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

Abstract

Introduction The Endosialin/CD248/TEM1 protein is expressed in adipose tissue and its expression increases with obesity. Recently, genetic deletion of CD248 has been shown to protect mice against atherosclerosis on a high fat diet. Objectives We investigated the effect of high fat diet feeding on visceral fat pads and circulating lipid profiles in CD248 knockout mice compared to controls. Methods From 10 weeks old, CD248−/− and +/+ mice were fed either chow (normal) diet or a high fat diet for 13 weeks. After 13 weeks the metabolic profiles and relative quantities of circulating lipid species were assessed using ultra high performance liquid chromatography-quadrupole time-of flight mass spectrometry (UHPLC–MS) with high resolution accurate mass (HRAM) capability. Results We demonstrate a specific reduction in the size of the perirenal fat pad in CD248−/− mice compared to CD248+/+, despite similar food intake. More strikingly, we identify significant, diet-dependent differences in the serum metabolic phenotypes of CD248 null compared to age and sex-matched wildtype control mice. Generalised protection from HFD-induced lipid accumulation was observed in CD248 null mice compared to wildtype, with particular reduction noted in the lysophosphatidylcholines, phosphatidylcholines, cholesterol and carnitine. Conclusions Overall these results show a clear and protective metabolic consequence of CD248 deletion in mice, implicating CD248 in lipid metabolism or trafficking and opening new avenues for further investigation using anti-CD248 targeting agents.

Sex-specific effects of CD248 on metabolism and the adipose tissue lipidome

“…The reduced weight gain phenotype seen in Cd248 -/males fed a high fat diet, whilst relatively mild, is consistent and robust, having been previously reported by a separate research group using a Cd248 -/mouse on a different background strain [11]. No such differences were seen in weight gain for Cd248 -/fed a chow diet [16]. Additionally, no differences were identified in circulating lipid levels or lipid accumulation in Cd248 -/mice fed chow diet, whilst these were identified on HFD [16].…”

“…No such differences were seen in weight gain for Cd248 -/fed a chow diet [16]. Additionally, no differences were identified in circulating lipid levels or lipid accumulation in Cd248 -/mice fed chow diet, whilst these were identified on HFD [16]. These previous findings suggest that HFD stress is required to induce a metabolic syndrome phenotype in the absence of Cd248.…”

“…In the adult, increased expression has been associated with pathological tissue remodelling and it is seen particularly highly expressed in cancer associated fibroblasts [12], in fibrotic kidney disease [13], in inflammation associated with arthritis [14], and in atherosclerotic plaques [15]. Recently, Cd248 has been associated with lipid accumulation and metabolism [11,16]. Specifically, Cd248 -/mice are protected from obesity and glucose intolerance when fed a high fat diet [11] and the serum lipid profile of Cd248 -/mice on a high fat diet is altered [16], suggesting differences in lipid synthesis pathways.…”

“…Recently, Cd248 has been associated with lipid accumulation and metabolism [11,16]. Specifically, Cd248 -/mice are protected from obesity and glucose intolerance when fed a high fat diet [11] and the serum lipid profile of Cd248 -/mice on a high fat diet is altered [16], suggesting differences in lipid synthesis pathways. Here, we demonstrate that reduced weight gain in Cd248 -/mice on a high fat diet is, in fact, sex specific; with only males showing this phenotype.…”

No Significant Association Between Plasma Endosialin Levels and the Presence or Severity of Coronary Artery Disease

“…Endosialin-knockout mice showed less inflammation with improvement in insulin sensitivity and glucose tolerance [13]. Furthermore, endosialin-knockout mice had a reduction in fat pad size and serum cholesterol levels [19]. These findings thus implicate endosialin in obesity, glucose tolerance and lipid metabolism, and these effects of endosialin may affect the progression of atherosclerosis.…”