TY - JOUR A1 - Bishop, Christopher Allen A1 - Schulze, Matthias Bernd A1 - Klaus, Susanne A1 - Weitkunat, Karolin T1 - The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism JF - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology N2 - Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Ppar alpha activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPAR alpha-dependent induction of alpha-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health. KW - fatty acid metabolism KW - leucine KW - liver KW - OCFA KW - valine Y1 - 2020 U6 - https://doi.org/10.1096/fj.202000195R SN - 0892-6638 SN - 1530-6860 VL - 34 IS - 7 SP - 9727 EP - 9739 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Graja, Antonia A1 - Garcia-Carrizo, Francisco A1 - Jank, Anne-Marie A1 - Gohlke, Sabrina A1 - Ambrosi, Thomas H. A1 - Jonas, Wenke A1 - Ussar, Siegfried A1 - Kern, Matthias A1 - Schürmann, Annette A1 - Aleksandrova, Krasimira A1 - Bluher, Matthias A1 - Schulz, Tim Julius T1 - Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism JF - Aging Cell N2 - Remodeling of the extracellular matrix is a key component of the metabolic adaptations of adipose tissue in response to dietary and physiological challenges. Disruption of its integrity is a well-known aspect of adipose tissue dysfunction, for instance, during aging and obesity. Adipocyte regeneration from a tissue-resident pool of mesenchymal stem cells is part of normal tissue homeostasis. Among the pathophysiological consequences of adipogenic stem cell aging, characteristic changes in the secretory phenotype, which includes matrix-modifying proteins, have been described. Here, we show that the expression of the matricellular protein periostin, a component of the extracellular matrix produced and secreted by adipose tissue-resident interstitial cells, is markedly decreased in aged brown and white adipose tissue depots. Using a mouse model, we demonstrate that the adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding is impaired in animals with systemic ablation of the gene encoding for periostin. Our data suggest that loss of periostin attenuates lipid metabolism in adipose tissue, thus recapitulating one aspect of age-related metabolic dysfunction. In human white adipose tissue, periostin expression showed an unexpected positive correlation with age of study participants. This correlation, however, was no longer evident after adjusting for BMI or plasma lipid and liver function biomarkers. These findings taken together suggest that age-related alterations of the adipose tissue extracellular matrix may contribute to the development of metabolic disease by negatively affecting nutrient homeostasis. KW - adipogenic progenitor cells KW - adipose tissue KW - aging KW - extracellular matrix KW - fatty acid metabolism KW - periostin Y1 - 2018 U6 - https://doi.org/10.1111/acel.12810 SN - 1474-9718 SN - 1474-9726 VL - 17 IS - 5 PB - Wiley CY - Hoboken ER - TY - GEN A1 - Wardelmann, Kristina A1 - Rath, Michaela A1 - Castro, José Pedro A1 - Blümel, Sabine A1 - Schell, Mareike A1 - Hauffe, Robert A1 - Schumacher, Fabian A1 - Flore, Tanina A1 - Ritter, Katrin A1 - Wernitz, Andreas A1 - Hosoi, Toru A1 - Ozawa, Koichiro A1 - Kleuser, Burkhard A1 - Weiß, Jürgen A1 - Schürmann, Annette A1 - Kleinridders, André T1 - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1165 KW - brain insulin signaling KW - mitochondria KW - oxidative stress KW - fatty acid metabolism Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-522985 SN - 1866-8372 IS - 5 ER - TY - JOUR A1 - Wardelmann, Kristina A1 - Rath, Michaela A1 - Castro, José Pedro A1 - Blümel, Sabine A1 - Schell, Mareike A1 - Hauffe, Robert A1 - Schumacher, Fabian A1 - Flore, Tanina A1 - Ritter, Katrin A1 - Wernitz, Andreas A1 - Hosoi, Toru A1 - Ozawa, Koichiro A1 - Kleuser, Burkhard A1 - Weiß, Jürgen A1 - Schürmann, Annette A1 - Kleinridders, André T1 - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus JF - Antioxidants N2 - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance. KW - brain insulin signaling KW - mitochondria KW - oxidative stress KW - fatty acid metabolism Y1 - 2021 U6 - https://doi.org/10.3390/antiox10050711 SN - 2076-3921 VL - 10 IS - 5 PB - MDPI CY - Basel ER -