In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Repression of Mfn2 caused morphological and functional fragmentation of the mitochondrial network into independent clusters. Concomitantly, repression of Mfn2 reduced glucose oxidation, mitochondrial membrane potential, cell respiration, and mitochondrial proton leak. We also show that the Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity by reduced Mfn2 expression. In all, our data indicate that Mfn2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced Mfn2 expression may explain some of the metabolic alterations associated with obesity.

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Mutations in the gene encoding hepatic nuclear factor 1-␣ (HNF1-␣) cause a subtype of human diabetes resulting from selective pancreatic ␤-cell dysfunction. We have analyzed mice lacking HNF1-␣ to study how this protein controls ␤-cell-specific transcription in vivo. We show that HNF1-␣ is essential for the expression of glut2 glucose transporter and L-type pyruvate kinase (pklr) genes in pancreatic insulin-producing cells, whereas in liver, kidney, or duodenum tissue, glut2 and pklr expression is maintained in the absence of HNF1-␣. HNF1-␣ nevertheless occupies the endogenous glut2 and pklr promoters in both pancreatic islet and liver cells. However, it is indispensable for hyperacetylation of histones in glut2 and pklr promoter nucleosomes in pancreatic islets but not in liver cells, where glut2 and pklr chromatin remains hyperacetylated in the absence of HNF1-␣. In contrast, the phenylalanine hydroxylase promoter requires HNF1-␣ for transcriptional activity and localized histone hyperacetylation only in liver tissue. Thus, different HNF1-␣ target genes have distinct requirements for HNF1-␣ in either pancreatic ␤-cells or liver cells. The results indicate that HNF1-␣ occupies target gene promoters in diverse tissues but plays an obligate role in transcriptional activation only in cellularand promoter-specific contexts in which it is required to recruit histone acetylase activity. These findings provide genetic evidence based on a live mammalian system to establish that a single activator can be essential to direct nucleosomal hyperacetylation to transcriptional targets.

To investigate if functional renal failure in cirrhosis could be related to disturbances of vasoactive systems, plasma renin activity, plasma catecholamines and urinary prostaglandin EZ (PGEz) were determined in twenty-two normal subjects and sixty-five cirrhotics. Furthermore, in thirty-three of these subjects, the effect of lysine-acetylsalicylate (450 mg i.v.) on renal function was studied.Patients with ascites without renal failure showed higher renin, noradrenalin and urinary PGEz than normal subjects (5.9f0.8 u. 1-1fO.1 ng ml-' h-I, P