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. 2020 Oct 31;21(21):8168.
doi: 10.3390/ijms21218168.

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

Andreas Schmid  1 , Jonas Gehl  1 , Miriam Thomalla  1 , Alexandra Hochberg  1 , Anja Kreiß  1 , Marissa Patz  1 , Thomas Karrasch  1 , Andreas Schäffler  1
Affiliations

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

Andreas Schmid et al. Int J Mol Sci. .

Abstract

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.

Keywords: C1q/TNF-related protein-3; bariatric surgery; bile acids; incretins; low calorie diet; obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Baseline serum C1q/TNF-related protein-3 (CTRP-3) concentrations in patient cohorts of bariatric surgery and low-calorie formula diet. CTRP-3 serum concentrations were measured by ELISA. AT, adipose tissue; BS, bariatric surgery; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LCD, low-calorie formula diet; sc, subcutaneous; vis, visceral. (A) CTRP-3 serum levels are decreased in BS patients with diagnosed type 2 diabetes. (B) CTRP-3 serum levels are higher in females when compared to male patients within the LCD cohort. (C) CTRP-3 serum levels are lower in LCD patients with hypertension. (D) CTRP-3 expression is significantly higher in subcutaneous adipose tissue when compared to visceral adipose tissue in BS patients.
Figure 2
Figure 2
Correlation of baseline CTRP-3 serum levels with anthropometric and biochemical parameters. Adiponectin and CTRP-3 serum concentrations were measured by ELISA. Gene expression levels in adipose tissues were analyzed via RT-PCR. AT, adipose tissue; BS, bariatric surgery; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LCD, low calorie formula diet; sc, subcutaneous; vis, visceral. (A) Positive correlation of CTRP-3 and adiponectin serum concentrations within the BS cohort. (B) Positive correlation of CTRP-3 and adiponectin serum concentrations within the LCD cohort. (C) Positive correlation of serum CTRP-3 and HDL levels within the LCD cohort. (D) Positive correlation of CTRP-3 gene expression in subcutaneous and visceral adipose tissue of bariatric patients.
Figure 3
Figure 3
CTRP-3 serum concentrations decrease during weight loss induced by bariatric surgery or low-calorie diet, respectively. CTRP-3 serum concentrations were measured by ELISA. BS, bariatric surgery; LCD, low calorie formula diet; study points: V0, start of intervention; V1, 3 days post-surgery; V3, V6, V12 = 3, 6, 12 months after start of intervention. (A) Rapid and sustained decline of circulating CTRP-3 levels upon bariatric surgery. Outliers; * extreme values; # p < 0.001 when compared to V0; p = 0.024 between V1 and V3. (B) Sustained decline of circulating CTRP-3 levels during LCD. *, outliers; # p < 0.001 when compared to V0.
Figure 4
Figure 4
CTRP-3 gene expression is affected by bile acids and incretins in adipocytes in vitro. 3T3-L1 adipocytes were stimulated with bile acids, incretins and the cholesterol inhibitor simvastatin. CTRP-3 gene expression was analyzed by real-time PCR. BS, bariatric surgery; CA, cholic acid; CDCA, chenodeoxycholic acid; Ctrl., control; DCA, deoxycholic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GIP, glucose-dependent insulinotropic polypeptide; GLCA, glycolithocholic acid; GLP-1, glucagon-like peptide 1; LCD, low calorie formula diet; SVS, simvastatin; TDCA, taurodeoxycholic acid; THCA, taurohyocholic acid, TLCA, taurolithocholic acid; UDCA, ursodeoxycholic acid. (A) Downregulation of adipocyte CTRP-3 mRNA expression by CA and THCA. (B) CDCA inhibits CTRP-3 gene expression in adipocytes. (C) GLCA downregulates CTRP-3 gene expression in adipocytes. (D) GLP-1 downregulates CTRP-3 gene expression in adipocytes. (E) Adipocyte CTRP-3 mRNA levels are unaffected by simvastatin.
Figure 5
Figure 5
CTRP-3 and bile acid receptor expression in adipose tissue in murine models in vivo. CTRP-3 and bile acid receptor (FXR, TGR5) gene expression levels in murine adipose tissues and primary adipocytes (derived from adipose progenitor cells isolated from adipose tissue) were analyzed by RT-PCR. AT, adipose tissue; ia, intra-abdominal; Ctrl., control mice; FXR, farnesoid x receptor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; sc, subcutaneous; KO, adipocyte-specific CTRP-3 knock out mice; TGR5, G-protein coupled bile acid receptor. (A) CTRP-3 mRNA levels in intra-abdominal and in subcutaneous AT of wildtype mice (C57BL/6J; age 6 months; n = 11). (B) Elevated gene expression of FXR in intra-abdominal AT of CTRP-3 knockout mice (age 6 months; n = 10–11). (C) Elevated gene expression of TGR5 in intra-abdominal AT of CTRP-3 knockout mice (age 6 months; n = 7–12). (D) Decreased gene expression of FXR in primary adipocytes derived from subcutaneous AT of CTRP-3 knockout mice (n = 6). (E) TGR5 gene expression in primary adipocytes derived from subcutaneous AT of CTRP-3 knockout mice (n = 6). (F) Downregulation of FXR gene expression in intra-abdominal AT of wildtype mice (C57BL/6J; age 10 weeks; n = 5–9) by intraperitoneal injection of recombinant CTRP-3. (G) Induction of TGR5 gene expression in intra-abdominal AT of wildtype mice (C57BL/6J; age 10 weeks; n = 5–9) by intraperitoneal injection of recombinant CTRP-3.
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References

    1. Schäffler A., Buechler C. CTRP family: Linking immunity to metabolism. Trends Endocrinol. Metab. 2012;23:194–204. doi: 10.1016/j.tem.2011.12.003. - DOI - PubMed
    1. Wong G.W., Krawczyk S.A., Kitidis-Mitrokostas C., Revett T., Gimeno R., Lodish H.F. Molecular, biochemical and functional characterizations of C1q/TNF family members: Adipose-tissue-selective expression patterns, regulation by PPAR-γ agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem. J. 2008;416:161–177. doi: 10.1042/BJ20081240. - DOI - PMC - PubMed
    1. Akiyama H., Furukawa S., Wakisaka S., Maeda T. CTRP3/cartducin promotes proliferation and migration of endothelial cells. Mol. Cell. Biochem. 2007;304:243–248. doi: 10.1007/s11010-007-9506-6. - DOI - PubMed
    1. Maeda T., Wakisaka S. CTRP3/cartducin is induced by transforming growth factor-β1 and promotes vascular smooth muscle cell proliferation. Cell Biol. Int. 2010;34:261–266. doi: 10.1042/CBI20090043. - DOI - PubMed
    1. Otani M., Furukawa S., Wakisaka S., Maeda T. A novel adipokine C1q/TNF-related protein 3 is expressed in developing skeletal muscle and controls myoblast proliferation and differentiation. Mol. Cell. Biochem. 2015;409:271–282. doi: 10.1007/s11010-015-2531-y. - DOI - PubMed

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