Person: Tseng, Yu-Hua
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Tseng
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Yu-Hua
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Tseng, Yu-Hua
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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 Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity(Springer Nature, 2018) Bartelt, Alexander; Widenmaier, Scott; Schlein, Christian; Johann, Kornelia; Goncalves, Renata; Eguchi, Kosei; Fischer, Alexander W; Parlakgul, Gunes; Snyder, Nicole; Nguyen, Truc B; Bruns, Oliver T; Franke, Daniel; Bawendi, Moungi G; Lynes, Matthew; Leiria, Luiz O; Tseng, Yu-Hua; Inouye, Karen; Arruda, Ana; Hotamisligil, GokhanObjective Brown adipose tissue (BAT) generates heat in response to cold, and low BAT activity has been linked to obesity. However, recent studies were inconclusive as to whether BAT is involved in diet‐induced thermogenesis and mitigates weight gain from prolonged overeating. Therefore, this study investigated whether BAT activity is related to metabolic adaptation arising from 8 weeks of overfeeding in humans. Methods Fourteen men (aged 24 ± 3 years, BMI 24.5 ± 1.6 kg/m2) were overfed by 40% for 8 weeks. Before and after, energy expenditure and metabolic adaptation were measured by whole‐room respiratory calorimetry. A marker of BAT activity was measured using infrared imaging of the supraclavicular BAT depot. Results At the end of 8 weeks of overfeeding, metabolic adaptation—defined as the percent increase in sleeping energy expenditure beyond that expected from weight gain—rose from −0.9 ± 3.9% to 4.7 ± 5.6% (P = 0.001). However, BAT thermal activity was unchanged (P = 0.81). Moreover, BAT thermal activity did not correlate with the degree of metabolic adaptation (P = 0.32) or with the change in body weight (P = 0.51). Conclusions BAT thermal activity does not change in response to overfeeding, nor does it correlate with adaptive thermogenesis. Our data suggest that BAT does not mediate metabolic adaptation to overeating in humans.Publication Anatomical Localization, Gene Expression Profiling, and Functional Characterization of Adult Human Neck Brown Fat(2013) Cypess, Aaron; White, Andrew; Vernochet, Cecile; Schulz, Tim J.; Xue, Ruidan; Sass, Christina A.; Huang, Tian Liang; Roberts-Toler, Carla; Weiner, Lauren S.; Sze, Cathy; Chacko, Aron T.; Deschamps, Laura N.; Herder, Lindsay M.; Truchan, Nathan; Glasgow, Allison L.; Holman, Ashley R.; Gavrila, Alina; Hasselgren, Per-Olof; Mori, Marcelo A.; Molla, Michael; Tseng, Yu-HuaPublication Isolation of Progenitors that Exhibit Myogenic/Osteogenic Bipotency In Vitro by Fluorescence-Activated Cell Sorting from Human Fetal Muscle(Elsevier, 2014) Castiglioni, Alessandra; Hettmer, Simone; Lynes, Matthew D.; Rao, Tata Nageswara; Tchessalova, Daria; Sinha, Indranil; Lee, Bernard T.; Tseng, Yu-Hua; Wagers, Amy J.Summary Fluorescence-activated cell sorting (FACS) strategies to purify distinct cell types from the pool of fetal human myofiber-associated (hMFA) cells were developed. We demonstrate that cells expressing the satellite cell marker PAX7 are highly enriched within the subset of CD45−CD11b−GlyA−CD31−CD34−CD56intITGA7hi hMFA cells. These CD45−CD11b−GlyA−CD31−CD34−CD56intITGA7hi cells lack adipogenic capacity but exhibit robust, bipotent myogenic and osteogenic activity in vitro and engraft myofibers when transplanted into mouse muscle. In contrast, CD45−CD11b−GlyA−CD31−CD34+ fetal hMFA cells represent stromal constituents of muscle that do not express PAX7, lack myogenic function, and exhibit adipogenic and osteogenic capacity in vitro. Adult muscle likewise contains PAX7+ CD45−CD11b−GlyA−CD31−CD34−CD56intITGA7hi hMFA cells with in vitro myogenic and osteogenic activity, although these cells are present at lower frequency in comparison to their fetal counterparts. The ability to directly isolate functionally distinct progenitor cells from human muscle will enable novel insights into muscle lineage specification and homeostasis.Publication Brown Fat Paucity Due to Impaired BMP Signaling Induces Compensatory Browning of White Fat(2013) Schulz, Tim J.; Huang, Ping; Huang, Tian Lian; Xue, Ruidan; McDougall, Lindsay E.; Townsend, Kristy L; Cypess, Aaron; Mishina, Yuji; Gussoni, Emanuela; Tseng, Yu-HuaSummary Maintenance of body temperature is essential for survival of homeotherms. Brown adipose tissue (BAT) is a specialized fat tissue that is dedicated to thermoregulation1. Due to its remarkable capacity to dissipate stored energy and its demonstrated presence in adult humans2-5, BAT holds great promise for the treatment of obesity