The initial reports about human BAT distribution and lack of plasma biomarkers indicated that it would be a particularly challenging organ to study. An acute need was the precise anatomical localization of the tissue and the availability of human-derived brown and white fat progenitor cell models to understand its distinct physiology. In collaboration with Yu-Hua Tseng, my group first reported the anatomical localization of the tissue and showed that human neck BAT shared the same developmental lineage as rodent interscapular BAT, the principal model system used for more than half a century. In collaboration with C. Ronald Kahn, we identified cell surface markers of white, brown, and beige human adipocytes that could be used to isolate and study the different adipocyte lineages. In parallel, Dr. Tsengs group generated clonal cell lines from human neck fat and characterized their adipogenic differentiation and metabolic function in vitro and in vivo after transplantation into immune deficient nude mice. Using clonal analysis and gene expression profiling, we identified unique sets of gene signatures in human preadipocytes that could predict the thermogenic potential of these cells once matured in culture into adipocytes. These data highlight the cellular heterogeneity in human BAT and WAT and provide novel gene targets to prime preadipocytes for thermogenic differentiation. Additional discoveries included the demonstration that altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy; HIV-infected subjects with metabolic complications demonstrate increases in FGF21 in relationship to BAT gene expression; and IRF4 is a transcriptional driver of a program of thermogenic gene expression and energy expenditure.

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1
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2015
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U.S. National Inst Diabetes/Digst/Kidney
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Lynes, Matthew D; Shamsi, Farnaz; Sustarsic, Elahu Gosney et al. (2018) Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. Cell Rep 24:781-790
Wankhade, Umesh D; Lee, Ji-Hyeon; Dagur, Pradeep K et al. (2018) TGF-? receptor 1 regulates progenitors that promote browning of white fat. Mol Metab 16:160-171
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Lynes, Matthew D; Leiria, Luiz O; Lundh, Morten et al. (2017) The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 23:631-637
Kriszt, Rókus; Arai, Satoshi; Itoh, Hideki et al. (2017) Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes. Sci Rep 7:1383
Hiraike, Yuta; Waki, Hironori; Yu, Jing et al. (2017) NFIA co-localizes with PPAR? and transcriptionally controls the brown fat gene program. Nat Cell Biol 19:1081-1092
Torriani, Martin; Srinivasa, Suman; Fitch, Kathleen V et al. (2016) Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients. J Clin Endocrinol Metab 101:1225-34
Srinivasa, Suman; Wong, Kimberly; Fitch, Kathleen V et al. (2015) Effects of lifestyle modification and metformin on irisin and FGF21 among HIV-infected subjects with the metabolic syndrome. Clin Endocrinol (Oxf) 82:678-85

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