Obesity and Diabetes: FGF1 Goes Long to Tackle Diabetes

RESEARCH HIGHLIGHTS

OBESITY AND DIABETES FGF1 goes long to tackle diabetes

Research published in Nature has FGF1 is a mitogenic signalling Importantly, chronic treatment found that subcutaneous delivery molecule that is regulated by PPARγ. with rFGF1 did not impair bone parenteral of fibroblast growth factor 1 (FGF1) Normally, it acts locally in an density or structure — problems confers novel insulin-sensitizing autocrine and paracrine fashion as that have been associated with the administration properties to this molecule in it rapidly binds to heparan sulphate endocrine FGF21 — and did not of rFGF1 diabetic mice while avoiding many proteoglycans in the extracellular cause weight gain or liver steatosis. could be a of the side effects associated with matrix. Several lines of evidence have To address the concern that the mito- novel diabetic current antidiabetic drugs. suggested a role for the FGF family genicity of FGF1 could give rise to Thiazolidinediones are highly of proteins in glucose homeostasis, adverse effects, Suh et al. developed therapy effective agents for improving insulin including the observation of insulin an FGF1 ligand that lacked the first sensitivity in patients with type 2 resistance in FGF1-knockout mice 24 residues from the amino terminus. diabetes, and act by switching on stressed by a high-fat diet. In the In vitro, this compound showed the nuclear receptor peroxisome current study, Suh et al. set out to significantly decreased mitogenic proliferator-activated receptor-γ determine whether enabling FGF1 activity compared with full-length (PPARγ), which regulates gene net- to signal in an endocrine fashion — FGF1, but retained the glucose- works involved in lipid and glucose by administering it parenterally lowering effect in mouse models. handling. The use of these drugs is — could be beneficial for treating This work suggests that the growth- limited, however, by serious adverse diabetes. inducing effect of FGF1 can be disso- effects including bone loss and liver The researchers subcutaneously ciated from its antidiabetic action. steatosis (‘fatty liver’). injected recombinant murine FGF1 can signal through all FGF1 (rFGF1) into genetic and alternatively spliced forms of FGF diet-induced obese mouse models receptors (FGFRs), but which sub- of diabetes, and observed rapid type is responsible for the glucose- glucose lowering that was sustained lowering effects of rFGF1? Previous for 48 hours. Even at the highest work highlighted FGFR1 as having a dose (2 mg per kg), hypoglycaemia role in regulating insulin sensitivity. was not induced, supporting the Indeed, in the current study, trans- potential safety of this approach. genic mice lacking Fgfr1 predomi- Piccillo Photography/Alamy Moreover, compared with vehicle- nantly in adipose tissue did not show treated diabetic mice, chronic the glucose-lowering response to (35-day) treatment with rFGF1 rFGF1, thus confirming the identity significantly improved performance of the key underlying receptor. in a glucose tolerance test and an Together, the findings illustrate insulin tolerance test. Such changes a novel side to FGF1 signalling that were associated with decreased could provide substantial and long- circulating levels of inflammatory lasting sensitization to insulin for cytokines, as well as increased the treatment of diabetes. hepatic and peripheral insulin Katie Kingwell

sensitivity. Taken together, the ORIGINAL RESEARCH PAPER Suh, J. M. et al. results suggest that parenteral Endocrinization of FGF1 produces a neomorphic administration of rFGF1 could and potent insulin sensitizer. Nature http://dx.doi. org/10.1038/nature13540 (2014) be a novel diabetic therapy.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | SEPTEMBER 2014