Distinct adipocyte progenitor cells are associated with regional phenotypes of perivascular aortic fat in mice

Abstract

ObjectivePerivascular adipose tissue depots around the aorta are regionally distinct and have specific functional properties. Thoracic aorta perivascular adipose tissue (tPVAT) expresses higher levels of thermogenic genes and lower levels of inflammatory genes than abdominal aorta perivascular adipose tissue (aPVAT). It is not known whether this distinction is due to the in-vivo functional environment or to cell-autonomous traits that persist outside the in-vivo setting. In this study, we asked whether the progenitor cells in tPVAT and aPVAT have cell-autonomous traits that lead to formation of regionally distinct PVAT.MethodsWe performed microarray analysis of thoracic and abdominal peri-aortic adipose tissues of C57Bl/6J mice to define gene expression profile of each depot. To derive adipocyte progenitor cells, C57Bl/6J mice were sacrificed and thoracic and abdominal aorta fragments were embedded in Matrigel and cultured under pro-angiogenic conditions. Adipogenesis was induced using the Ppar-γ agonist rosiglitazone, a thiazolidinedione (TZD). TZD-induced adipocyte populations were analyzed using immunofluorescence and qRT-PCR.ResultsMicroarray analysis showed that tPVAT expressed higher levels of transcription factors related brown adipose tissue development compared to aPVAT. Classic brown adipose tissue (BAT) genes such as Ucp-1, Prdm16, Dio2, Slc27a displayed a concordant trend of higher level expression in tPVAT, while white adipose tissue (WAT) genes such as Hoxc8, Nnat, Sncg, and Mest were expressed at a higher level in aPVAT. The adipokines resistin and retinol binding protein 4 were also higher in aPVAT. Furthermore, adipocyte progenitors from abdominal and thoracic aortic rings responded to TZD with expression of canonical adipocyte genes Acrp30, Plin1, and Glut4. Adipocytes differentiated from thoracic aorta progenitors displayed markedly higher induction of Ucp-1 and Cidea.ConclusionsThoracic aorta PVAT expresses higher levels of brown adipocyte transcription factors than aPVAT. Precursor cells from the thoracic aorta give rise to adipocytes that express significantly higher levels of Ucp-1 and Cidea ex vivo, suggesting that progenitor cells in tPVAT and aPVAT have cell-autonomous properties that dictate adipocyte phenotype.

“Multiple human adipocyte subtypes and mechanisms of their development”

“…As an alternative approach to studying human adipocyte subtypes and their development, we leveraged a recent finding by our laboratory that allows us to generate large numbers of mesenchymal progenitor cells from human adipose tissue with little loss of multipotency [17][18][19].…”

Perivascular adipose tissue in cardiovascular diseases – an update

“…The molecular phenotype of tPVAT involves the Ucp-1, CIDE-A, and PRDM16 positivity, along with the TCF-1 negativity, in a similar manner to that of BAT (5,11). In contrast, aPVAT adipocytes have a phenotype similar to WAT cells (5,12), expressing a spectrum of genes codifying characteristic markers such as adiponectin, resistin, lipoprotein lipase (LPL), and glyceraldehyde 3-phosphate dehydrogenase (G3PDH) (7,11,12).…”

“…Supplementary, aPVAT is less vascularized compared to tPVAT, synthesizes a panel of cytokines, and contains more fibroblasts, macrophages, and other immune cells, in physiological conditions (6). Hence, aPVAT is more pro-inflammatory and more atherogenic than tPVAT, corresponding to its high concentration in the abdominal region of the aorta (12).…”

Potential role of perivascular adipose tissue in modulating atherosclerosis

“…In contrast, PVAT surrounding the upper thoracic aorta of lean, healthy humans may exhibit a morphology similar to brown adipose tissue; however, the majority of studies report that white adipocytes predominate in human PVAT depots [9]. Conversely, PVAT surrounding the thoracic aorta of rodents exhibits a predominant brown phenotype, whereas PVAT surrounding the abdominal aorta is phenotypically a mixture of white and brown [10]. As a metabolically active endocrine tissue, PVAT is ideally positioned to directly govern vascular pathophysiology relative to other fat depots [1,8,11].…”