Galectin-3 promotes the adipogenic differentiation of PDGFRα+ cells and ectopic fat formation in regenerating muscle

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFR alpha(+) mesenchymal progenitors, the processes underlying this adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing and mass spectrometry. Our single-cell RNA sequencing analysis identified a small PDGFR alpha(+) cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPAR gamma signals in PDGFR alpha(+) cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 knockout mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

Automated summary

The worldwide prevalence of obesity is connected to lifestyle-related diseases. This study investigated the processes underlying the formation of intermuscular adipose tissue (IMAT) in obese mice and identified a small population of PDGFR alpha(+) cells that were strongly directed towards adipogenesis. The increase in galectin-3 in the interstitial environments was found to activate adipogenic signals, while the knockout of galectin-3 significantly suppressed IMAT formation during muscle regeneration. These findings provide insights into the microenvironmental networks during muscle regeneration and highlight potential therapeutic targets for IMAT formation in obesity.