Inhibition of Adipocyte and Preadipocyte Fusion Reduces Abdominal Adipose Tissue Mass in Obese Mice

In adipose tissue, adipose stem cell‐differentiated preadipocytes are the committed adipocytes for adipogenesis. The adipocyte hypertrophy and insufficiency of adipogenesis in abdominal adipose tissue underscore the obesity‐associated metabolic syndrome. The moribund hypertrophic adipocytes display robust viability given the overall turnover rate of adipocytes is less than 10% annually in adults. The short of adipogenesis and robustness in hypertrophic adipocyte may be correlated by adipocyte and preadipocyte fusion, an event that would lead to consume preadipocytes while energizing hypertrophic adipocytes. We therefore hypothesize that the fusion of adipocytes and preadipocytes prevents adipogenesis and vitalizes hypertrophic adipocytes, thereby, contributes to the pathogenesis of obesity. By 3D co‐culturing adipocytes and preadipocytes and immunostaining their marker proteins, PPARγ of adipocytes (green in nuclei) and DLK1 of preadipocytes (red in cytoplasma), we found cell fusion occurred between them at a rate of approximate 14%. These fused adipocytes featured one or two green nuclei situated near plasma membrane in the red‐stained cytoplasm. Similarly, this cell fusion was also observed in diet‐induced C57BL/6 obese mice after immunostaining abdominal adipose tissue using cytoplasmic marker proteins, FABP in adipocytes (red) and DLK1 in preadipocytes (green). The fused adipocytes had distinct yellowed cytoplasmic rim in the overlaid confocal images. Co‐culturing Cre‐expressed adipocytes with preadipocytes that were stably transfected with LoxP‐flanked GFP and RFP construct (Loxp/GFP/RFP, green), a Cre‐controlled color switchable system, in a 3D mode, we visualized red cells–the fused adipocytes–among the green preadipocytes by fluorescence microscopy. The appearance of red in the fused cells came from the cleavage of loxP‐flanked GFP in preadipocytes by Cre from Cre‐expressed adipocytes, a process concurrently leading to RFP expression that could be only occurred after adipocyte and preadipocyte fusion. However, when the expression of T‐cadherin, a specific adhesive molecule on adipocytes, was silenced in Cre‐adipocytes by T‐cadherin shRNA lentivirus transfection, the adipocyte fusion was blocked as no red cell observed. When these LoxP/GFP/RFG‐borne preadipocytes were injected into abdominal fat tissue in diet‐induced obese Cre‐mice–the ones with adipose tissue‐specifically expressed Cre, in vivo imaging also detected red adipocytes–an indication of cell fusion. Functionally, after injection of T‐cadherin shRNA lentivirus into diet‐induced obese Cre‐mice, the body weight in these mice was significantly decreased 8 weeks postinjection. Consistently, the MRI images demonstrated the abdominal fat mass was markedly decreased. These results for the first time demonstrated that fusion of adipocytes and preadipocytes contributes to the pathogenesis of obesity. Understanding these pathological processes may facilitate developing effective remedies in the treatment of obesity. Support or Funding Information Supported by NIH R01HL115068