Skeletal muscle provides a pro‐browning microenvironment for transplanted brown adipose tissue to maintain its effect to ameliorate obesity in ob/ob mice

Abstract

Brown adipose tissue (BAT) transplantation is a promising means of increasing whole‐body energy metabolism to ameliorate obesity. However, the changes in BAT following transplantation and the effects of the microenvironment of the recipient site on graft function have yet to be fully characterized. Therefore, we aimed to determine the effects of transplanting BAT from C57BL/6 mice into the dorsal subcutaneous region or deep to the quadriceps femoris muscle of leptin‐deficient ob/ob mice. Subcutaneously transplanted BAT lost features of BAT and demonstrated greater inflammatory cell infiltration and more oil cysts 16 weeks following transplantation. By contrast, the sub‐muscularly transplanted BAT maintained features of BAT and was more highly vascularized. Interestingly, sub‐muscular BAT transplantation led to a significant increase in oxygen consumption and less inflammation in subcutaneous fat, which was associated with long‐term reductions in insulin resistance and body mass gain, whereas the subcutaneous transplants failed after 16 weeks. These results demonstrate that the beneficial effects of BAT transplantation depend upon the microenvironment of the recipient site. Skeletal muscle may provide a microenvironment that maintains the inherent features of BAT grafts over a long period of time, which facilitates a reduction in obesity and improvements in glucose homeostasis.

Use of brown adipose tissue transplantation and engineering as a thermogenic therapy in obesity and metabolic disease

“…Conversely, when BAT is transplanted into the interscapular region, it has been shown to maintain its characteristic browning and exhibit long‐term metabolic improvement. These findings suggest that the recipient site plays a significant role in determining the outcomes of BAT transplantation and highlight the importance of considering the specific anatomical location for optimal metabolic benefits 33 . Therefore, in order to maximize the metabolic improvement, optimized transplanting procedures and recipient regions need to be further explored.…”

“…According to Cai et al, subcutaneously grafted brown fat gradually lost its brown fat characteristics after 16 weeks, as well as exhibiting more inflammatory cell infiltration and oil cysts. Conversely, intramuscularly grafted brown fat retained its characteristics and was more vascularized 33 . Table 1 summarizes the characteristics of white, brown, and beige adipocytes.…”

The fates of different types of adipose tissue after transplantation in mice

“…For example, as shown in our previous study, the BAT transplanted submuscularly presented prolonged browning features and long-term metabolic improvements than that transplanted subcutaneously, which might result from the difference of paracrine cytokines and innervation of sympathetic system. 49 Therefore, whether the three kinds of adipose tissue transplanted to other recipient sites showed the same results remained unclear and required further exploration.…”

Progress and obstacles in transplantation of brown adipose tissue or engineered cells with thermogenic potential for metabolic benefits

“…Syngeneic intramuscular transplantation of brown fat fragments in rats showed that fat pads formed well in the recipient site based on the magnetic resonance imaging and ultrastructural studies ( 76 ). Our previous study showed that the transplanted BAT from WT mice deep into the quadriceps femoris muscle in ob/ob mice could maintain the BAT features up to 16 weeks, exerting a lasting influence on the reduction of body mass gain, increase of energy expenditure, and reduction of subcutaneous adipose tissue inflammation ( 33 ). The better microvascular foundation and more abundant secretion of paracrine factors acting as browning agents, such as irisin and other myokines in muscle microenvironment, were the possible mechanism for the long-term browning feature maintenance of intramuscular BAT transplantation ( 77 – 79 ).…”