within the crystal. They found that holes formed on the surface of the nanoparticles, and then moved to energetically stable areas inside. The reason for the holes’ movement inwards was hypothesized to be organic molecules coating the nanocrystals’ surface. Once these organic molecules were removed, the group discovered the crystal spontaneously ejected the holes to the surface and out, returning to its original pristine structure — in other words, the crustal repaired itself.

This discovery is an important step towards understanding the processes that enable perovskite nanoparticles to heal themselves, and paves the way to their incorporation in solar panels and other electronic devices.

Prof. Yehonadav Bekenstein completed his degrees in Physics and Chemistry at the Hebrew University of Jerusalem. Following a postdoctoral fellowship at the University of California, Berkeley, he joined the Technion faculty in 2018. He has received multiple awards, including the Käte and Franz Wiener Prize (Excellent PhD Thesis Award), the Rothschild Fellowship for postdoctoral scholars, and the Alon Scholarship for the Integration of Outstanding Faculty. In 2020 he was awarded the ERC Starting Grant for early-career scientists.

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Materials provided by Technion-Israel Institute of Technology. Note: Content may be edited for style and length.