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U. Michel, J. W. McMaster, and J. K. Findlay


The regulation of steady-state follistatin mRNA levels by different pituitary hormones and peptide factors was examined in granulosa cell cultures derived from diethylstilboestrol-treated immature rats. Cytosolic RNA from cell cultures was prepared by lysis and equal amounts of RNA from all samples were analysed with a solution—hybridization assay using a 32P-labelled antisense probe corresponding to a part of exon 5 together with a part of the 5′ end of exon 6 of the rat follistatin gene. In addition, a specific 35S-labelled probe for cyclophilin was used as an internal standard.

The results show that 5 μg FSH/1 for 24 to 72 h stimulated steady-state follistatin mRNA levels, reaching levels 18·5-fold higher than controls. LH (0·2-100 μg/l) had only minor effects on follistatin mRNA levels in FSH-primed granulosa cells and prolactin, GH and IGF-I did not show any significant effects. Activin raised basal as well as FSH-stimulated steady-state follistatin mRNA levels up to ten- and twofold above controls respectively, whereas epidermal growth factor was found to inhibit FSH-stimulated follistatin mRNA levels in a dose-dependent manner.

It is concluded that follistatin mRNA levels in granulosa cells are regulated by FSH rather than LH, and that the stimulation by FSH can be inhibited by epidermal growth factor but enhanced by activin. Activin alone was also capable of stimulating follistatin mRNA.

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M Saleh, S Garcia, J E Mercer, and J K Findlay


Seven bovine follistatin (FS) cDNA clones were isolated from a bovine ovarian follicle cDNA library. The predicted amino acid sequences revealed that six of the cDNA clones represented an FS precursor of 344 amino acids which corresponded to a mature FS of 315 amino acids (FS 315), with one cDNA clone containing the entire coding sequence including 180 nucleotides of 5′ untranslated sequence. The predicted amino acid sequence of the seventh cDNA clone, which differed in the 3′ coding sequence, represented a precursor protein of 317 amino acids, corresponding to a mature FS of 288 amino acids (FS 288). This clone encoded an identical amino acid sequence to the other six cDNA clones except that the C terminal of FS 315 was truncated by 27 amino acids. The sequence of bovine FS was found to contain 36 cysteine residues and 2 potential N-linked glycosylation sites. The predicted amino acid sequence of bovine FS has overall sequence homologies of 98% with ovine FS and 97% with human FS.

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Darren S D Martin, Siobhán Leonard, Robert Devine, Clara Redondo, Gemma K Kinsella, Conor J Breen, Victoria McEneaney, Mary F Rooney, Tim S Munsey, Richard K Porter, Asipu Sivaprasadarao, John C Stephens, and John B C Findlay

Metformin is the main drug of choice for treating type 2 diabetes, yet the therapeutic regimens and side effects of the compound are all undesirable and can lead to reduced compliance. The aim of this study was to elucidate the mechanism of action of two novel compounds which improved glucose handling and weight gain in mice on a high-fat diet. Wildtype C57Bl/6 male mice were fed on a high-fat diet and treated with novel, anti-diabetic compounds. Both compounds restored the glucose handling ability of these mice. At a cellular level, these compounds achieve this by inhibiting complex I activity in mitochondria, leading to AMP-activated protein kinase activation and subsequent increased glucose uptake by the cells, as measured in the mouse C2C12 muscle cell line. Based on the inhibition of NADH dehydrogenase (IC50 27µmolL−1), one of these compounds is close to a thousand fold more potent than metformin. There are no indications of off target effects. The compounds have the potential to have a greater anti-diabetic effect at a lower dose than metformin and may represent a new anti-diabetic compound class. The mechanism of action appears not to be as an insulin sensitizer but rather as an insulin substitute.