” Finding a 2nd hormonal agent that suppresses lipolysis and decreases glucose is a clinical advancement,” states co-senior author and Professor Ronald Evans, holder of the March of Dimes Chair in Developmental and molecular Biology. “We have identified a new player in regulating fat lipolysis that will assist us understand how energy stores are handled in the body.”
Insulin normally shuttles these nutrients to cells in muscles and fat tissue, where they are either used immediately or saved for later use. In people with insulin resistance, glucose is not effectively eliminated from the blood, and higher lipolysis increases the fatty acid levels.
From left: Emma Tilley, Kyeongkyu Kim, Ruth T. Yu, Gencer Sancar, Ronald M Evans, Annette R. Atkins and Michael Downes. Credit: Salk Institute
Previously, the lab revealed that injecting FGF1 dramatically decreased blood sugar in mice which chronic FGF1 treatment relieved insulin resistance. But how it worked remained a mystery.
In the present work, the team examined the systems behind these phenomena and how they were linked. Initially, they showed that FGF1 suppresses lipolysis, as insulin does. Then they revealed that FGF1 regulates the production of glucose in the liver, as insulin does. These similarities led the group to question if FGF1 and insulin utilize the exact same signaling (interaction) pathways to control blood glucose.
It was already understood that insulin reduces lipolysis through PDE3B, an enzyme that starts a signaling pathway, so the group evaluated a complete variety of comparable enzymes, with PDE3B at the top of their list. They were shocked to find that FGF1 utilizes a various pathway– PDE4.
In insulin resistance, insulin signaling is impaired. That method you still have the control of lipolysis and blood glucose regulation,” says initially author Gencer Sancar, a postdoctoral scientist in the Evans lab.
Finding the PDE4 pathway opens new chances for drug discovery and standard research study focused on high blood glucose (hyperglycemia) and insulin resistance. The researchers are eager to investigate the possibility of modifying FGF1 to improve PDE4 activity. Another path is targeting numerous points in the signaling path before PDE4 is triggered.
” The distinct capability of FGF1 to induce continual glucose lowering in insulin-resistant diabetic mice is an appealing restorative route for diabetic clients. We hope that comprehending this pathway will result in better treatments for diabetic patients,” says co-senior author Michael Downes, a senior staff researcher in the Evans lab. “Now that weve got a brand-new path, we can find out its role in energy homeostasis in the body and how to manipulate it.”
Referral: “FGF1 and insulin control lipolysis by convergent pathways” by Gencer Sancar, Sihao Liu, Emanuel Gasser, Jacqueline G. Alvarez, Christopher Moutos, Kyeongkyu Kim, Tim van Zutphen, Yuhao Wang, Timothy F. Huddy, Brittany Ross, Yang Dai, David Zepeda, Brett Collins, Emma Tilley, Matthew J. Kolar, Ruth T. Yu, Annette R. Atkins, Theo H. van Dijk, Alan Saghatelian, Johan W. Jonker, Michael Downes and Ronald M. Evans, 4 January 2022, Cell Metabolism.DOI: 10.1016/ j.cmet.2021.12.004.
Other authors consisted of 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.
Like insulin, FGF1 controls blood glucose by inhibiting lipolysis, however the two hormones do so in different ways. Importantly, this difference could enable FGF1 to be used to safely and effectively lower blood glucose in people who suffer from insulin resistance.
They showed that FGF1 controls the production of glucose in the liver, as insulin does. These similarities led the group to question if FGF1 and insulin utilize the same signaling (interaction) pathways to control blood glucose.
In insulin resistance, insulin signaling is impaired.
Insulin and FGF1 both control blood glucose levels using independent paths. Credit: Salk Institute
New molecular pathway controls blood sugar, circumventing insulin resistance.
The discovery of insulin 100 years ago opened a door that would cause life and wish for countless people with diabetes. Since then, insulin, produced in the pancreas, has been considered the main methods of treating conditions identified by high blood glucose (glucose), such as diabetes. Now, Salk researchers have actually discovered a 2nd molecule, produced in fat tissue, that, like insulin, likewise potently and quickly regulates blood sugar. Their finding could lead to the advancement of brand-new treatments for dealing with diabetes, and likewise lays the structure for promising brand-new avenues in metabolic process research.
The research study, which was published in Cell Metabolism on January 4, 2022, reveals that a hormonal agent called FGF1 manages blood sugar by hindering fat breakdown (lipolysis). Like insulin, FGF1 controls blood sugar by inhibiting lipolysis, however the two hormones do so in different methods. Notably, this difference could make it possible for FGF1 to be utilized to safely and successfully lower blood glucose in individuals who struggle with insulin resistance.
