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preferentially expressed in tissues related with metabolic functions, such as liver (7) and pancreas (J.X., S. Sheila, unpublished data).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 ...

Acute gastrointestinal infections due to rotaviruses and other enteric pathogens are major causes of morbidity and mortality in infants and young children throughout the world. Breastfeeding can reduce the rate of serious gastroenteritis in infants; however, the degrees of protection offered against rotavirus infection vary in different populations. The mechanisms associated with milk-mediated protection against viral gastroenteritis have not been fully elucidated.We have isolated a macromolecular component of human milk that inhibits the replication of rotaviruses in tissue culture and prevents the development of gastroenteritis in an animal model system. Purification of the component indicates that the antiviral activity is associated with an acidic fraction (pI = 4.0-4.6), which is free of detectable immunoglobulins. Furthermore, high levels of antiviral activity are associated with an affinity-purified complex of human milk mucin. Deglycosylation of the mucin complex results in the loss of antiviral activity. Further purification indicated that rotavirus specifically binds to the milk mucin complex as well as to the 46-kD glycoprotein component ofthe complex. Binding to the 46-kD component was substantially reduced after chemical hydrolysis of sialic acid.We have documented that human milk mucin can bind to rotavirus and inhibit viral replication in vitro and in vivo. Variations in milk mucin glycoproteins may be associated with different levels of protection against infection with gastrointestinal pathogens. (J. Clin. Invest. 1992. 90:1984

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...

Key Points miR-142 is an essential regulator of lymphocyte ontogenesis and is required for the generation of humoral and cellular immunity in mice. miR-142-3p regulates B-cell homeostasis by controlling expression of BAFF-R.

Fibroblast growth factor 21 (FGF21) is a potent metabolic regulator, and pharmacological administration elicits glucose and lipid lowering responses in mammals. To delineate if adipose tissue is the predominant organ responsible for anti-diabetic effects of FGF21, we treated mice with reduced body fat (lipodystrophy mice with adipose specific expression of active sterol regulatory element binding protein 1c; Tg) with recombinant murine FGF21 (rmuFGF21). Unlike wildtype (WT) mice, Tg mice were refractory to the beneficial effects of rmuFGF21 on body weight, adipose mass, plasma insulin and glucose tolerance. To determine if adipose mass was critical for these effects, we transplanted WT white adipose tissue (WAT) into Tg mice and treated the mice with rmuFGF21. After transplantation, FGF21 responsiveness was completely restored in WAT transplanted Tg mice compared to sham Tg mice. Further, leptin treatment alone was sufficient to restore the anti-diabetic effects of rmuFGF21 in Tg mice. Molecular analyses of Tg mice revealed normal adipose expression of Fgfr1, Klb and an 8-fold over-expression of Fgf21. Impaired FGF21-induced signaling indicated that residual adipose tissue of Tg mice was resistant to FGF21, whilst normal FGF21 signaling was observed in Tg livers. Together these data suggest that adipose tissue is required for the triglyceride and glucose, but not the cholesterol lowering efficacy of FGF21, and that leptin and FGF21 exert additive anti-diabetic effects in Tg mice.