No abstract

AIM: This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity. METHOD: Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another. RESULT: Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie d > 0.80; amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs vs placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as an obesity medication. Effects of methodological factors are also presented along with suggestions for future research.

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

No abstract

The adaptation of facultative intracellular bacteria to host macrophages involves regulation of the synthesis of bacterial proteins. We analyzed the protein synthesis of Francisella tularensis LVS growing intracellularly in the macrophage-like murine cell line J774 and extracellularly in culture medium. After pulse-labeling with [ 35 S]methionine and separation by one-and two-dimensional polyacrylamide gel electrophoresis, induction of a few proteins during intracellular growth was demonstrated. One of them, a 23-kDa protein, was prominently induced in the macrophages and also when extracellularly growing F. tularensis was exposed to hydrogen peroxide. After isolation of the 23-kDa protein from a preparative two-dimensional gel, a 22-amino-acid N-terminal peptide and two peptides obtained by trypsin digestion were sequenced. Based on the sequences, degenerate oligonucleotides were constructed for use as primers in a PCR. Hybridization of amplified DNA to XbaI-digested LVS DNA identified the gene of the 23-kDa protein in a 1.3-kb DNA fragment. Nucleotide sequence analysis revealed an open reading frame encoding a putative protein of a calculated molecular mass of 22.2 kDa. The open reading frame was preceded by a sequence typical of ribosome-binding sites in Escherichia coli. The amplified gene was successfully expressed by the pTrc99A vector in E. coli under control of the trc promoter. The gene product showed the same mobility and immunoreactivity as the 23-kDa protein of F. tularensis. The deduced amino acid sequence showed no significant homology with protein sequences in current data banks. Thus, intracellular growth of F. tularensis in macrophages was associated with prominent upregulation of a novel 23-kDa protein.