Objective. Obesity is a potent risk factor in knee osteoarthritis (OA). It has been suggested that adipokines, secreted by adipose tissue (AT) and largely found in the synovial fluid of OA patients, derive in part from the infrapatellar fat pad (IFP), also known as Hoffa's fat pad. The goal of this study was to characterize IFP tissue in obese OA patients and to compare its features with thigh subcutaneous AT to determine whether the IFP contributes to local inflammation in knee OA via production of specific cytokines.Methods. IFP and subcutaneous AT samples were obtained from 11 obese women (body mass index >30 kg/m 2 ) with knee femorotibial OA. Gene expression was measured by real-time quantitative polymerase chain reaction. Cytokine concentrations in plasma and in conditioned media of cultured AT explants were determined by enzyme-linked immunosorbent assay or by Luminex xMAP technology.Results. In IFP tissue versus subcutaneous AT, there was a decrease in the expression of genes for key enzymes implicated in adipocyte lipid metabolism, whereas the expression levels of genes for AT markers remained similar. A 2-fold increase in the expression of the gene for interleukin-6 (IL-6), a 2-fold increase in the release of IL-6, and a 3.6-fold increase in the release of soluble IL-6 receptor (sIL-6R) were observed in IFP samples, compared with subcutaneous AT, but the rates of secretion of other cytokines in IFP samples were similar to the rates in subcutaneous AT. In addition, leptin secretion was decreased by 40%, whereas adiponectin secretion was increased by 70%, in IFP samples versus subcutaneous AT.Conclusion. Our results indicate that the IFP cytokine profile typically found in OA patients could play a role in paracrine inflammation via the local production of IL-6/sIL-6R and that such a profile might contribute to damage in adjacent cartilage.

Cancer cells exhibit an altered metabolism which is characterized by a preference for aerobic glycolysis more than mitochondrial oxidation of pyruvate. This provides anabolic support and selective growth advantage for cancer cells. Recently, a new concept has arisen suggesting that these metabolic changes may be due, in part, to an attenuated mitochondrial function which results from the inhibition of the pyruvate dehydrogenase complex (PDC). This mitochondrial complex links glycolysis to the Krebs cycle and the current understanding of its regulation involves the cyclic phosphorylation and dephosphorylation by specific pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs).Here we review literature pertinent to provide an overview of the multiple levels of PDC regulation to allow cancer cells to adapt their metabolism to their bioenergetic demands. In particular, new post-translational modifications, such as phosphorylation, acetylation or succinylation of different PDC components have been highlighted and could act in a concerted manner to provide a high metabolic flexibility. In addition, we presented recent studies that underline the role of PDC in the control of cancer cell proliferation and metastasis.Finally, the therapeutic potential of PDK inhibitors is quickly regaining a forefront position in cancer. Several studies have shown that the decline in PDK activity either by pharmacological inhibition or a decreased expression leading to an enhanced PDC activity is associated with a reduction in tumor growth in vivo. The current understanding of properties of different inhibitors targeting PDKs which could have potential therapeutic effects in different types of cancer is presented.The mitochondrial pyruvate dehydrogenase complex (PDC) acts as a gatekeeper enzyme for energy metabolism by catalyzing irreversible decarboxylation of pyruvate into acetyl-CoA. The activity of PDC is highly regulated, at least in part, by reversible phosphorylation through pyruvate dehydrogenase kinases (PDKs) and pyruvate dehydrogenase phosphatases (PDPs) the functions of which are regulated by cellular nutrient cues. Here, we provide an overview of the complexities and peculiarities in the regulation of PDC for the control of substrate metabolism and flexibility in cancer cells. Particular attention is devoted to newly identified posttranslational modifications, such as phosphorylation, acetylation or succinylation, of the different PDC components and the mechanisms by which these modifications may act in concert to provide an optimal metabolic adaptation to sustain energy demands in cancer cells. We also discuss new pharmacological approaches used to develop effective PDK inhibitors as well as the properties and potential usefulness of these inhibitors for complex human diseases such as cancer. The Pyruvate Dehydrogenase Complex: A Crucial Role in the Regulation of Energy MetabolismThe multi-subunit mitochondrial PDC is at the center of glucose oxidative metabolism. PDC inserts pyruvate into the t...