Explore the headline Cell sub-journal: New breakthroughs in diabetes treatment!

The discovery of insulin 100 years ago opened a door to life and hope for millions of people with diabetes
.

Since then, insulin produced by the pancreas has been considered the mainstay of treatment for diseases characterized by high blood sugar (glucose), such as diabetes
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What is exciting is that recently experts from research institutions such as the Salk Institute for Biological Studies in the United States and the University of Groningen in the Netherlands have surprisingly discovered a second hypoglycemic molecule, which is produced in adipose tissue and, like insulin, also It can effectively and quickly regulate blood sugar
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Their findings could lead to the development of new treatments for diabetes, and also lay the foundation for promising new avenues of metabolic research
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The study, published in the internationally renowned journal Cell Metabolism, showed that a hormone called FGF1 regulates blood sugar by inhibiting the breakdown of fat
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Like insulin, FGF1 controls blood sugar by inhibiting lipolysis, but the two hormones work in different ways
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What's more, this unique difference could allow FGF1 to safely and successfully lower blood sugar in insulin-resistant patients
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 Research results (Source: Cell Metabolism) Previously, the team's researchers found that peripheral administration of FGF1 could rapidly reduce blood glucose levels in a mouse model of diabetes through the mediation of adipose FGF receptor 1, but its mechanism of action was unclear
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In this article, they further explore the mechanisms behind these phenomena and the connections between them
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First, to verify that FGF1-induced glucose reduction is dependent on the expression of FGFR1 in adipose tissue, FGFR1 was selectively knocked out in mature adipocytes (adR1KO mice)
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Findings showed that FGF1 rapidly reduced blood glucose levels in diet-induced obesity (DIO) wild-type (WT) mice, but failed to affect blood glucose in adR1KO mice, further validating their previous findings
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Given the increased insulin levels in adR1KO mice, and the link between hepatic glucose production (HGP) and lipolysis, the researchers hypothesized that FGF1 might influence lipolysis
.

To explore this concept, the researchers initially determined whether lipolysis was disturbed in FGF1 knockout (F1KO) mice
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In vitro lipolysis experiments showed that the lipolysis of gonadal adipose tissue (gWAT) was significantly increased in F1KO mice
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In addition, FGF1 significantly inhibited basal and isoproterenol (ISO)-induced lipolytic responses of mouse and adipocyte-derived human stromal vascular fraction (SVF), consistent with adipocyte intrinsic effects
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Similarly, FGF1 inhibited ISO-induced lipolysis in 3T3-L1 adipocytes in a dose-dependent manner, which was blocked by FGFR1 inhibition
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To determine whether exogenous FGF1 could similarly affect lipolysis in vivo, the researchers fasted DIO adR1WT and adR1KO mice overnight before FGF1 injection to minimize compensatory changes in insulin
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The findings showed that FGF1 reduced serum free fatty acid levels by approximately 30% in adR1WT mice, but failed to affect adR1KO mice
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Furthermore, FGF1 inhibits lipolysis in vitro in an adipose FGFR1-dependent manner
.

As a measure of in vivo fat breakdown, the researchers injected both FGF1-pretreated adR1WT and adR1KO mice with radiolabeled oleic acid
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Partial turnover of oleic acid was reduced in FGF1-treated adR1WT mice, indicating lower basal lipolysis
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In contrast, oleic acid turnover in adR1KO mice was not affected by FGF1 pretreatment
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The above data suggest that FGF1-FGFR1 signaling is a novel pathway that regulates lipolysis
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 To determine whether inhibition of lipolysis by FGF1 would significantly reduce HGP, the researchers explored the ability of FGF1 to affect gluconeogenesis
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The results showed that ob/ob mice pretreated with FGF1 had a significantly reduced ability to synthesize glucose from pyruvate (pyruvate tolerance test, PTT), whereas glycerol was an exogenous substrate (glycerol tolerance test).
, glycerol TT), no difference was found
.

Furthermore, the ability of FGF1 to inhibit pyruvate utilization depends on adipocyte FGFR1 expression
.

