FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.he FGF19 subfamily members, consisting of FGF19, FGF21, and FGF23, are distinctive members of the FGFs. Most of the FGF family members function in paracrine fashion to regulate processes of development, transformation, and angiogenesis. In contrast, the weak affinity toward heparan sulfate of the pericellular space as well as the presence of intramolecular disulfide bonds allows the FGF19 subfamily members to escape from the extracellular compartment into circulation and to function as endocrine hormones (1-3).The subfamily members FGF19 and FGF21 share the ability to regulate glucose, lipid, and energy homeostasis (4-7). Both FGF19-and FGF21-transgenic mice are resistant to diet-induced obesity and have decreased body fat mass and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (7,8). Injection of recombinant FGF19 or FGF21 protein into diabetic mice resulted in the reduction of serum glucose and insulin levels, improved glucose tolerance, and reduced hepatosteatosis and body weight (4-6, 9-11). These effects regarding correction of metabolic imbalances were potent, beneficial, and suggested that FGF19 and FGF21 might be exciting candidates for combating the growing epidemics of diabetes and obesity. Potential unwanted mitogenic activity, however, has been observed in FGF19-transgenic mice, which developed hepatocellular carcinoma within 12 mo and showed increased hepatocyte proliferation as early as 2-4 mo of age (12). The increased hepatocyte proliferation also has been observed in normal mice injected with recombinant FGF19 for 6 d (12); however, such a proliferative effect has not been observed in FGF21-treated animals (13). Therefore, the key distinction between FGF19 and FGF21 is that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects.The interactions between para...
Pharmacological treatment of recombinant growth differentiation factor 15 (GDF15) proteins reduces body weight in obese rodents and primates. Paradoxically, circulating GDF15 levels are increased in obesity. To investigate the role of endogenous GDF15 in obesity development, we put GDF15 knockout mice and wildtype controls on high fat diet for the mice to develop diet-induced obesity. Compared to wildtype animals, GDF15 knockout mice were more prone to high fat diet-induced obesity. Male knockout mice showed worse glucose tolerance, lower locomotor activity and lower metabolic rate than wildtype mice. Additionally, GDF15 deficiency increased occurrences of high fat diet-induced skin lesions. Our data suggests that endogenous GDF15 has a protective role in obesity development and lack of GDF15 aggravates the progression of obesity and associated pathological conditions. Elevated GDF15 levels in obesity may have resulted from a response to overcome GDF15 resistance.
hormone ( 3 ). In lieu of heparan sulfate binding, FGF19 requires a protein cofactor,  Klotho, to effectively interact with and activate FGF receptors ( 4-6 ). The requirement for a co-receptor is a unique feature common to the FGF19 subfamily and is further exemplifi ed by another subfamily member, FGF21, which also lacks heparan sulfate affi nity and uses  Klotho as its co-receptor ( 4 ). Consistent with their shared ability to use the same co-receptor for signaling, there is extensive overlap in the reported pharmacological effects of FGF19 and FGF21. FGF19 and FGF21 transgenic mice, as well as chronic administration of recombinant FGF19 or FGF21 proteins, similarly lowered serum glucose, triglyceride (TG), and cholesterol levels and improved insulin sensitivity and reduced body weight in high-fat diet-induced obesity models ( 7-9 ). Chronic treatment with FGF19 or FGF21 similarly reduced blood glucose levels and improved glucose disposal in ob/ob (B6.V-Lep ob /J) leptin-defi cient mice; however, plasma TG and cholesterol levels after treatment with FGF19 have not been reported in this model ( 8,9 ).The common co-receptor for FGF19 and FGF21,  Klotho, is a single-pass transmembrane protein with two homologous extracellular domains that share sequence homology to  -glucosidases in bacteria and plants ( 10 ).  Klotho has a short intracellular domain and is unlikely to signal by itself. Its primary role is believed to mediate interactions between these two FGF molecules and FGF receptors (FGFR) to activate FGFR tyrosine kinase activity ( 11 ).  Klotho interacts with only four of the seven major FGFRs, the "c" isoforms of FGFR1, -2, -3. and -4 ( 11 ). FGF19 and FGF21 can activate FGFR1c, -2c, and -3c complexed with  Klotho in vitro ( 4, 6, 11-13 ). Recent results using an engineered FGF19 variant with altered receptor specifi city Abstract Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fi broblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specifi cities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.VLep ob /J leptin-defi cient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed signifi cant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising an...
Background:The role of FGFR4 in glucose and energy metabolism is not well defined. Results: FGFR4-deficient mice display improved glucose metabolism and insulin sensitivity under high fat conditions. Conclusion: These improvements are mediated in part by bile acid actions and induction of endocrine hormones. Significance: FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.
Diabetes and associated metabolic conditions have reached pandemic proportions worldwide, and there is a clear unmet medical need for new therapies that are both effective and safe. FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Both have potent effects on normalizing glucose, lipid, and energy homeostasis, and therefore, represent attractive potential next generation therapies for combating the growing epidemics of type 2 diabetes and obesity. The mechanism responsible for these impressive metabolic effects remains unknown. While both FGF19 and FGF21 can activate FGFRs 1c, 2c, and 3c in the presence of co-receptor βKlotho in vitro, which receptor is responsible for the metabolic activities observed in vivo remains unknown. Here we have generated a variant of FGF19, FGF19-7, that has altered receptor specificity with a strong bias toward FGFR1c. We show that FGF19-7 is equally efficacious as wild type FGF19 in regulating glucose, lipid, and energy metabolism in both diet-induced obesity and leptin-deficient mouse models. These results are the first direct demonstration of the central role of the βKlotho/FGFR1c receptor complex in glucose and lipid regulation, and also strongly suggest that activation of this receptor complex alone might be sufficient to achieve all the metabolic functions of endocrine FGF molecules.
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