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FGF1: a novel metabolic regulator involved in insulin sensitization and glycemic control

Final Report Summary - FGF1T2D (FGF1: a novel metabolic regulator involved in insulin sensitization and glycemic control)

FGF1: a novel metabolic regulator involved in insulin sensitization and glycemic control

Background:
Type 2 diabetes (T2D) and obesity are leading causes of mortality and are associated with the Western lifestyle, which is characterized by excessive nutrient intake and lack of exercise. T2D is a complex, multisystem disease with a pathophysiology that includes insulin resistance, suppression of glucose disposal by the liver and peripheral tissues, and dysregulated insulin secretion by the pancreatic β-cells. T2DM is the most common form of diabetes, affecting 8.1% (53 million) of the adult population within the EU and has complex etiologies involving both genetic and nutritional factors. The initiation and development of T2DM is strongly linked to a high-fat diet and obesity and involves the nuclear receptor PPARg as a critical component.
Our work to date provides evidence for a novel PPARg-FGF1 endocrine signaling pathway that regulates the diverse metabolic aspects of the adaptive response to a high-fat diet. Basis for this proposal was our recent discovery that administration of FGF1 to diabetic mice has potent and long lasting metabolic effects including lowering of glucose and insulin to the same extent as TZDs (Rosiglitazone). Out of the many (>100) PPARg targets, we have thus identified one single target that can mediate the insulin sensitising effects of TZDs. As FGF1 is situated downstream of PPARg, we speculate that therapeutic targeting of FGF1 might eliminate some of the adverse effects of TZDs that are mediated through direct activation of PPARg.

Aims:
The specific aims of this application were to get insight into:
1. The pharmacological effects of FGF1 on whole body energy metabolism and insulin resistance.
2. The in vivo consequences of genetic gain- and loss-of FGF1 function on whole body energy metabolism and the development of T2DM.

Major findings:
1) We have identified the hormone FGF1 as a critical regulator of adipose tissue remodelling. We have shown that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet (Jonker et al., Nature 2012).

2) We have shown that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. These findings identify FGF1 as a potential therapeutic for the treatment of insulin resistance and type 2 diabetes. (Suh, Jonker et al., Nature 2014)

3) We have shown that a mutant FGF1, lacking the N-terminal region, lacks the potential to induce growth, yet has retained metabolic effects. We thus show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity. (Suh, Jonker et al., Nature 2014)

4) We have shown that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves steatosis, hepatic inflammation and damage in mouse models of NAFLD and that its anti-steatotic effect was through stimulation of hepatic lipid catabolism (Liu et al., 2015).

Socio-economic Impact:
Type 2 diabetes (T2D) and obesity are leading causes of mortality and are associated with the Western life-style, which is characterized by high-fat diet and lack of exercise. T2D affects 8% of the adult population witih the EU and has complex etiologies involving both genetic and nutritional factors. Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But drugs, such as Byetta, which increase the body’s production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycemia, as well as other side effects.
Under normal conditions, metabolic homeostasis is achieved, in part, through the coordinated activities of the Nuclear Hormone Receptor (NR) family, a collection of 49 ligand-modulated transcription factors (TFs) that mediate responses to a wide range of lipophilic signaling molecules including lipids, steroids, retinoids, hormones and xenobiotics. As sensors for these signals, they provide an important link between transcriptional regulation and physiology. Currently, 13% of FDA approved therapeutics target the NR-family, including drugs for the treatment of insulin resistance (TZDs), hyperlipidemia (fibrates), inflammation (dexamethasone) and cancer (tamoxifen). Thus, NRs have become a primary target for drug development aimed at metabolic disease. The nuclear hormone receptor PPARγ is a master regulator of adipogenesis and controls the activation and differentiation of fat cells, fat storage, and the release of insulin sensitizing factors. PPARγ is also the molecular target for the Thiazolidinedione (TZD)-class of insulin sensitizers of which the clinical use has been limited due to a number of serious side effects. Despite intensive effort, relatively few PPARγ gene targets have been identified to date, highlighting the need for new approaches to identify candidate genes in order to better understand the roles of PPARγ in diabetes.
Our work has identified FGF1 as a novel target of PPARγ and revealed an unexpected role for FGF1 as a critical transducer that couples nutrient storage with insulin sensitivity through adipose tissue remodelling (Jonker et al., 2012). We are the first to define a physiological role for FGF1, a hormone which was already discovered over 30 years ago but the function of which was not yet identified. In addition, our finding that FGF1 can be used as a recombinant hormone effectively improving glycemia and insulin resistance, suggest that FGF1 could be therapeutically used in the treatment of type 2 diabetes. Application of FGF1 as recombinant protein in the treatment of wound and fracture healing and cardiovascular diseases has been actively pursued. However, low thermal stability and high sensitivity to proteases has strongly limited the potential pharmaceutical use of FGF1. Based on the limited succes in clinical trials, FGF1 is therefore currently regarded as a “dead” FGF. In this light, our finding that administration of recombinant FGF1 to diabetic mouse models results in acute and prolonged lowering of blood glucose was therefore highly unexpected and has “resurrected” its potential clinical application.