FGF1-based Drugs for The Treatment of Obesity-related Complications / 生物化学与生物物理进展

ABSTRACT

At present, the incidence of overweight and obesity has reached epidemic levels worldwide, which call a challenge to the prevention and control of chronic metabolic diseases. Because obesity is a major risk factor for a range of metabolic diseases, including type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD), cardiovascular and neurodegenerative diseases, sleep apnea, and some types of cancer. However, the drugs remain limited. Therefore, there is an urgent need to develop effective long-term treatments to address obesity-related complications. Fibroblast growth factor 1 (FGF1) is an important regulator of systemic energy homeostasis, glycolipid metabolism and insulin sensitivity. FGF1 is a non-glycosylated polypeptide consisting of 155 amino acids, consisting of 12 inverted parallel β chains with amino and carboxyl terminus, and N-terminus extending freely without the typical secretory signaling sequence, closely related to its own biological activity. Thus, FGF1 mutants or derivatives with different activities can be designed by substitution or splicing modification at theN-terminal. FGF1 plays an irreplaceable role in the development, deposition and function of fat. High-fat diet can regulate available FGF1 through two independent mechanisms of nutritional perception and mechanical perception, and influence the function of fat cells. FGF1 controls blood glucose through peripheral and central effects, enhances insulin sensitivity, improves insulin resistance, and plays a role in diabetic complications, which is expected to become a new target for the treatment of T2DM in the future. FGF1 may be involved in the regulation of NAFLD from mild steatosis to severe non-alcoholic steatohepatitis. FGF1 is closely related to the occurrence and development of a variety of cancers, improve the efficacy of anti-cancer drugs, and play a direct and indirect anti-cancer role. In addition, FGF1 plays an important role in the occurrence and development of the cardiovascular system and the improvement of cardiovascular diseases such as ischemia/reperfusion injury, myocardial infarction, pathological cardiac remodeling, cardiotoxicity. Therefore, FGF1 shows a number of therapeutic benefits in the treatment of obesity and obesity-related complications. But because FGF1 has strong mitotic activity and long-term use has been associated with an increased risk of tumorigenesis, its use in vivo has been limited and enthusiasm for developing it to treat obesity-related complications has been dampened. However, FGF1 was found to induce cell proliferation primarily through FGFR3 and FGFR4, but its metabolic activity was mainly mediated by FGFR1. That is, FGF1 activity that promotes mitosis and anti-obesity-related complications appears to be separable. Currently, many engineered FGF1 variants have been developed, such as FGF1ΔHBS, MT-FGF1ΔHBS, FGF1∆NT, ∆nFGF1, FGF1R50E. Although the effect of FGF1 or its analogues on obesity-related complications has been demonstrated in many rodent studies, there are no relevant clinical results. This may be due to the unknown safety and therapeutic efficacy of FGF1 in large animals and humans, as well as concerns about tumorigenesis that hinder its development into a lifelong therapeutic agent. This review summarizes recent advances in the development of FGF1-based biologic drugs for the treatment of obesity-related complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these obstacles.