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Thermogenic adipocytes regulate axonal growth, innervation, and thermogenic remodeling of white adipose tissue via retinoic acid‐ephrin A5‐dependent pathway
Author(s) -
Ziouzenkova Ouliana,
Shen Qiwen,
Rumana Yasmeen,
Popovich Phillip
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb145
Subject(s) - thermogenesis , medicine , endocrinology , biology , white adipose tissue , adipose tissue , microbiology and biotechnology
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. Objective We test thermogenic adipocytes in WAT regulate neuronal growth. Methods We 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. Results We 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 rescues diminished innervation in obese WT mice. The gain of function studies identified ephrin A5 as an inducer of innervation. Ephrin A5 and A4 are under the control of aldehyde dehydrogenase 1a1 (Aldh1a1) and retinoic acid which represses expression of ephrins and axon growth. Conclusions Our data support a neuroregulatory role of thermogenic adipocytes and a mechanism for WAT innervation via bidirectional communication between thermogenic adipocytes and the nervous system. Support or Funding Information This research was supported by the American Egg Board (20020728), from Novo Nordisk Pharmaceuticals (10040042), and the Ray W. Poppleton Endowment (P.G.P., J.M.), and NSF Center funding (EEC‐0914790). The project was supported by NIH grants R21OD017244 and R01NS047175 (P.G.P., J.M.), and by the National Center for Research Resources UL1RR025755, UL1TR001070, and NCI P30CA16058 (OSUCCC), and supported by the NIH Roadmap for Medical Research.