Investigation of signaling cascades and transcriptional regulation associated with FGF1 action in metabolic tissues

• Applicant: Dr. Gencer Sancar, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Biochemistry ; Nephrology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278992880

Sedentary lifestyle and easy access to high-calorie food have increased the prevalence of obesity and associated metabolic disorders over the last few decades. Increased white adipose tissue observed in obese individuals contributes to metabolic abnormalities including insulin resistance and type 2 diabetes mellitus (T2DM). The first line of treatment of obesity and T2DM is life-style changes promoting energy expenditure and decreasing calorie intake. However, changes in life-style alone are not sufficient to yield long-term success without an effective pharmacological intervention. Currently, thiazolidinediones (TZDs) are widely and effectively used to treat T2DM by targeting the nuclear receptor peroxisome proliferator activated receptor gamma (PPARg) to regulate lipid metabolism and mediate insulin sensitization. However, beneficial insulin sensitization effects of TZDs are outweighed by the adverse side effects such as bone fracture, weight gain and congestive heart failure. Consequently, improved insulin sensitizing therapies with detailed molecular understanding and more focused site of action are required. Fibroblast growth factors (FGFs) are signaling proteins that are involved in diverse developmental, metabolic and neural processes. Recently, an unexpected metabolic role of FGF1 on adaptive remodeling of adipose tissue has been described. When challenged with high-fat diet (HFD) fgf1 knock-out mice exhibit diabetic phenotype and abnormal expansion of adipose tissue with signs of inflammation. In a follow-up study, injection of recombinant FGF1 (rFGF1) resulted in insulin-dependent lowering of glucose levels in diabetic mice. rFGF had no effect upon injection to healthy mice with normal glucose and insulin levels. Chronic administration of rFGF1 showed sustained glucose lowering and whole body insulin sensitization without any side effects of weight gain and bone loss. These properties of exogenous FGF1 designate rFGF1 and its derivatives as strong therapeutic candidates for treatment for metabolic disorders. Although it has been shown that blood glucose lowering by rFGF1 is mediated via activation of FGF1 receptor 1 in adipose tissue, downstream signaling cascades and associated transcriptional changes that lead to its beneficial effects have not been investigated. Moreover, potential involvement of other receptors and tissues needs to be addressed for a full understanding of the FGF1 role on insulin sensitization. This project aims to identify the molecular mechanisms underlying FGF1 action on diabetic mouse models. The approach involves spatial and temporal investigation of activated signaling cascades upon rFGF1 injection by phosphoproteomics. In addition, we will explore transcriptional and metabolic changes of potentially involved tissues such as adipose tissues, liver, and muscle by RNAseq and metabolomics, respectively.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Ronald M. Evans