The discovery of insulin 100 years ago opened a door that would lead to life and hope for millions of people with diabetes. Ever since then, insulin, produced in the pancreas, has been considered the primary means of treating conditions characterized by high blood sugar (glucose), such as diabetes.
Now, Salk scientists have discovered a second molecule, produced in fat tissue, that, like insulin, also potently and rapidly regulates blood glucose.
Their finding could lead to the development of new therapies for treating diabetes, and also lays the foundation for promising new avenues in metabolism research.
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.
Fibroblast growth factor 1 (FGF1) is a prototypical FGF that, in addition to its role in biologic functions ranging from brain development to angiogenesis and wound repair, is implicated in the regulation of feeding and glucose homeostasis (Suh et al., 2014; Zakrzewska et al., 2008).
Recently, FGF1 emerged as a potential antidiabetic agent that following a single intracerebroventricular (icv) injection induces remission of diabetic hyperglycemia lasting weeks or months in both mouse (Lepob/ob and LepRdb/db) and rat (Zucker diabetic fatty [ZDF]) models of type 2 diabetes (T2D) (Brown et al., 2019; Scarlett et al., 2016, Scarlett et al., 2019; Tennant et al., 2019).
Since the effect of icv FGF1 administration to normalize diabetic hyperglycemia in a sustained manner is recapitulated by microinjection of a lower dose of FGF1 directly into mediobasal hypothalamus (MBH), this brain area is implicated as a key target for this sustained antidiabetic response (Brown et al., 2019). While recent work points to a role for glia-neuron interactions leading to increased melanocortin signaling (Bentsen et al., 2020), as well as to FGF1-induced changes in MBH extracellular matrix (Alonge et al., 2020), the signal transduction mechanisms by which FGF1 action in the MBH induces sustained remission of diabetic hyperglycemia is unknown.
A key intracellular signaling cascade activated by binding of FGF1 to FGF receptors (FGFRs) is the extracellular-signal-regulated kinase (ERK) pathway, a major signaling cassette of the mitogen-activated protein kinase (MAPK) signal transduction system that communicates signals arising from activation of cell surface receptors to changes of gene expression occurring in the cell nucleus (Raju et al., 2014).
Previous work demonstrates that MAPK/ERK signaling is rapidly induced in the hypothalamus of diabetic mice by FGF19, a member of the endocrine FGF family, and that this ERK activation is required for its transient glucose-lowering action (Marcelin et al., 2014).
Activation of ERK signaling in the MBH has also been documented following icv administration of FGF1 and is associated with robust transcriptional changes related to the ERK pathway in both tanycytes and astrocytes (Bentsen et al., 2020; Brown et al., 2019). However, neither the role played by ERK signaling in these responses nor the extent to which they contribute to the sustained antidiabetic effect of icv FGF1 is known. The current work was undertaken to address these questions.
We report that in diabetic Lepob/ob mice, the sustained antidiabetic effect of icv FGF1 is abolished by pharmacologic blockade of hypothalamic MAPK/ERK signaling (achieved by central administration of the MAPK inhibitor U0126) but only if this blockade lasts for the 24 h duration of FGF1-induced activation of MAPK/ERK signaling in the hypothalamus.
We further report that icv injection of FGF1 R50E, a FGF1 mutant that activates FGFRs and induces transient, but not sustained MAPK/ERK signaling (Mori et al., 2008, Mori et al., 2013) fails to mimic the sustained diabetes remission induced by icv FGF1 administration. We also report transcriptomic evidence pointing to a role for astrocytes (and possibly tanycytes) as primary targets for the hypothalamic response to FGF1.
Collectively, these data indicate that durable induction of hypothalamic MAPK/ERK signaling is required for sustained remission of diabetic hyperglycemia induced by icv FGF1 administration and adds to growing evidence of a role for glia-neuron interaction in this response.
reference link :https://www.cell.com/iscience/fulltext/S2589-0042(21)00912-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004221009123%3Fshowall%3Dtrue
More information: Ronald M Evans, FGF1 and insulin control lipolysis by convergent pathways, Cell Metabolism (2022). DOI: 10.1016/j.cmet.2021.12.004. www.cell.com/cell-metabolism/f … 1550-4131(21)00623-9