OBJECTIVE—Metformin is an antidiabetic drug commonly used to treat type 2 diabetes. The aim of the study was to determine whether metformin regulates hepatic gluconeogenesis through the orphan nuclear receptor small heterodimer partner (SHP; NR0B2). RESEARCH DESIGN AND METHODS—We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing a constitutive active form of AMP-activated protein kinase (AMPK) (Ad-AMPK) and evaluated SHP, PEPCK, and G6Pase promoter activities via transient transfection assays in hepatocytes. Knockdown of SHP using siRNA SHP was conducted to characterize the metformin-induced inhibition of hepatic gluconeogenic gene expression in hepatocytes, and metformin–and adenovirus SHP (Ad-SHP)–mediated hepatic glucose production was measured in B6-Lepob/ob mice. RESULTS—Hepatic SHP gene expression was induced by metformin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing the dominant negative form of AMPK (Ad-DN-AMPK), as well as by compound C. Metformin inhibited hepatocyte nuclear factor-4α–or FoxA2-mediated promoter activity of PEPCK and G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6-Lepob/ob mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lepob/ob mice. CONCLUSIONS—We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP.

In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis.

Background: BMP2 activates UPR transducers during osteoblast differentiation. Results: BMP2 signaling increased ATF6 expression and cleavage, and activated ATF6 increased OC expression. Conclusion: BMP2 induced osteoblast differentiation through Runx2-dependent ATF6 expression, which directly regulates OC transcription. Significance: BMP2-induced mild ER stress positively regulates osteoblast differentiation via activation of UPR transducers, including ATF6.

ObjectiveTo determine the reliability and validity of hand-held dynamometer (HHD) depending on its fixation in measuring isometric knee extensor strength by comparing the results with an isokinetic dynamometer.MethodsTwenty-seven healthy female volunteers participated in this study. The subjects were tested in seated and supine position using three measurement methods: isometric knee extension by isokinetic dynamometer, non-fixed HHD, and fixed HHD. During the measurement, the knee joints of subjects were fixed at a 35° angle from the extended position. The fixed HHD measurement was conducted with the HHD fixed to distal tibia with a Velcro strap; non-fixed HHD was performed with a hand-held method without Velcro fixation. All the measurements were repeated three times and among them, the maximum values of peak torque were used for the analysis.ResultsThe data from the fixed HHD method showed higher validity than the non-fixed method compared with the results of the isokinetic dynamometer. Pearson correlation coefficients (r) between fixed HHD and isokinetic dynamometer method were statistically significant (supine-right: r=0.806, p<0.05; seating-right: r=0.473, p<0.05; supine-left: r=0.524, p<0.05), whereas Pearson correlation coefficients between non-fixed dynamometer and isokinetic dynamometer methods were not statistically significant, except for the result of the supine position of the left leg (r=0.384, p<0.05). Both fixed and non-fixed HHD methods showed excellent inter-rater reliability. However, the fixed HHD method showed a higher reliability than the non-fixed HHD method by considering the intraclass correlation coefficient (fixed HHD, 0.952-0.984; non-fixed HHD, 0.940-0.963).ConclusionFixation of HHD during measurement in the supine position increases the reliability and validity in measuring the quadriceps strength.

Background:The PAP function of LIPINs is involved in the regulation of intracellular lipid levels and hepatic insulin receptor signaling. Results: ERR␥-mediated induction of LIPIN1 results in the perturbation of hepatic insulin signaling through DAG-mediated activation of PKC⑀. Conclusion: ERR␥ is a novel transcriptional regulator of LIPIN1. Significance: An ERR␥ inverse agonist could ameliorate LIPIN1-mediated perturbation of hepatic insulin signaling.