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Takahashi, Hirokazu

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Takahashi

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Hirokazu

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Takahashi, Hirokazu

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2015 - 20172

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Author's Publications: search.filters.isAuthorOfPublication.19e610e0-17e1-4377-a9d2-2106aeafcbd3

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    Clonal analyses and gene profiling identify genetic biomarkers of human brown and white preadipocyte thermogenic potential
    (2015) Xue, Ruidan; Lynes, Matthew; Dreyfuss, Jonathan M.; Shamsi, Farnaz; Schulz, Tim J.; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L.; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S.; White, Andrew; Lynes, Maureen S.; Rubin, Lee; Goodyear, Laurie; Cypess, Aaron M.; Tseng, Yu-Hua
    Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generated clones of brown and white preadipocytes from human neck fat of four individuals and characterized their adipogenic differentiation and thermogenic function. Combining an uncoupling protein 1(UCP1) reporter system and expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated in culture. Knocking out the positive UCP1 regulators identified by this approach, PREX1 and EDNRB in brown preadipocytes using CRISPR/Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer the identification of possible biomarkers of thermogenically competent preadipocytes.
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    The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue
    (Springer Nature, 2017) Lynes, Matthew; Leiria, Luiz; Lundh, Morten; Bartelt, Alexander; Shamsi, Farnaz; Huang, Tianwen; Takahashi, Hirokazu; Hirshman, Michael F; Schlein, Christian; Lee, Alexandra; Baer, Lisa A; May, Francis J; Gao, Fei; Narain, Niven R; Chen, Emily Y; Kiebish, Michael A; Cypess, Aaron; Blüher, Matthias; Goodyear, Laurie; Hotamisligil, Gokhan; Stanford, Kristin I; Tseng, Yu-Hua
    Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia1,2. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism3–5. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as ‘lipokines’6–8. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.