Mechanisms Underlying Adipose Tissue Thermogenesis

我们与波士顿哈佛医学院Joslin糖尿病中心的Tseng博士的团队合作，从人类颈部脂肪中生成克隆细胞系，并在移植到免疫缺陷裸鼠体内后，在体外和体内表征了它们的成脂分化和代谢功能。通过克隆分析和基因表达谱，我们在人类前脂肪细胞中发现了一组独特的基因特征，这些基因特征可以预测这些细胞在培养中成熟为脂肪细胞后的产热潜力。这些数据突出了人类BAT和WAT的细胞异质性，并为产热分化的主要前脂肪细胞提供了新的基因靶点。在过去的一年里，我们还使用这些永生的人类脂肪细胞来描述肾上腺素能受体的表达和功能分析，这将指导可用于激活人类BAT和治疗肥胖和代谢疾病的药理化合物的开发。

In collaboration with Dr. Tseng's group at the Joslin Diabetes Center / Harvard Medical School in Boston, we 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. This past year, we also used these immortalized human adipocytes to describe the adrenergic receptor expression and functional profiling that will guide the develop of pharmacological compounds that can be used to activate human BAT and treat obesity and metabolic disease. With ATCC, we are developing an additional collection of human adipose tissue cell populations and cell lines from additional depots. These will help enrich the functional and anatomical mapping of human adipose tissue. In parallel, we tested the effects of diet-induced obesity (DIO) on brown adipose tissue (BAT). We fed 6-week-old C57BL/6 mice either a normal chow diet (NCD) or a high-fat diet (HFD). After 16 additional weeks, we measured body fat, WAT, and BAT mRNA expression, glucose tolerance, and rates of glucose uptake in response to insulin and the beta3-AR agonist mirabegron. We saw that compared with NCD, HFD increased body fat and impaired glucose tolerance. Both WAT and BAT had higher mRNA levels of markers of inflammation, including TNF and F4/80. Insulin signaling in BAT and WAT was reduced, with decreased Akt phosphorylation. Diet-normalized BAT glucose uptake rates were lower in response to mirabegron. These results support a model in which DIO leads to BAT inflammation and insulin resistance, leading to a broader impairment of BAT function.