C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no changes in any of the metabolic parameters. These data suggest that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.
OBJECTIVE-Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model. RESEARCH DESIGN AND METHODS-DIOor normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS-FGF21dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.CONCLUSIONS-FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes. Diabetes 58:250-259, 2009 F ibroblast growth factor (FGF) 21 is a member of the FGF superfamily (1). It is most closely related to FGF19 and FGF23, sharing ϳ30 -35% amino acid sequence homology (1). The FGF19 subfamily comprises FGF19, FGF21, and FGF23 (2), and all three FGF19 subfamily members have recently emerged as metabolic hormones involved in the regulation of glucose, lipid, bile acid, and phosphate metabolism (2-6).FGF21 was isolated from a mouse embryo cDNA library and appeared as an atypical FGF preferentially expressed in tissues related with metabolic functions, such as liver (7) and pancreas (J.X., S. Sheila, unpublished data). A biological activity of FGF21 was revealed in a high-throughput assay looking for secreted proteins that stimulate glucose uptake in 3T3-L1 adipocytes (5). Further studies demonstrated that FGF21 increased the expression of GLUT1 and stimulated GLUT1-mediated glucose uptake in differentiated adipocytes (5). When recombinant FGF21 protein was administered to ob/ob and db/db mice and Zucker fatty rats, which are rodent models of diabetes, it lowered blood glucose and triglycerides to near-normal levels (5). In diabetic rhesus monkeys, treatment also resulted in a favorable lipoprotein profile, which included reduced LDL cholesterol and increased HDL cholesterol (8). Furthermore, transgenic mice with hepatic overexpression of FGF21 were lean and protected from high-fat diet-induced insulin resistance (5,9).Recent progress has also been made in elucidating the ...
Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40-60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.
FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/ FGF21 chimeric molecules, we determined that amino acids residues 38 -42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation. FGF19, FGF21, and FGF23 form a unique subfamily of fibroblast growth factors (FGFs).3 Unlike other FGFs, all three have been shown to function as endocrine hormones in the regulation of various metabolic processes (1). FGF23 originates in bone and regulates phosphate homeostasis in kidney (2), FGF21 is expressed predominantly in liver and signals in adipose tissue (3), and FGF19 is secreted from ileum and functions as an enterohepatic signal for the regulation of bile acid metabolism (4).FGF19 and FGF21 have similar effects on regulating glucose, lipid, and energy metabolism. Both FGF19 and FGF21 transgenic mice are resistant to diet-induced obesity, have decreased body fat mass and improved insulin sensitivity, glucose disposal, and plasma lipid parameters (5-8). Administration of recombinant FGF19 or FGF21 protein to diabetic mice resulted in the reduction of serum glucose and insulin levels, improved glucose tolerance, and reduced liver steatosis and body weight (7,8). In addition, FGF21 improved glucose, insulin, and lipid profiles and reduced body weight in diabetic rhesus monkeys (9). Taken together, these observations suggest the potential utility of FGF19 and FGF21 for the treatment of diabetes and obesity (1).Because of the sequence and structural homology between FGF19 and FGF21 with the other FGFs, most of which have well established roles in cell proliferation and mitogenesis, whether FGF19 and FGF21 could induce cell proliferation have also been investigated. In the case of FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (10). In addition, increases in the proliferation of pericentral hepatocytes, as measured by enhanced BrdU labeling, was observed both in FGF19 transgenic animals and wild-type mice administered recombinant FGF19 (10). Because constitutive hepatocellular proliferation may be a prerequisite for transformation (11), it is interesting to note that cell...
Edited by Gianni Cesareni Keywords:Fibroblast growth factor-21 b-Klotho Fibroblast growth factor receptor Partial agonist a b s t r a c t Fibroblast growth factor-21 (FGF21) signaling requires the presence of b-Klotho, a co-receptor with a very short cytoplasmic domain. Here we show that FGF21 binds directly to b-Klotho through its Cterminus. Serial C-terminal truncations of FGF21 weakened or even abrogated its interaction with b-Klotho in a Biacore assay, and led to gradual loss of potency in a luciferase reporter assay but with little effect on maximal response. In contrast, serial N-terminal truncations of FGF21 had no impact on b-Klotho binding. Interestingly, several of them exhibited characteristics of partial agonists with minimal effects on potency. These data demonstrate that the C-terminus of FGF21 is critical for binding to b-Klotho and the N-terminus is critical for fibroblast growth factor receptor (FGFR) activation.
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