Increased adiposity is a feature of aging in both mice and humans, but the molecular mechanisms underlying age-related changes in adipose tissue stores remain unclear. In previous studies, we noted that 18-month-old normocalcemic vitamin D receptor (VDR) knockout (VDRKO) mice exhibited atrophy of the mammary adipose compartment relative to wild-type (WT) littermates, suggesting a role for VDR in adiposity. Here we monitored body fat depots, food intake, metabolic factors, and gene expression in WT and VDRKO mice on the C57BL6 and CD1 genetic backgrounds. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1alpha-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D(3), the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-gamma or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. Collectively, these studies identify a novel role for 1,25-dihydroxyvitamin D(3) and the VDR in the control of adipocyte metabolism and lipid storage in vivo.

Timely and selective recruitment of transcription factors to their appropriate DNA-binding sites represents a critical step in regulating gene activation; however the regulatory strategies underlying each factor’s effective recruitment to specific promoter and/or enhancer regions are not fully understood. Here, we identify an unexpected regulatory mechanism by which promoter-specific binding, and therefore function, of PPARγ in adipocytes requires G protein Suppressor 2 (GPS2) to prime the local chromatin environment via inhibition of the ubiquitin ligase RNF8 and stabilization of the H3K9 histone demethylase KDM4A/JMJD2. Integration of genome-wide profiling data indicates that the pioneering activity of GPS2/KDM4A is required for PPARγ–mediated regulation of a specific transcriptional program, including the lipolytic enzymes ATGL and HSL. Hence, our findings reveal that GPS2 exerts a biologically important function in adipose tissue lipid mobilization by directly regulating ubiquitin signaling and indirectly modulating chromatin remodeling to prime selected genes for activation.

In humans, uropathogenic Escherichia coli (UPEC) is the most common etiological agent of uncomplicated urinary tract infections (UTIs). Cranberry extracts have been linked to the prevention of UTIs for over a century; however, a mechanistic understanding of the way in which cranberry derivatives prevent bacterial infection is still lacking. In this study, we used a fliC-lux reporter as well as quantitative reverse transcription-PCR to demonstrate that when UPEC strain CFT073 was grown or exposed to dehydrated, crushed cranberries or to purified cranberry-derived proanthocyanidins (cPACs), expression of the flagellin gene (fliC) was inhibited. In agreement with these results, transmission electron microscopy imaging of bacteria grown in the presence of cranberry materials revealed fewer flagella than those in bacteria grown under control conditions. Furthermore, we showed that swimming and swarming motilities were hindered when bacteria were grown in the presence of the cranberry compounds. Because flagellum-mediated motility has been suggested to enable UPEC to disseminate to the upper urinary tract, we propose that inhibition of flagellum-mediated motility might be a key mechanism by which cPACs prevent UTIs. This is the first report to show that cranberry compounds inhibit UPEC motility via downregulation of the fliC gene. Further studies are required to establish whether these inhibitors play a role in vivo.There are more than 150 million cases of urinary tract infection (UTI) in the world every year, with correspondingly significant morbidity and health care costs (12). Uncomplicated UTIs, i.e., infections that occur in healthy, immunocompetent individuals, are caused over 80% of the time by uropathogenic Escherichia coli (UPEC) (44). Among UPEC strains, E. coli CFT073, a strain isolated from the blood and urine of a woman diagnosed with acute pyelonephritis (34), is one of the most prevalent clonal lines (21,22). The majority of UTIs develop in an ascending manner (1, 44) that commences when bacteria inoculate the periurethral area and then the bladder (20,35,46). The bacteria may then ascend to the upper urinary tract and kidneys and establish a secondary infection (44). Once in the kidneys, the bacteria can access the bloodstream, causing bacteremia and (potentially) death (44).The bacterial flagellum is a molecular machine driven by a motor which rotates a long, curved filament (2). This filament extends from the basal body outward and is a polymer of flagellin subunits encoded by the fliC gene (6, 31). Mutations in fliC result in loss of flagellation and motility (31). Flagellummediated motility has been suggested to contribute to virulence by enabling UPEC to disseminate to the urinary tract, to escape host immune responses, and to disperse to new sites within the urinary tract (24). Even though this hypothesis remains to be demonstrated, several groups have shown that fliC mutants are outcompeted by motile, wild-type strains during experimental cochallenge of mice (24,40,45), thereby demonstrating tha...

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