The Molecular, Cellular, and Genetic characterization of Human Adipose Tissue and its Role in Metabolism

点击翻译按钮获取中文摘要

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 at Harvard Medical School, 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. Tseng's 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. In collaboration with Kong Chen, Acting Chief of the Energy Metabolism Section, and Peter Herscovitch, Chief of the Positron Emission Tomography Department in the CRC, we have completed the first version of an PET/CT-based atlas of human BAT known as the BATlas 1.0. Anatomical and functional information about each depot is being catalogued as part of the larger effort of understanding the function and structure of the human brown and white adipose tissue mass. We are now in the process of expanding this collaboration with Bradford Wood, Director of NIH Center for Interventional Oncology, to be able to collect ultrasound-guided biopsies of the BAT. Recent collaborations with Dr. Siegfried Ussar and Dr. Chad Hunter have been established to better define human BAT lineage and adipogenesis. In addition, the ability of BAT activation to improve insulin sensitivity will be considered in the context of Covid-19 since patients with dysglycemia are at increased risk for complications. We will also determine if BAT is susceptible to Covid-19 entry. Finally, working in collaboration with ATCC, we have developed a paired set of immortalized clonal human brown and white adipocytes that can be used by the larger community as an in vitro model system to study human brown and white adipocyte cellular physiology.