A Renewable Source of Human Beige Adipocytes for Development of Therapies to Treat Metabolic Syndrome

Abstract

Summary: Molecular- and cellular-based therapies have the potential to reduce obesity-associated disease. In response to cold, beige adipocytes form in subcutaneous white adipose tissue and convert energy stored in metabolic substrates to heat, making them an attractive therapeutic target. We developed a robust method to generate a renewable source of human beige adipocytes from induced pluripotent stem cells (iPSCs). Developmentally, these cells are derived from FOXF1+ mesoderm and progress through an expandable mural-like mesenchymal stem cell (MSC) to form mature beige adipocytes that display a thermogenically active profile. This includes expression of uncoupling protein 1 (UCP1) concomitant with increased uncoupled respiration. With this method, dysfunctional adipogenic precursors can be reprogrammed and differentiated into beige adipocytes with increased thermogenic function and anti-diabetic secretion potential. This resource can be used to (1) elucidate mechanisms that underlie the control of beige adipogenesis and (2) generate material for cellular-based therapies that target metabolic syndrome in humans. : Su et al. demonstrate a method for producing beige adipocytes from human induced pluripotent stem cells in a stepwise manner through defined precursor lineages. This renewable resource provides a developmental framework to study human beige adipogenesis and can be used to develop treatments for obesity-related disorders. Keywords: adipogenesis, beige adipocytes, UCP1, metabolic syndrome, diabetes, mesoderm