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

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.

Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro.

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system.

Role of progranulin in adipose tissue innate immunity.

Regulation of progranulin in adipocytes and its role in inflammation is poorly understood. AIM: (i) to investigate regulation of progranulin in adipocyte differentiation and adipose tissue compartments, (ii) to address progranulin expression in two murine (C57BL/6) models of inflammation. RESULTS: Progranulin expression was induced during adipocyte differentiation. Neither estradiol nor testosterone or metabolic stimuli such as glucose and insulin modified progranulin synthesis. Fatty acids, bile acids and incretins GLP-1 and GIP-1 exerted potent and differential effects on progranulin secretion. LPS, TNF and IL6 significantly increased progranulin secretion. TLR9 agonists decreased and TLR1/2, TLR3, TLR5, and TLR2/6 ligands increased progranulin expression. TLR3-mediated progranulin induction was abrogated by inhibitors of NF-κB and PI3K pathways. Progranulin expression between murine epididymal and subcutaneous adipose tissue did not differ in total adipose tissue, in isolated adipocytes or in the stromal-vascular cell fraction (SVC). However, SVC expressed significantly higher levels of progranulin than adipocytes at all sites. In adipocytes, female mice had significantly higher progranulin expression at all sites. An intra-peritoneal LPS challenge in mice did not affect adipose tissue progranulin expression, whereas peritoneal infection by S. aureus increased progranulin expression after 24 h. CONCLUSIONS: There are relevant sex-, site- and cell-specific effects on progranulin gene expression that is induced during adipocyte differentiation and modulated by various inflammatory and metabolic factors. Most importantly, ligands for TLR1/2 and TLR2/6 (recognizing S. aureus) in vitro and infection by S. aureus in vivo induce progranulin expression suggesting a role of adipocytes in protection against infection by gram-positive bacteria.