![]() One of the main obstacles preventing the use of thermogenic adipocytes in a cell therapy setting, however, is the availability of a sufficiently pure cell source with functional characteristics that enable translational development 5. It has been proposed that beige adipocytes could have utility as a cell therapeutic for treating T2D by serving to normalize circulating blood glucose levels. This signaling pathway functions through cyclic-AMP (cAMP)/protein Kinase-A (PKA), which induces lipolysis and uncoupling protein-1 (UCP1) activity, resulting in elevated uncoupled respiration and thermogenesis. In the mouse, β3 receptor-dependent signaling is required for thermogenic activation 17. Thermogenic adipocytes are stimulated by norepinephrine-dependent activation of β-adrenergic signaling. Moreover, thermogenic adipocytes modulate circulating glucose and triglyceride levels and use these to fuel heat generation. Unlike WA, that serve as a storage depot for triglycerides, thermogenic adipocytes oxidize fatty acids and generate heat through uncoupled mitochondrial respiration, thereby impacting non-shivering thermogenesis. Thermogenic adipocytes are distinguished from white adipocytes (WA) by their high mitochondrial mass and uncoupling activity 3. Together, these observations indicate that thermogenic adipocytes are an important determinant of metabolic disease, including T2D. These proof-of-concept experiments are further supported by clinical observations, demonstrating an inverse correlation between body mass index and the amount of brown fat depots in the body 12, 13, 14, 15, 16. This is supported by animal model experiments showing that transplantation of mouse and human brown or beige adipocytes reduce obesity and hyperglycemia in recipients 6, 7, 8, 9, 10, 11. Thermogenic (brown, beige/brite) adipocytes have therapeutic potential for the treatment of obesity-associated diseases, such as T2D 3, 4, 5 based on their ability to modulate circulating glucose levels. Therefore, there is a clear need to develop new pharmaceuticals or cell-based therapies that could reduce or prevent this disease burden. Owing to drug efficacies and disease severity, diabetics often require combination drug therapies, including injectable insulin, resulting in complicated drug regimens and long-term management care programs. Most medications such as metformin, dipeptidyl-peptidase inhibitors, and meglitinides, function mainly to inhibit glucose production or stimulate insulin secretion 2, and are used as long-term treatments. These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases.Ĭurrent medications for type 2 diabetes (T2D) are neither preventative, nor curative, and only serve to manage the disease 1. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing body-weight in recipient mice. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. Here, we describe the generation of BAs from human adipose-derived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Although several reports have described the generation of beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. ![]()
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