C1q/TNF-Related Protein 3 (CTRP-3) Deficiency of Adipocytes Affects White Adipose Tissue Mass but Not Systemic CTRP-3 Concentrations

Abstract

CTRP-3 (C1q/TNF-related protein-3) is an adipokine with endocrine and immunological function. The impact of adipocyte CTRP-3 production on systemic CTRP-3 concentrations and on adipocyte biology is unknown. A murine model of adipocyte CTRP-3 knockout (KO) was established (via the Cre/loxP system). Serum adipokine levels were quantified by ELISA and adipose tissue (AT) gene expression by real-time PCR. Preadipocytes were isolated from AT and differentiated into adipocytes. Comparative transcriptome analysis was applied in adipocytes and liver tissue. Body weight and AT mass were reduced in CTRP-3 KO mice together with decreased serum leptin. In primary cells from visceral AT of KO mice, expression of adiponectin, progranulin, and resistin was induced, while peroxisome proliferator activated receptor γ (PPARγ) was decreased. M1/M2 macrophage polarization markers were shifted to a more anti-inflammatory phenotype. CTRP-3 expression in AT did not contribute to serum concentrations. AT and liver morphology remained unaffected by CTRP-3 KO. Myelin transcription factor 1-like (Myt1l) was identified as a highly upregulated gene. In conclusion, adipocyte CTRP-3 has a role in adipogenesis and AT weight gain whereas adipocyte differentiation is not impaired by CTRP-3 deficiency. Since no effects on circulating CTRP-3 levels were observed, the impact of adipocyte CTRP-3 KO is limited to adipose tissue. Modified AT gene expression indicates a rather anti-inflammatory phenotype.

Anti-Inflammatory Effects of C1q/Tumor Necrosis Factor-Related Protein 3 (CTRP3) in Endothelial Cells

“…These findings strongly argue against adipose tissue as the dominant site of Ctrp3 expression (at least in mice) leaving the status of CTRP3 as a classical adipokine in question. These results and conclusions are in logical accordance with the recently published observation that adipocyte CTRP3 deficiency does not significantly alter systemic CTRP3 concentrations, indicating alternative and likely more potent sources for the circulating protein levels [14]. Importantly, the observation of pronounced Ctrp3 expression in well-perfused tissues and organs, especially in the aorta, suggests a putative role of this protein in endothelium-related processes.…”

“…Similar to its paralog adiponectin, systemic CTRP3 is negatively associated with obesity [11,12]. Among diverse regulatory effects, CTRP3 has recently been reported to affect adipose tissue mass and obesity [13][14][15]; to exert protective effects on metabolic dysregulations, such as hepatic steatosis and insulin resistance [16,17]; and to exhibit anti-inflammatory properties in diverse pathophysiological contexts [18,19]. Of particular interest, CTRP3 antagonizes adipose tissue inflammation induced by lipopolysaccharides (LPS) through the Toll-like receptor (TLR) 4 in vitro and in vivo [20,21] and represents an effective inhibitor of metabolic inflammation mediated by free fatty acids and TLR4 [22].…”

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation

“…Whole-body CTPR3 knockout mice on a HFD show a reduced epididymal white AT weight and a lower expression of genes involved in lipogenesis, lipolysis, and adipogenesis (Maeda, T,2020). However, in adipocyte-specific CTRP3 knockout mice, neither adipocyte differentiation nor circulating CTRP3 concentrations are affected ( 230 ), indicating that compensatory mechanisms may be involved in rescuing the normal adipocyte phenotype.…”