Systemic Impact of Insulin-Sensitized Adipocytes and Their Precursors

Abstract

Maintenance of healthy adipose, especially when challenged with a prolonged unhealthy diet, is crucial for the prevention of diabetes and metabolic disease. Previous studies have shown that healthy expansion of adipose tissue occurs via hyperplasia, rather than hypertrophy. Therefore, a better understanding of the adipocyte precursor can potentially lead to interventions that favor new adipocyte formation over unhealthy, hypoxic adipocyte enlargement. Insulin signaling is central to the development of type 2 diabetes mellitus; resistance within this pathway leads to global metabolic dysfunction and cardiometabolic disease. Downregulation of adipocyte PTEN, a downstream inhibitor of the insulin signaling pathway, can lead to insulin sensitization of the adipose tissue and, as a result, in whole body insulin sensitivity. Previous work from our lab has shown that insulin sensitization of mature adipocytes, or of only thermogenic adipocytes, is sufficient to improve global metabolic health. We now report that by sensitizing murine adipocyte precursor cells to insulin action, we can induce durable improvements in glucose tolerance, lower circulating insulin levels, and eliminate steatohepatitis, without a change in overall body weight, even in high fat diet-fed mice. Remarkably, transplantation of small amounts of murine gonadal adipose tissue, containing insulin-sensitized precursors, is sufficient to induce improvements of global glucose handling and insulin signaling. The transplantation of such an insulin-sensitized fat pad can induce a durable reduction in circulating insulin even in high fat diet-fed mice. These studies demonstrate that targeting the relatively small cell population of adipocyte precursors is sufficient to induce widespread improvements in metabolic health, and that these cells may hold the key to future therapies for diabetes and metabolic disease