Edited by Jeffrey E. Pessin Patients with fatty liver diseases present altered mitochondrial morphology and impaired metabolic function. Mitochondrial dynamics and related cell function require the uncleaved form of the dynamin-like GTPase OPA1. Stabilization of OPA1 might then confer a protective mechanism against stress-induced tissue damages. To study the putative role of hepatic mitochondrial morphology in a sick liver, we expressed a cleavage-resistant long form of OPA1 (L-OPA1⌬) in the liver of a mouse model with mitochondrial liver dysfunction (i.e. the hepatocyte-specific prohibitin-2 knockout (Hep-Phb2 ؊/؊) mice). Liver prohibitin-2 deficiency caused excessive proteolytic cleav-ageofL-OPA1,mitochondrialfragmentation,andincreasedapoptosis. These molecular alterations were associated with lipid accumulation, abolished gluconeogenesis, and extensive liver damage. Such liver dysfunction was associated with severe hypoglycemia. In prohibitin-2 knockout mice, expression of L-OPA1⌬ by in vivo adenovirus delivery restored the morphology but not the function of mitochondria in hepatocytes. In prohibitin-competent mice, elongation of liver mitochondria by expression of L-OPA1⌬ resulted in excessive glucose production associated with increased mitochondrial respiration. In conclusion, mitochondrial dynamics participates in the control of hepatic glucose production. This work was supported by Swiss National Science Foundation Sinergia Grants CRSII3_147637 (to P. M. and J.-C. M.) and 310030_172862 (to M. F.) and by a fellowship from the Fundación Alfonso Martín Escudero (to C. J. S). The authors declare that they have no conflicts of interest with the contents of this article. This article was selected as one of our Editors' Picks. This article contains Tables S1 and S2 and Figs. S1-S8.

Glucose, the main energy substrate used in the CNS, is continuously supplied by the periphery. Glutamate, the major excitatory neurotransmitter, is foreseen as a complementary energy contributor in the brain. In particular, astrocytes actively take up glutamate and may use it through oxidative glutamate dehydrogenase (GDH) activity. Here, we investigated the significance of glutamate as energy substrate for the brain. Upon glutamate exposure, astrocytes generated ATP in a GDH-dependent way. The observed lack of glutamate oxidation in brain-specific GDH null CnsGlud1(-/-) mice resulted in a central energy-deprivation state with increased ADP/ATP ratios and phospho-AMPK in the hypothalamus. This induced changes in the autonomous nervous system balance, with increased sympathetic activity promoting hepatic glucose production and mobilization of substrates reshaping peripheral energy stores. Our data reveal the importance of glutamate as necessary energy substrate for the brain and the role of central GDH in the regulation of whole-body energy homeostasis.

Identification of pre-diabetic individuals with decreased functional ß-cell mass is essential for the prevention of diabetes. However, in vivo detection of early asymptomatic ß-cell defect remains unsuccessful. Metabolomics emerged as a powerful tool in providing read-outs of early disease states before clinical manifestation. We aimed at identifying novel plasma biomarkers for loss of functional ß-cell mass in the asymptomatic pre-diabetic stage. Non-targeted and targeted metabolomics were applied on both lean ß-Phb2 -/mice (ß-cell-specific prohibitin-2 knockout) and obese db/db mice (leptin receptor mutant), two distinct mouse models requiring neither chemical nor diet treatments to induce spontaneous decline of functional ß-cell mass promoting progressive diabetes development.Non-targeted metabolomics on ß-Phb2 -/mice identified 48 and 82 significantly affected metabolites in liver and plasma, respectively. Machine learning analysis pointed to deoxyhexose sugars consistently reduced at the asymptomatic pre-diabetic stage, including in db/db mice, showing strong correlation with the gradual loss of ß-cells. Further targeted metabolomics by GC-MS uncovered the identity of the deoxyhexose with 1,5-anhydroglucitol displaying the most significant changes. In conclusion, this study identified 1,5-anhydroglucitol associated with the loss of functional ß-cell mass and uncovered metabolic similarities between liver and plasma, providing insights into the systemic effects caused by early decline in ß-cells.

Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate and ammonia, thus bridging amino acid-to-glucose pathways. Here we generated inducible liver-specific GDH-knockout mice (Hep ) to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in Hep mice characterized by increased circulating ammonia associated with reduced detoxification process into urea. The abrogation of hepatic GDH also modified energy homeostasis. In the fasting state, Hep mice could barely produce glucose in response to alanine due to impaired liver gluconeogenesis. Compared with control mice, lipid consumption in Hep mice was favored over carbohydrates as a compensatory energy fuel. The changes in energy partitioning induced by the lack of liver GDH modified the circadian rhythm of food intake. Overall, this study demonstrates the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis.

a b s t r a c tUnderstanding the interactions between miRNAs and genes they regulate during the acute phase response is crucial to our understanding of inflammatory diseases and processes. Inducing the acute phase response in hepatocytes by stimulating them with interleukin-6 [1] and then examining global changes in mRNA and miRNA expression can provide insight into the timing and dynamics of these interactions. Here we provide additional data for our study, Ref. [2]. In this data, we identify and validate IL-6-induced changes in gene expression [3][4][5][6] and their functional relationships over time and between cell types by gene ontology [7,8]. We also provide data showing the enrichment of miRNA binding motifs in the 3'UTRs of differentially expressed genes [9], and their predicted gene targets derived from our RNA-seq data [10].