Thermogenic adipocytes regulate axonal growth, innervation, and thermogenic remodeling of white adipose tissue via retinoic acid-ephrin A5-dependent pathway

Innervation regulates lipolysis, thermogenesis, and vascularization in white adipose tissue (WAT) and undergoes pathological changes in obesity. It is widely believed that mechanisms responsible for innervation during WAT remodeling depend on the central nervous system or neural precursor cells. ObjectiveWe test thermogenic adipocytes in WAT regulate neuronal growth. MethodsWe examined this hypothesis using gene expression analysis, neronal and adipose co-cultures in vitro. We also used diet induced obesity models including a xenograft model inducing thermogenesis in WAT in obese mice. ResultsWe showed that thermogenic adipocytes in WAT efficiently stimulate neurite outgrowth in vitro and innervation in vivo. We identified their axon guiding secretome that includes ephrin A5 and A4, semaphorins and adamtS9 protease. Diet-induced and genetically obese mice have decreased expression of these axon guiding molecules in WAT. However, engraftment of encapsulated Aldh1a1−/− adipocytes in intra-abdominal WAT resc...