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This review provides a summary of currently available pharmaceutical therapies for the treatment of obesity, along with an overview of the pipeline of products currently in development, and the key mechanisms on which the major development candidates are based. In particular, the recent increase in understanding of the role of gut peptides in energy homeostasis is highlighted as a promising source of potential future obesity therapies.

The N-terminal 15 amino acids of the major protein associated with inorganic pyrophosphatase activity in Bacillus subtilis WB600 are identical to those of B. subtilis ORF yybQ. This ORF was amplified from B. subtilis WB600 DNA by PCR and cloned into an overexpression vector in Escherichia coli. Induction of overexpression produced a soluble protein of 34000 Da by SDS-PAGE and by matrix-assisted laser desorption and ionization mass spectrometry. The overexpressed protein had a high specific activity for the hydrolysis of magnesium pyrophosphate, and was specifically and reversibly activated by Mn2+ ions. These properties are identical to those of inorganic pyrophosphatase purified from B. subtilis WB600. No significant similarity was found between the derived sequence of the B. subtilis yybQ-encoded protein and published sequences of identified inorganic pyrophosphatases of Eukarya, Bacteria or Archaea domains. However, there is significant similarity to three putative proteins of unknown function from the archaea Methanococcus jannaschii and Archaeoglobus fulgidus, and from Streptococcus gordonii. The genomes of B. subtilis, M. jannaschii and A. fulgidus do not contain sequences similar to those of hitherto known soluble inorganic pyrophosphatases. The present findings, together with a survey of the properties of inorganic pyrophosphatases from 38 different sources, suggest that the B. subtilis yybQ-encoded protein is the first fully characterized member of a new class of inorganic pyrophosphatase.

Food intake and bodyweight are tightly regulated by the brainstem, hypothalamus and reward circuits. These centres integrate diverse cognitive inputs with humoral and neuronal signals of nutritional status. Our knowledge of the role of gut hormones in this complex homeostatic system has expanded enormously in recent years. This review discusses both the role of gut hormones in appetite regulation, and the current state of development of gut hormone-based obesity therapies, with a particular focus on pancreatic polypeptide, peptide YY, amylin, glucagon-like peptide-1, oxyntomodulin, cholecystokinin and ghrelin. Several gut hormone-based treatments for obesity are under investigation in phase II and III clinical trials, and many more are in the pipeline.

KorB protein (358 amino acids) binds to 12 highly conserved sequences on the RK2 genome and co-ordinates the expression of at least five operons encoding genes for stable inheritance and plasmid transfer. KorB represses the trfA, korA and klaA promoters where it binds 4 bp upstream of the -35 region (class I KorB operators, OB). We show here that KorB on its own can also repress the trbA, trbB, kfrA and kleA promoters where OB is between 80 and 189 bp away from the transcription start point (class II operator). A C-terminal deletion of 17 amino acids resulted in the loss of KorB's ability to repress through class II operator but not through class I operator. This deletion reduced multimerization of His6-tailed KorB protein in vitro and greatly reduced binding specificity for fragments containing OB sequences. At the trbBp region, where OB9 lies 189 bp upstream of the transcription start point, mutagenesis of a proposed secondary binding site overlapping the trbBp -35 region had no effect on the ability of KorB to repress trbBp. Nevertheless, gel retardation analysis showed that KorB binding is promoted by sequences upstream and downstream of OB9 and that KorB can form higher order complexes on DNA. However, DNase I footprinting suggested that RNA polymerase may interact directly with KorB bound at OB9 and implied that contacts between these proteins could be responsible for the action of KorB at a distance.