Abstract
Accumulation of visceral (VIS) is a predictor of metabolic disorders and insulin resistance. This is due in part to the limited capacity of VIS fat to buffer lipids allowing them to deposit in insulin-sensitive tissues. Mechanisms underlying selective hypertrophic growth and tissue remodeling properties of VIS fat are not well understood. We identified subsets of adipose progenitors (APs) unique to VIS fat with differential Cd34 expression and adipogenic capacity. VIS low (Cd34 low) APs are adipogenic, whereas VIS high (Cd34 high) APs are not. Furthermore, VIS high APs inhibit adipogenic differentiation of SUB and VIS low APs invitro through the secretion of soluble inhibitory factor(s). The number of VIS high APs increased with adipose tissue expansion, and their abundance invivo caused hypertrophic growth, fibrosis, inflammation, and metabolic dysfunction. This study unveils the presence of APs unique to VIS fat involved in the paracrine regulation of adipogenesis and tissue remodeling.
Highlights
Obesity is a growing public health problem and is associated with cardiovascular complications (Calle et al, 1999)
Murine VIS Fat in Mice Contains Two adipose progenitors (APs) Subsets with Distinct Adipogenic Capacity Using a previously established fluorescence-activated cell sorting (FACS) strategy (Figure S1) to isolate White adipose tissue (WAT) APs from C57BL/6 (B6) mice (Rodeheffer et al, 2008), we identified two major cell populations in VIS fat of B6 mice distinguished by their differential expression of CD34 (Figure 1A)
Consistent with lipid accumulation, SUB and VIS low APs expressed 8- and 7-fold more Pparg mRNA, respectively, as compared to VIS high APs (Figure 1D). These cells had far greater expression of the Pparg target Fabp4, which was enhanced by 4- and 8-fold in SUB and VIS low APs, respectively, as compared to VIS high APs (Figure 1E). To verify whether these differences in adipogenic regulators persisted in cultured and differentiated AP subsets, we sorted SUB, VIS low, and VIS APs and differentiated them in the presence of a differentiation media (DM) containing dexamethasone, insulin, and IBMX for 3 days followed by growth media for 3 more days
Summary
Obesity is a growing public health problem and is associated with cardiovascular complications (Calle et al, 1999). Studies of adipogenesis in VIS and subcutaneous (SUB) fat have yielded conflicting results, with most in vitro studies showing increased adipogenesis in cultured SUB but not VIS APs (Grandl et al, 2016; Joe et al, 2009; Macotela et al, 2012), whereas in vivo studies reported enhanced adipogenesis in VIS but not in SUB fat especially in response to dietary obesity (Jeffery et al, 2015; Kim et al, 2014; Wang et al, 2013) The reasons for these discrepant findings are not currently known, but there is an agreement that, during the initial phase of WAT expansion, hypertrophic growth predominates, suggesting the existence of a mechanism that negatively regulates adipogenesis
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