Hypoxia Inducible Factor as a Central Regulator of Metabolism – Implications for the Development of Obesity

Gaspar, Joana M.; Velloso, Lı́cio A.

doi:10.3389/fnins.2018.00813

Cited by 68 publications

(58 citation statements)

References 134 publications

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“…This interplay is further evidence of hypoxia and the AR controlling a metabolic switch that promotes CRPC development (Geng et al 2018). HIF itself plays a central metabolic role evidenced by an overexpression of both HIF1α and HIF2α in the hypothalamus involved in both weight gain functions, glucose uptake and energy expenditure (Gaspar & Velloso 2018). HIFs are also involved in lipid metabolism, as uptake of extracellular fatty acids and triglyceride synthesis are upregulated during hypoxia through PPARg activated by HIF1 which additionally mediates the expression of FABP3 and FABP4 in tumour cells (Mylonis et al 2019).…”

Section: Other Drivers Of Crpc Include Cytoskeletal Ar/upr-related Chmentioning

confidence: 76%

The role of the androgen receptor as a driver and mitigator of cellular stress

Doultsinos

Mills

2020

Journal of Molecular Endocrinology

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Prostate cancer is a high-incidence male cancer, which is dependent on the activity of a nuclear hormone receptor, the androgen receptor (AR). Since the AR is required for both normal prostate gland development and for prostate cancer progression, it is possible that prostate cancer evolves from perturbations in AR-dependent biological processes that sustain specialist glandular functions. The archetypal example of course is the use of PSA, an organ-type specific component of the normal prostate secretome, as a biomarker of prostate cancer. Furthermore, localised prostate cancer is characterised by a low proliferative index and a heterogenous array of somatic mutations aligned to a multifocal disease pattern. We and others have identified a number of biological processes that are AR-dependent and represent aberrations in significant glandular processes. Glands are characterised by high-rates of metabolic activity including protein synthesis supported by co-dependent processes such as glycosylation, organelle biogenesis and vesicle trafficking. Impairment in anabolic metabolism, protein folding and processing will inevitably impose proteotoxic and oxidative stress on glandular cells, and in particular, luminal epithelial cells for which secretion is their primary function. As cancer develops there is also significant metabolic dysregulation including impaired negative feedback effects on glycolytic and anabolic activity under conditions of hypoxia and heightened protein synthesis due to dysregulated PI 3-kinase/mTOR activity. In this review we will focus on the components of the AR regulome that support cancer development as well as glandular functions focussing on the unfolded protein response and on regulators of mTOR activity.

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Section: Other Drivers Of Crpc Include Cytoskeletal Ar/upr-related Chmentioning

confidence: 76%

The role of the androgen receptor as a driver and mitigator of cellular stress

Doultsinos

Mills

2020

Journal of Molecular Endocrinology

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Section: Discussionmentioning

confidence: 99%

“…Hypoxia-inducible factors are key molecules that regulate the cellular response to hypoxia and inflammation and play a major role in normal cell function and survival [49]. Current evidence also indicates that the HIF-1α pathway in the hypothalamus may be involved in the regulation of food intake and energy expenditure [49]. Previous studies have shown that 30 cycles of intermittent hypoxia per hour for 8 hours per day for 21 days reduces body weight and BAT wet weight in rats [50].…”

Section: Discussionmentioning

confidence: 99%

Hypobaric hypoxia preconditioning protects against hypothalamic neuron apoptosis in heat-exposed rats by reversing hypothalamic overexpression of matrix metalloproteinase-9 and ischemia

et al. 2020

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Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ. Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO2), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O2) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke.

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“…Consistent with reports that proliferating hMSCs have a glycolytic phenotype, undifferentiated cells have high levels of hypoxia-inducible factor 1 (HIF-1), a transcriptional regulator central to regulation of genes that are involved in hypoxic responses. It is also a crucial physiological regulator of anaerobic metabolism (Gaspar and Velloso, 2018). Cells undergoing OD downregulate HIF-1.…”

Section: Metabolism Of Mscs Msc Function Is Linked To Metabolismmentioning

confidence: 99%

Current Status and Future Prospects of Genome-Scale Metabolic Modeling to Optimize the Use of Mesenchymal Stem Cells in Regenerative Medicine

Sigmarsdóttir

McGarrity

Rolfsson

et al. 2020

Front. Bioeng. Biotechnol.

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Mesenchymal stem cells are a promising source for externally grown tissue replacements and patient-specific immunomodulatory treatments. This promise has not yet been fulfilled in part due to production scaling issues and the need to maintain the correct phenotype after re-implantation. One aspect of extracorporeal growth that may be manipulated to optimize cell growth and differentiation is metabolism. The metabolism of MSCs changes during and in response to differentiation and immunomodulatory changes. MSC metabolism may be linked to functional differences but how this occurs and influences MSC function remains unclear. Understanding how MSC metabolism relates to cell function is however important as metabolite availability and environmental circumstances in the body may affect the success of implantation. Genome-scale constraint based metabolic modeling can be used as a tool to fill gaps in knowledge of MSC metabolism, acting as a framework to integrate and understand various data types (e.g., genomic, transcriptomic and metabolomic). These approaches have long been used to optimize the growth and productivity of bacterial production systems and are being increasingly used to provide insights into human health research. Production of tissue for implantation using MSCs requires both optimized production of cell mass and the understanding of the patient and phenotype specific metabolic situation. This review considers the current knowledge of MSC metabolism and how it may be optimized along with the current and future uses of genome scale constraint based metabolic modeling to further this aim.

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Hypoxia Inducible Factor as a Central Regulator of Metabolism – Implications for the Development of Obesity

Cited by 68 publications

References 134 publications

The role of the androgen receptor as a driver and mitigator of cellular stress

The role of the androgen receptor as a driver and mitigator of cellular stress

Hypobaric hypoxia preconditioning protects against hypothalamic neuron apoptosis in heat-exposed rats by reversing hypothalamic overexpression of matrix metalloproteinase-9 and ischemia

Current Status and Future Prospects of Genome-Scale Metabolic Modeling to Optimize the Use of Mesenchymal Stem Cells in Regenerative Medicine

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