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Deriving functional beige fat from capillaries









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发表于 2016-3-4 12:17:07 | 显示全部楼层 |阅读模式
An exciting and potentially safe strategy proposed for the improvement of insulin sensitivity and glucose homeostasis is to promote controlled energy dissipation and fuel utilization through the activation of brown adipose tissue (BAT). BAT is a key organ that controls nonshivering thermogenesis in small mammals by converting nutrients such as lipids into heat. Promoting BAT thermogenesis in mice works as a therapeutic approach for obesity and diabetes. Given that active brown fat has been found in lean human subjects, its induction could also potentially be a valid anti-obesity and glucose-tolerance therapeutic strategy in humans1. At least two embryologically and anatomically distinct types of BAT have been identified so far in humans and rodents. Canonical brown fat is anatomically organized as distinct small depots, whereas the alternative 'beige' or 'brite' (also known as 'beige/brite') cellular type is organized as dispersed cells within the white adipose tissue (WAT). Although this notion is still controversial, BAT in humans seems to be molecularly and structurally closer to that of beige fat than to that of the canonical brown depot2. Hence, there is interest in finding ways to increase the 'beigeing' or 'browning' cell mass in humans

The main challenges of using browning to alleviate insulin insensitivity are that brown fat is scarce in people with obesity and diabetes, and that it needs to be activated. One approach to overcoming this challenge aims to increase the amount of functional beige cells to promote WAT browning by first recruiting adipose progenitor cells and then promoting their commitment to beige cells that are thermogenically competent in response to environmental and pharmacological activators. In this issue of Nature Medicine, Min et al.3 demonstrate that human functional beige adipocytes can be developed from capillary-derived adipocyte progenitors of human subcutaneous WAT and then induced to function as a regulator of blood glucose in mice (Fig. 1).

Both brown and beige adipocytes arise from a two-step process of differentiation. First, the adipogenic precursor cells commit to brown/beige fates, and then they differentiate into mature adipocytes. Concomitantly, angiogenesis within the tissue occurs to extend the vasculature to provide the appropriate perfusion, oxygenation and nutrition of the growing BAT. Both angiogenesis and adipogenesis occur in close temporal-spatial association, which is ensured by cross-talks between endothelial cells and other vascular cells, such as pericytes and/or adipocytes4, 5.

The authors first derived adipogenic progenitors. On the basis of a previously developed ex vivo model, the authors exposed subcutaneous fat biopsies, which had been obtained from patients undergoing panniculectomy surgery, to angiogenic growth factors (hFGF-B, hEGF, R3-IGF1 and VEGF) to induce vascular sprouting on Matrigel3. The authors rationalized that vascular sprouting from these tissue explants reflects the ability of adipose cells to proliferate, migrate and interact with vascular structures5. Min et al.3 made the unexpected observation that the capillary networks contained, in addition to endothelial cells, adipose progenitors with the ability to give rise to adipocytes when submitted to a well-established adipogenic cocktail of growth factors. This supports previous work reporting that microvascular fragment–derived cells display higher adipogenic potential than do classical adipose-derived stem cells6. Furthermore, the authors found that capillary-derived precursors committed to a beige fate in vitro upon the activation of β-adrenergic–dependent pathways after stimulation with forskolin. The induced pathways increased the levels of cyclic adenosine monophosphate (cAMP) and promoted the activation of the thermogenic program in beige adipocytes7. These progenitors displayed all the structural and functional features of a beige/brite cell in vitro, including high expression of endogenous uncoupling protein 1 (UCP1), and they regulated uncoupled cellular respiration. This result confirmed the key role of the vasculature in promoting adipogenesis, as initially suggested in lineage-tracing studies5.



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