In view of the above differences in the utilization of pyruvate and glycerol, the researchers focused their attention on the downstream of pyruvate
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The researchers measured the levels of gluconeogenesis intermediates in the liver of ob/ob mice by mass spectrometry
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Intermediates downstream of pyruvate, including glucose 6-phosphate (G6P), fructose 6-phosphate (F6P), phosphoglycerate (PG), phosphoenolpyruvate (PEP), and oxaloacetate (OAA) during injection of FGF1 was reduced in mice, whereas the acid cycle (TCA) cycle, a metabolite involved in tricarboxylic acids, was not affected
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In addition, levels of the allosteric activator of pyruvate carboxylase, acetyl-CoA, were decreased
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The reduction of these gluconeogenic substrates was mainly reproduced in adR1WT mice, whereas adR1KO mice were insensitive to treatment with FGF1
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In addition, the fatty FGFR1-dependent reduction of acetyl-CoA was accompanied by an approximately 50% reduction in pyruvate carboxylase activity
.

To explore the relevance of these findings to glucose homeostasis, the researchers performed hyperinsulinemic clamp experiments in ob/ob mice following short-term continuous FGF1 administration (0.
5 mg/kg, every other day, one week)
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The results of the study showed that endogenous glucose production (EGP) was reduced by approximately 25%
.

Under clamp conditions, mice treated with FGF1 required a higher exogenous glucose infusion rate (GIR) to maintain the glucose set point, an effect that was largely attributable to a reduction in EGP due to glucose metabolic clearance ( GDR) unchanged
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The above data suggest that FGF1 inhibits HGP in an adipose FGFR1-dependent manner
.

FGF1 inhibits HGP in an adipose FGFR1-dependent manner (Credit: Cell Metabolism) Insulin inhibits lipolysis through PI3K-dependent activation of PDE3B
.

Since FGFR1 activation can also signal through the PI3K pathway, we investigated whether the antilipolytic effect of FGF1 is affected by the PI3K inhibitor wortmannin
.

The findings showed that, in parallel with the insulin signaling pathway, the inhibitor wortmannin abrogated the FGF1-induced reduction in FFA release in 3T3-L1 adipocytes
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Furthermore, FGF1 attenuated ISO-induced increases in cAMP and cAMP/PKA signaling in a CRE-luciferase-based reporter assay, suggesting a possible effect on phosphodiesterase activity
.

Interestingly, inhibition of PDE3B did not impair FGF1-induced inhibition of lipolysis
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In contrast, the antilipolytic activity of FGF1 was blocked by a selective inhibitor of PDE4 in 3T3-L1 adipocytes as well as in mouse and human SVF-derived adipocytes
.

To further determine whether PDE4 activity is required for FGF1-induced inhibition of lipolysis in vivo, DIO mice were gavaged with a PDE4 inhibitor 1 hour before FGF1 injection
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The findings showed that PDE4 inhibition blocked FGF1's ability to inhibit lipolysis
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Given the above findings, the researchers speculated that FGF1-PDE4 signaling regulates hormone-sensitive lipase (HSL) phosphorylation
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The results showed that the ability of FGF1 to inhibit HSL phosphorylation was lost in the presence of the PDE4 inhibitor roflumilast in both basal and ISO-stimulated cells
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To further monitor the ability of FGF1 to affect pHSL-perilipin interaction in living cells, we used an adeno-associated virus (AAV) vector that binds the human adiponectin promoter/enhancer to express GFP-tagged perilipin (perilipin-GFP) and mCherry-tagged HSL (HSL-mCherry) in 3T3-L1 adipocytes
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The findings showed that FGF1 reduced ISO-induced co-localization of perilipin-GFP and HSL-mCherry, as monitored by temporal fluorescence overlap
.

In the absence of HSL fusion, no effect was seen in cells expressing perilipin-GFP and mCherry
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Furthermore, while selective inhibition of PDE4 or PDE3 increased perilipin-HSL colocalization, consistent with increased cAMP levels and PKA activation, only PDE4 inhibition abolished the FGF1 effect
.

 Building on previous studies linking PDE4D to lipolysis, the researchers next explored whether overexpression of PDE4D was sufficient to recapitulate FGF1's ability to inhibit lipolysis
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The findings showed that overexpression of the three PDE4D isoforms inhibited lipolysis in 3T3-L1 adipocytes in a dose-dependent manner, with the PDE4D3 isoform showing the highest efficacy
.

To continue to deepen their understanding of this finding, the researchers constructed adAAV vectors that restricted PDE4D3 expression in mature adipocytes
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Our results showed that adAAV-PDE4D3-driven expression potently suppressed ISO-induced increases in lipolysis, cAMP and perilipin-GFP/HSL-mCherry co-localization in 3T3-L1 adipocytes
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The above data suggest that FGF1 inhibits the cAMP-PKA pathway by activating PDE4
.

