Person: Shamsi, Farnaz
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Shamsi
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Farnaz
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Shamsi, Farnaz
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Publication MicroRNA Regulation of Brown Adipogenesis and Thermogenic Energy Expenditure(Frontiers Media S.A., 2017) Shamsi, Farnaz; Zhang, Hongbin; Tseng, Yu-HuaObesity, diabetes, and associated metabolic diseases have become global epidemics. Obesity results from excess accumulation of white fat, while brown and its related beige fat function to dissipate energy as heat, thus counteracting obesity and its related metabolic disorders. Understanding the regulatory mechanisms for both white and brown adipogenesis provides new insights for prevention and treatment of these metabolic diseases. In addition to traditional gene transcription and translation, microRNA (miRNA) represents a new layer of regulatory mechanism in many biological processes and has attracted a great deal of research interests in exploring their roles in physiological and pathophysiological conditions. This review focuses on the recent advances of regulating brown adipogenesis and energy metabolism by miRNAs, aiming to delineate the regulatory principles of miRNAs on this unique aspect of energy homeostasis.Publication 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-HuaTargeting 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.Publication 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-HuaBrown 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.Publication Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes(Nature Publishing Group UK, 2017) Kriszt, Rókus; Arai, Satoshi; Itoh, Hideki; Lee, Michelle H.; Goralczyk, Anna G.; Ang, Xiu Min; Cypess, Aaron M.; White, Andrew; Shamsi, Farnaz; Xue, Ruidan; Lee, Jung Yeol; Lee, Sung-Chan; Hou, Yanyan; Kitaguchi, Tetsuya; Sudhaharan, Thankiah; Ishiwata, Shin’ichi; Lane, E. Birgitte; Chang, Young-Tae; Tseng, Yu-Hua; Suzuki, Madoka; Raghunath, MichaelThe identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.Publication Vascular smooth muscle-derived Trpv1+ progenitors are a source of cold-induced thermogenic adipocytes(Springer Science and Business Media LLC, 2021-04-12) Shamsi, Farnaz; Piper, Mary; Ho, Li-Lun; Huang, Tian Lian; Gupta, Anushka; Streets, Aaron; Lynes, Matthew D.; Tseng, Yu-HuaBrown adipose tissue (BAT) and related beige fat function in energy expenditure in part due to their role in thermoregulation. The prominent capacity of thermogenic fat to enhance fuel utilization and energy expenditure makes it an attractive target for treating obesity and metabolic disorders. While prolonged cold exposure increases BAT mass through de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we sought to investigate the cellular origin of cold-induced brown adipocytes using single-cell RNA sequencing. We identify two distinct types of adipocyte progenitors that contribute to de novo recruitment of brown adipocytes in response to cold challenge. One population is the previously-known Pdgfr-expressing mesenchymal progenitors, while the other is a previously-unidentified vascular smooth muscle-derived adipocyte progenitor (VSM-APC) population, which expresses the temperature-sensitive ion channel transient receptor potential cation channel subfamily V member 1 (Trpv1). Using flow cytometry and lineage tracing, we demonstrate that the Trpv1-positive VSM-APCs are distinct from the Pdgfr-positive progenitors, and can give rise to thermogenic adipocytes in response to cold. Together, these findings illustrate the landscape of the thermogenic adipose niche at the single cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.