Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While the effects of various signaling pathways on gluconeogenesis are well established, the downstream signaling events repressing gluconeogenic gene expression are not as well understood. The cell-cycle regulator cyclin D1 is expressed in the liver, despite the liver being a quiescent tissue. The most well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 (CDK4), promoting progression of the cell cycle. We show here a novel role for cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) gene expression. In mice, fasting decreases liver cyclin D1 expression, while refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the gluconeogenic gene expression, whereas cyclin D1–mediated activation of CDK4 represses the gluconeogenic gene-expression program in vitro and in vivo. Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part via inhibition of peroxisome proliferator–activated receptor γ coactivator-1α (PGC1α) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1α is novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 on metabolism via PGC1α and reveal a potential link between cell-cycle regulation and metabolic control of glucose homeostasis.

BackgroundHox genes encode master regulators of regional fate specification during early metazoan development. Much is known about the initiation and regulation of Hox gene expression in Drosophila and vertebrates, but less is known in the non-arthropod invertebrate model system, C. elegans. The C. elegans Hox gene lin-39 is required for correct fate specification in the midbody region, including the Vulval Precursor Cells (VPCs). To better understand lin-39 regulation and function, we aimed to identify transcription factors necessary for lin-39 expression in the VPCs, and in particular sought factors that initiate lin-39 expression in the embryo.ResultsWe used the yeast one-hybrid (Y1H) method to screen for factors that bound to 13 fragments from the lin-39 region: twelve fragments contained sequences conserved between C. elegans and two other nematode species, while one fragment was known to drive reporter gene expression in the early embryo in cells that generate the VPCs. Sixteen transcription factors that bind to eight lin-39 genomic fragments were identified in yeast, and we characterized several factors by verifying their physical interactions in vitro, and showing that reduction of their function leads to alterations in lin-39 levels and lin-39::GFP reporter expression in vivo. Three factors, the orphan nuclear hormone receptor NHR-43, the hypodermal fate regulator LIN-26, and the GATA factor ELT-6 positively regulate lin-39 expression in the embryonic precursors to the VPCs. In particular, ELT-6 interacts with an enhancer that drives GFP expression in the early embryo, and the ELT-6 site we identified is necessary for proper embryonic expression. These three factors, along with the factors ZTF-17, BED-3 and TBX-9, also positively regulate lin-39 expression in the larval VPCs.ConclusionsThese results significantly expand the number of factors known to directly bind and regulate lin-39 expression, identify the first factors required for lin-39 expression in the embryo, and hint at a positive feedback mechanism involving GATA factors that maintains lin-39 expression in the vulval lineage. This work indicates that, as in other organisms, the regulation of Hox gene expression in C. elegans is complicated, redundant and robust.

This study tried to propose an innovated idea of solidifying the resolution of gamma camera in routine quality control and recommended a quantified index as minimum detectable difference (MDD) of gamma camera SPECT images using the Taguchi analysis and an indigenous V-shaped slit gauge. The gauge was customized to fulfill the quantitative requirement of the Taguchi analysis. The MDD among slit gauge of derived SPECT image was calculated from two overlapped peak profiles collected from a tangent slice of the V-shaped slit gauge with two nearby peaks. In particular, MDD was evaluated as minimum distance between two peak centers through the Student’s t-test with a constant, 1.96, which indicates that two peak centers separated distant enough to create a 95% confidence level of separation. Eighteen combinations of six gamma camera scanned factors were organized according to Taguchi analysis. Accordingly, (A) collimator, (B) detector to targe distance, (C) total counts, (D) acquired energy width, (E) Matrix size, and (F) zoom of collected ROI with each of two or three levels were organized into 18 groups to collect the slit gauge images according to Taguchi L18 orthogonal array. Then, three well-trained radiologists were ranked the scanned gauge images to derive the fish-bone-plot of signal-to-noise ratio (S/N, dB) and correlated ANOVA. Furthermore, the quantified MDD was proposed to verify the optimal suggestion of gamma camera scanned protocol, and obtained the MDD as 8.4, 7.9, and 7.1 mm for the second group of original L18 preset, conventional, and the optimal preset, respectively. Thus, the optimal preset of gamma camera was achieved in this study. The MDD proved to be a successful index in quantifying the imaging resolution of a gamma camera.