Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation

Abstract

Background: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. Methods: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. Findings: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocytespecific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. Interpretation: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases

“…A recent study has reported that the transmembrane glycoprotein CD248 affects several pathways related to hypoxia in adipocytes and modulates the vascularity of WAT, establishing a link between the lack of oxygen and angiogenesis. They also observed an increase in CD248 expression in human white adipocytes that was positively associated with obesity and metabolic complications [159].…”

Exploring Therapeutic Targets to Reverse or Prevent the Transition from Metabolically Healthy to Unhealthy Obesity

“…Although the mechanisms involved are not fully understood, hypoxia is known to increase adipose expression of the transcriptional factor hypoxia inducible factor-1α (HIF-1α), which can induce inflammation, fibrosis and IR in rodent WAT [ 56 , 57 , 58 ]. Possibly related are the recently observed associations of CD248 with adipose tissue hypoxia, inflammation, and fibrosis [ 59 ]. CD248 is a sensing transmembrane glycoprotein that is highly expressed in WAT of individuals with obesity, IR and diabetes, and reduced after bariatric surgery [ 59 ].…”

“…Possibly related are the recently observed associations of CD248 with adipose tissue hypoxia, inflammation, and fibrosis [ 59 ]. CD248 is a sensing transmembrane glycoprotein that is highly expressed in WAT of individuals with obesity, IR and diabetes, and reduced after bariatric surgery [ 59 ]. In human adipocytes, in vitro knock down of CD248 by siRNA attenuated hypoxia-induced HIF-1α promoter activity, as well as the expression of a whole cluster of hypoxia-induced genes.…”

“…In human adipocytes, in vitro knock down of CD248 by siRNA attenuated hypoxia-induced HIF-1α promoter activity, as well as the expression of a whole cluster of hypoxia-induced genes. Furthermore, adipocyte-specific CD248 knockout in mice protected against high fat diet-induced insulin resistance, glucose intolerance and WAT dysfunction, the latter evidenced by increased vascularization, reduced HIF-1α, reduced macrophage infiltration, and reduced markers of fibrosis [ 59 ]. Therefore, adipose vascularization, its extracellular matrix composition, and CD248 could be targets for the prevention of adipose tissue transition to MUO.…”

Metabolic consequences for mice lacking Endosialin: LC–MS/MS-based metabolic phenotyping of serum from C56Bl/6J Control and CD248 knock‐out mice

“…CD248 (Endosialin/Tumour Endothelial Marker 1) is a transmembrane glycoprotein expressed widely by stromal cells including pericytes (Tomkowicz et al 2010 ; Naylor et al 2014 ), fibroblasts (MacFadyen et al 2005 ), osteoblasts (Naylor et al 2012 ) and adipocytes (Petrus et al 2019 ). CD248 expression is high on all mesenchymal cells in embryonic and new-born tissues but is expressed at very low levels postnatally in normal tissue (Rupp et al 2006 ).…”