Ectopic brown adipose tissue formation within skeletal muscle after brown adipose progenitor cell transplant augments energy expenditure

Abstract

Brown adipose tissue (BAT) thermogenesis increases energy expenditure (EE). Expanding the volume of active BAT via transplantation holds promise as a therapeutic strategy for morbid obesity and diabetes. Brown adipose progenitor cells (BAPCs) can be isolated and expanded to generate autologous brown adipocyte implants. However, the transplantation of brown adipocytes is currently impeded by poor efficiency of BAT tissue formation in vivo and undesirably short engraftment time. In this study, we demonstrated that transplanting BAPCs into limb skeletal muscles consistently led to the ectopic formation of uncoupling protein 1 (UCP1)+pos adipose tissue with long‐term engraftment (>4 mo). Combining VEGF with the BAPC transplant further improved BAT formation in muscle. Ectopic engraftment of BAPC‐derived BAT in skeletal muscle augmented the EE of recipient mice. Although UCP1 expression declined in long‐term BAT grafts, this deterioration can be reversed by swimming exercise because of sympathetic activation. This study suggests that intramuscular transplantation of BAPCs represents a promising approach to deriving functional BAT engraftment, which may be applied to therapeutic BAT transplantation and tissue engineering.—Liu, Y., Fu, W., Seese, K., Yin, A., Yin, H. Ectopic brown adipose tissue formation within skeletal muscle after brown adipose progenitor cell transplant augments energy expenditure. FASEB J. 33, 8822–8835 (2019). http://www.fasebj.org

Engineered human brown adipocyte microtissues improved glucose and insulin homeostasis in high fat diet-induced obese and diabetic mice

“…A recent study showed that about 12.1% of immortalized mouse BAPs survived in SCID mice 7 days after transplantation with Matrigel, while only 2.7% of mature BA (differentiated from BAPs in vitro) were live after 7 days using the same transplantation procedure [18]. Consequently, only BAPs showed an efficacy in vivo [18]. However, there are potential problems with using BAPs.…”

“…However, there are potential problems with using BAPs. First, the differentiation efficiency in vivo is typically low [18]. Second, proliferating cells have a higher tumorigenic risk, especially for immortalized cells.…”

“…Prior studies showed transplanting mouse BATs prevented/reversed OB and its associated metabolic disorders. It should be noted that only transplanting intact 3D BAT, not dissociated single BAs, achieved long-term survival and function [17][18][19][20], indicating that 3D BAT, not single BAs, should be used as therapeutics in the future. Researchers typically inject cultured BAPs with Matrigel to mimic a 3D tissue.…”

“…Researchers typically inject cultured BAPs with Matrigel to mimic a 3D tissue. Matrigel can both restrict the cells at the transplantation size and enhance their survival [18]. However, Matrigel is extracted from mouse tumor tissue and is not chemically defined, and not compatible with clinical applications.…”

“…An alternative approach to overcome these problems is to augment BAT mass and activity via tissue transplantation. Several groups transplanted BAT (0.1-0.2 g) from healthy mouse donors to diet-induced or genetically obese mice [17][18][19][20]. The transplantation significantly reduced plasma glucose, triglyceride, lipid levels, body weight gain, fat composition, and hepatic steatosis [19,20] while increasing the body energy expenditure, oxygen consumption rate (OCR), glucose homeostasis, and insulin sensitivity [21,22].…”