and metabolic syndrome1. Rodent data suggest the existence of two types of brown fat cells: the constitutive BAT (cBAT), which is of embryonic origin and anatomically located in the interscapular region of mice, and the recruitable BAT (rBAT) that resides within white adipose tissue (WAT)6 and skeletal muscle7, that has alternatively been called beige8, brite9, or inducible BAT10. Bone morphogenetic proteins (BMPs) regulate the formation and thermogenic activity of BAT10-12. We here provide evidence for a systemically active regulatory mechanism that serves to control whole body BAT-activity for thermoregulation and energy homeostasis. Genetic ablation of type 1A BMP-receptor (Bmpr1A) in brown adipogenic progenitor cells leads to a severe paucity of cBAT. This in turn increases sympathetic input to WAT, thereby promoting the formation of rBAT within white fat depots. This previously unknown compensatory mechanism, aimed at restoring total brown fat-mediated thermogenic capacity in the body, is sufficient to maintain normal temperature homeostasis and resistance to diet-induced obesity. These data suggest an important physiological cross-talk between the constitutive and recruitable brown fat cells. This sophisticated regulatory mechanism of body temperature may participate in the control of energy balance and metabolic disease.Publication Intrinsic Differences in Adipocyte Precursor Cells From Different White Fat Depots(American Diabetes Association, 2012) Macotela, Yazmín; Emanuelli, Brice; Mori, Marcelo A.; Gesta, Stephane; Schulz, Tim J.; Tseng, Yu-Hua; Kahn, C.Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. In the current study, we demonstrate that adipocyte precursor cells (APCs) isolated from visceral and subcutaneous white adipose depots of mice have distinct patterns of gene expression, differentiation potential, and response to environmental and genetic influences. APCs derived from subcutaneous fat differentiate well in the presence of classical induction cocktail, whereas those from visceral fat differentiate poorly but can be induced to differentiate by addition of bone morphogenetic protein (BMP)-2 or BMP-4. This difference correlates with major differences in gene expression signature between subcutaneous and visceral APCs. The number of APCs is higher in obesity-prone C57BL/6 mice than obesity-resistant 129 mice, and the number in both depots is increased by up to 270% by exposure of mice to high-fat diet. Thus, APCs from visceral and subcutaneous depots are dynamic populations, which have intrinsic differences in gene expression, differentiation properties, and responses to environmental/genetic factors. Regulation of these populations may provide a new target for the treatment and prevention of obesity and its metabolic complications.Publication Ablation of TRIP-Br2, a novel regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance(2012) Liew, Chong Wee; Boucher, Jeremie; Cheong, Jit Kong; Vernochet, Cecile; Koh, Ho-Jin; Mallol, Cristina; Townsend, Kristy L; Langin, Dominique; Kawamori, Dan; Hu, Jiang; Tseng, Yu-Hua; Hellerstein, Marc K; Farmer, Stephen R; Goodyear, Laurie; Doria, Alessandro; Blüher, Matthias; Hsu, Stephen I-Hong; Kulkarni, RohitSUMMARY Obesity develops due to altered energy homeostasis favoring fat storage. Here we describe a novel transcription co-regulator for adiposity and energy metabolism, TRIP-Br2 (also called SERTAD2). TRIP-Br2 null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of the knockout (KO) mice exhibited greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The KOs also exhibit higher energy expenditure due to increased adipocyte thermogenesis and oxidative metabolism by up-regulating key enzymes in respective processes. Our data show for the first time that a cell cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data together with the observation that TRIP-BR2 expression is selectively elevated in visceral fat in obese humans suggests that this transcriptional co-regulator is a novel therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.Publication Curcumin analogues as selective fluorescence imaging probes for brown adipose tissue and monitoring browning(Nature Publishing Group, 2015) Zhang, Xueli; Tian, Yanli; Zhang, Hongbin; Kavishwar, Amol; Lynes, Matthew; Brownell, Anna-Liisa; Sun, Hongbin; Tseng, Yu-Hua; Moore, Anna; Ran, ChongzhaoManipulation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) can be promising new approaches to counter metabolic disorder diseases in humans. Imaging probes that could consistently monitor BAT mass and browning of WAT are highly desirable. In the course of our imaging