Biology subjects

Bartelt, A.

Publications and source records attributed to Bartelt, A..

3 recordsLinked to original sources

bioRxiv2020

ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue

Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status but the molecular mechanisms underlying this regulation are incompletely understood. Protein S-nitrosylation, the nitric oxide-mediated cysteine thiol modification of proteins, plays important roles in cellular redox regulation. Here we show that both diet-induced obesity (DIO) and acute cold exposure elevates protein S-nitrosylation of BAT proteins, including UCP1, to regulate thermogenesis. This effect in BAT is regulated largely by S-nitrosoglutathione reductase (GSNOR, ADH5), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 specifically in BAT impairs UCP1-dependent thermogenesis during acute cold challenge and worsens metabolic dysfunction during diet-induced obesity. Mechanistically, we demonstrate that Adh5 expression in BAT is controlled by the transcription factor heat shock factor 1 (HSF1) and administration of an HSF1 activator to the BAT of mice with DIO increased Adh5 expression and significantly improved UCP1-mediated mitochondrial respiration. Together, these data demonstrate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis which may be therapeutically targeted to improve metabolic health. HighlightsO_LIThermogenesis induces protein S-nitrosylation modification in the BAT; C_LIO_LIADH5, a major cellular denitrosylase, is required for maintaining BAT metabolic homeostasis under both overnutrition and cold stress conditions; C_LIO_LIDiet-induced obesity suppresses HSF1-mediated activation of Adh5 in the BAT; C_LIO_LIADH5 overexpression in BAT improves whole-body glucose homeostasis in obesity. C_LI

molecular biology↗

bioRxiv2020

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

molecular biology↗

bioRxiv2020

An unexpected lack of difference in superoxide/H2O2 production rates in isolated heart and skeletal muscle mitochondria from a mouse model of Barth Syndrome

Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial superoxide/H2O2 production has been implicated in the cardiomyopathy observed in different BTHS models. There are at least 11 mitochondrial sites that produce superoxide/H2O2 at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2 production from each site in mitochondria isolated from heart and skeletal muscle of the tafazzin knockdown mice (tazkd) at 3, 7 and 12 months of age. Strikingly, the superoxide/H2O2 production capacities of these sites were overall indistinguishable between tazkd mice and their wildtype littermates across the time points analyzed. The only exception was site GQ in glycerol phosphate dehydrogenase, which was increased in the skeletal muscle of 7 months old tazkd mice. Mitochondrial superoxide/H2O2 production was also measured ex vivo during the oxidation of a complex mixture of substrates mimicking either heart or skeletal muscle cytosol and was found to be indistinguishable between wildtype and tazkd mice. However, we consistently measured decreased FAD-linked respiration in mitochondria isolated from tazkd mice. We conclude that the maximum capacity and ex vivo rates of superoxide/H2O2 production were not increased in mitochondria isolated from heart and skeletal muscle of tazkd mice, despite reduced oxidative capacity. Therefore, it seems unlikely that mitochondrial oxidants contribute to the development of cardiomyopathy in tazkd mice. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.

biochemistry↗