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preferentially expressed in tissues related with metabolic functions, such as liver (7) and pancreas (J.X., S. Sheila, unpublished data).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

Nuclear migration and positioning within cells are critical for many developmental processes and are governed by the cytoskeletal network. Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain. Analysis of Caenorhabditis elegans mutants has implicated UNC-84 in actin-mediated nuclear positioning by regulating NE anchoring of a giant actin-binding protein, ANC-1. Here, we report the identification of SUN1 as a lamin A-binding protein in a yeast two-hybrid screen. We demonstrate that SUN1 is an integral membrane protein located at the inner nuclear membrane. While the N-terminal domain of SUN1 is responsible for detergent-resistant association with the nuclear lamina and lamin A binding, lamin A/C expression is not required for SUN1 NE localization. Furthermore, SUN1 does not interact with type B lamins, suggesting that NE localization is ensured by binding to an additional nuclear component(s), most likely chromatin. Importantly, we find that the luminal C-terminal domain of SUN1 interacts with the mammalian ANC-1 homologs nesprins 1 and 2 via their conserved KASH domain. Our data provide evidence of a physical nuclear-cytoskeletal connection that is likely to be a key mechanism in nuclearcytoplasmic communication and regulation of nuclear position.The nuclear envelope (NE) is a double-membrane structure that separates chromatin from the cytoplasm, thereby allowing regulation of DNA replication and gene expression in eukaryotic cells. Nuclear pore complexes span the double membrane and regulate the passage of molecules between the cytoplasm and the nucleus (16). The outer nuclear membrane (ONM) is contiguous with, and biochemically similar to, the endoplasmic reticulum (ER). In contrast, the inner nuclear membrane (INM) contains a unique set of integral membrane proteins. Both nuclear pore complexes and INM proteins are anchored by association with the nuclear lamina, a network of lamin intermediate filaments that underlies the INM. The lamina, together with the associated INM proteins, provides structural support for the NE and sites for attachment of chromatin to the nuclear periphery (reviewed in reference 11).Most mammalian cells express two classes of lamin protein, types A and B (reviewed in reference 26). A-type lamins, the major isoforms of which are lamins A and C, are alternative splice products of the LMNA gene (8, 23). B-type lamins are mainly composed of lamins B1 and B2, which are encoded by separate genes (LMNB1 and LMNB2, respectively). A-and B-type lamins differ in their patterns of expression. While type B lamins are found in all nucleated somatic cells, type A lamins are absent in early embryos, their expression correlating with terminal differentiation (33). This has led to the suggestion that A-type lamins, although not essential for individual cell survival, are involved in determining differentiation patterns, possibly through effects on c...

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The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.