Brown adipocytes from induced pluripotent stem cells-how far have we come?

Abstract

A global increase in the number of individuals who are either overweight or obese is leading to a higher incidence of type 2 diabetes (T2D). Behavioral interventions for the treatment of obesity have yet to deliver desired outcomes, thus introducing a pressing need for molecular- and cellular-based therapies. Excess energy from food is stored in the form of triglycerides in white adipose tissue, which expands during weight gain and can lead to insulin resistance and T2D. By contrast, brown adipose tissue (BAT) releases energy from metabolic substrates in the form of heat and secretes factors that can reverse metabolic disease by acting systemically. Therefore, the ability to increase BAT activity is a promising approach to improve energy balance and metabolic homeostasis. Methods are now being developed to generate brown adipocytes from human induced pluripotent stem cells (hiPSCs), which would (1) provide an unlimited source of cellular material to study human brown adipogenesis, and (2) could be used to develop drug- and cell-based therapies for the treatment of metabolic complications associated with obesity. This article reviews basic BAT biology and details the current progress toward developing brown adipocytes from hiPSCs.

Keywords: UCP1; adipogenesis; brown adipocytes; diabetes; mesoderm; metabolic syndrome.

Figure 1:

Activation of brown and beige adipocytes. During cold exposure norepinephrine (NE), secreted from sympathetic nerves, binds to β-adrenergic receptors (dark green) at the plasma membrane surface of brown and beige adipocytes. This increases cAMP and activates protein kinase A, triggering the breakdown of triglycerides within lipid droplets into free fatty acids (FFAs). Additionally, activated brown adipocytes increase uptake of FFAs and glucose from outside the cell. FFAs are transported into the mitochondria where they activate UCP1, which results in proton leak across the inner mitochondrial membrane and heat release. Activated brown adipocytes can also secrete factors that act locally or systemically to improve metabolic homeostasis.

Figure 2:

Embryonic origins of adipocytes. Lineage tracing studies in mice demonstrate that white and brown adipocytes arise from different mesodermal layers during development, including the lateral plate (visceral white) and paraxial mesoderm (brown). In addition, some adipocytes are derived from the neural crest. The ultimate developmental origins of subcutaneous white and beige adipocytes are currently under investigation.

Figure 3:

Generation of beige adipocytes through multiple well-defined cellular stages. hiPSCs can be differentiated into beige adipocytes by simulating multiple differentiation stages in cell culture as they occur naturally during mammalian development. Figure adopted and modified from Ref. .