probe screening, we found that BAT could be imaged with curcumin analogues in mice. However, the poor BAT selectivity over WAT and short emissions of the lead probes promoted further lead optimization. Limited uptake mechanism studies suggested that CD36/FAT (fatty acid transporter) probably contributed to the facilitated uptake of the probes. By increasing the stereo-hindrance of the lead compound, we designed CRANAD-29 to extend the emission and increase the facilitated uptake, thus increasing its BAT selectivity. Our data demonstrated that CRANAD-29 had significantly improved selectivity for BAT over WAT, and could be used for imaging BAT mass change in a streptozotocin-induced diabetic mouse model, as well as for monitoring BAT activation under cold exposure. In addition, CRANAD-29 could be used for monitoring the browning of subcutaneous WAT (sWAT) induced by β3-adrenoceptor agonist CL-316, 243.Publication Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance(Springer Berlin Heidelberg, 2016) Schulz, Tim J.; Graja, Antonia; Huang, Tian Lian; Xue, Ruidan; An, Ding; Poehle-Kronawitter, Sophie; Lynes, Matthew; Tolkachov, Alexander; O’Sullivan, Lindsay E.; Hirshman, Michael F.; Schupp, Michael; Goodyear, Laurie; Mishina, Yuji; Tseng, Yu-HuaAims/hypothesis Adipose tissue dysfunction is a prime risk factor for the development of metabolic disease. Bone morphogenetic proteins (BMPs) have previously been implicated in adipocyte formation. Here, we investigate the role of BMP signalling in adipose tissue health and systemic glucose homeostasis. Methods: We employed the Cre/loxP system to generate mouse models with conditional ablation of BMP receptor 1A in differentiating and mature adipocytes, as well as tissue-resident myeloid cells. Metabolic variables were assessed by glucose and insulin tolerance testing, insulin-stimulated glucose uptake and gene expression analysis. Results: Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype. Knockout mice were clearly resistant to age-related impairment of insulin sensitivity during normal and high-fat-diet feeding and showed significantly improved insulin-stimulated glucose uptake in brown adipose tissue and skeletal muscle. Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation. Deletion of Bmpr1a in myeloid cells had no impact on insulin sensitivity, while ablation of Bmpr1a in mature adipocytes partially recapitulated the initial phenotype from aP2-Cre driven deletion. Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes. Conclusions/interpretation Our findings show that altered BMP signalling in adipose tissue affects the tissue’s metabolic properties and systemic insulin resistance by altering the pattern of immune cell infiltration. The phenotype is due to ablation of Bmpr1a specifically in pre-adipocytes and maturing adipocytes rather than an immune cell-autonomous effect. Mechanistically, we provide evidence for a BMP-mediated direct crosstalk between pre-adipocytes and macrophages. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-3990-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.Publication Monoacylglycerol Analysis Using MS/MSALL Quadruple Time of Flight Mass Spectrometry(MDPI, 2016) Gao, Fei; McDaniel, Justice; Chen, Emily Y.; Rockwell, Hannah; Lynes, Matthew; Tseng, Yu-Hua; Sarangarajan, Rangaprasad; Narain, Niven R.; Kiebish, Michael A.Monoacylglycerols (MAGs) are structural and bioactive metabolites critical for biological function. Development of facile tools for measuring MAG are essential to understand its role in different diseases and various pathways. A data-independent acquisition method, MS/MSALL, using electrospray ionization (ESI) coupled quadrupole time of flight mass spectrometry (MS), was utilized for the structural identification and quantitative analysis of individual MAG molecular species. Compared with other acylglycerols, diacylglycerols (DAG) and triacylglycerols (TAG), MAG characteristically presented as a dominant protonated ion, [M + H]+, and under low collision energy as fatty acid-like fragments due to the neutral loss of the glycerol head group. At low concentrations (<10 pmol/µL), where lipid-lipid interactions are rare, there was a strong linear correlation between ion abundance and MAG concentration. Moreover, using the MS/MSALL method the major MAG species from human plasma and mouse brown and white adipose tissues were quantified in less than 6 min. Collectively, these results demonstrate that MS/MSALL analysis of MAG is an enabling strategy for the direct identification and quantitative analysis of low level MAG species from biological samples with high throughput and sensitivity.