The discovery that FGF1-induced inhibition of lipolysis is dependent on PDE4 raises the possibility that this pathway contributes to glucose homeostasis in insulin-resistant mice
.

To explore this possibility, the researchers treated randomly fed DIO mice with the PDE4 inhibitor roflumilast
.

The findings showed that inhibition of PDE4 transiently increased blood glucose, serum FFA and insulin levels
.

Notably, the ability of FGF1 to lower blood glucose levels was abolished after pretreatment of ad lib-fed mice with roflumilast
.

In contrast, inhibition of PDE3 failed to affect the ability of FGF1 to regulate glucose levels
.

Given the ability of PDE4D to regulate lipolysis in vivo, the researchers further explored the role of this PDE family in the metabolic activity of FGF1
.

Our results showed that fat explants from PDE4DKO mice displayed higher basal and ISO-stimulated lipolysis, whereas PDE4DKO SVF-derived adipocytes were insensitive to FGF1 treatment
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More importantly, FGF1 failed to reduce blood glucose in these HFD-fed PDE4DKO mice, and this defect was restored by adAAV-driven PDE4D3 expression in adipose tissue
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The above data suggest that FGF1-induced lipolysis and glycemic suppression are dependent on PDE4D in vivo
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FGF1-induced lipolysis and blood sugar suppression depend on PDE4D (Source: Cell Metabolism) Next, the researchers demonstrated through a series of experiments that the anti-lipolytic activity of the FGF1/PDE4D pathway requires the specific phosphorylation of PDE4D at S44, thus functioning
.

To confirm the in vivo relevance of this finding, the researchers injected adAAV-GFP, adAAV-PDE4D3, or adAAV-PDE4D3 S44A into ob/ob mice
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The results showed that overexpression of PDE4D3 resulted in lower glucose and serum FFA levels in ad hoc feeding and overnight fasting, as well as a trend towards lower insulin levels in the fed state
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In contrast, overexpression of the S44A mutant failed to affect these metabolic parameters
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Importantly, FGF1 induced a greater reduction in glucose levels in mice overexpressing PDE4D3, whereas the responses of mice expressing the S44A mutant were indistinguishable from those of control mice
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To link endogenous FGF1 signaling to S44 phosphorylation, we collected gWAT pools from chow- and HFD-fed mice under overnight fasting and refeeding conditions
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The results of the study showed that pS44 levels in the re-fed mice nearly doubled
.

Interestingly, HFD significantly reduced S44 phosphorylation in both fasted and fed states, suggesting a role for PDE4D in insulin-resistant hyperlipidemia
.

The above data support a mechanism by which exogenous FGF1 reduces blood glucose levels by inhibiting lipolysis in a PDE4D3-dependent manner, and that this mechanism is related to the physiological response to feeding
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PDE4D3-S44 phosphorylation is required for PDE4D3 metabolism (Credit: Cell Metabolism) In conclusion, we report that FGF1 significantly reduces HGP by inhibiting fat lipolysis
.

Insulin inhibits lipolysis via adipose PDE3B, whereas FGF1 is PDE4D-dependent, allowing the FGF1/PDE4D pathway to remain functional under insulin resistance
.

Finally, they further identified Ser44 as a regulatory site for FGF1-induced PDE4D phosphorylation, regulated by the satiety-fasting cycle
.

"This mechanism is basically a second loop, with all the advantages of a parallel insulin pathway," says author Gencer Sancar
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Insulin signaling is impaired in insulin resistance, however if there are different signaling cascades, if one doesn't work, the other one is okay
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This way you can still control lipolysis and blood sugar regulation
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Michael Downes, co-senior author of the study, said: "The unique ability of FGF1 to induce sustained lowering of blood sugar in insulin-resistant diabetic mice is a promising therapeutic avenue for diabetics
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We hope that understanding this pathway will lead to diabetic patients.
better treatment
.

”End Reference: [1]Sancar G, LiuSH, Gasser E, et al.
FGF1 and insulincontrol lipolysis by convergent pathways [J].
Cell Metabolism 2021, 34,171-183.
DOI: 10.
1016/j.
cmet.
2021.
12.
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