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C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.

ABSTRACT: C1q/TNF-related proteins (CTRPs) are a family of secreted regulators of glucose and lipid metabolism. Here, we describe CTRP11, a novel and phylogenetically conserved member of the C1q family. Our studies revealed that white and brown adipose are major tissues that express CTRP11, and its expression is acutely regulated by changes in metabolic state. Within white adipose tissue, CTRP11 is primarily expressed by stromal vascular cells. As a secreted multimeric protein, CTRP11 forms disulfide-linked oligomers. Although the conserved N-terminal Cys-28 and Cys-32 are dispensable for the assembly of higher-order oligomeric structures, they are unexpectedly involved in modulating protein secretion. When co-expressed, CTRP11 forms heteromeric complexes with closely related CTRP10, CTRP13, and CRF (CTRP14) via the C-terminal globular domains, combinatorial associations that potentially generate functionally distinct complexes. Functional studies revealed a role for CTRP11 in regulating adipogenesis. Ectopic expression of CTRP11 or exposure to recombinant protein inhibited differentiation of 3T3-L1 adipocytes. The expression of peroxisome proliferator-activated receptor-? and CAAT/enhancer binding protein-?, which drive the adipogenic gene program, was markedly suppressed by CTRP11. Impaired adipogenesis was caused by a CTRP11-mediated decrease in p42/44-MAPK signaling and inhibition of mitotic clonal expansion, a process essential for adipocyte differentiation in culture. These results implicate CTRP11 as a novel secreted regulator of adipogenesis and highlight the potential paracrine cross-talk between adipocytes and cells of the stromal vascular compartment in maintaining adipose tissue homeostasis.

SUBMITTER: Wei Z

PROVIDER: S-EPMC3624406 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.

Wei Zhikui Z Seldin Marcus M MM Natarajan Niranjana N Djemal David C DC Peterson Jonathan M JM Wong G William GW

The Journal of biological chemistry 20130228 15

C1q/TNF-related proteins (CTRPs) are a family of secreted regulators of glucose and lipid metabolism. Here, we describe CTRP11, a novel and phylogenetically conserved member of the C1q family. Our studies revealed that white and brown adipose are major tissues that express CTRP11, and its expression is acutely regulated by changes in metabolic state. Within white adipose tissue, CTRP11 is primarily expressed by stromal vascular cells. As a secreted multimeric protein, CTRP11 forms disulfide-link ...[more]

PMID: 23449976

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Project description:Mesenchymal stromal cells (MSCs) transplantation offers an attractive alternative in myocardial infarctive therapy. However, poor cell engraftment and survival limit their restorative capacity. C1q/tumor necrosis factor-related protein-3 (CTRP3) inhibits reverse remodeling after myocardial infarction (MI) and was found to be secreted by MSCs in our preliminary experiments. We examined whether the overexpression of CTRP3 improved the survival of transplanted MSCs and augmented their efficacy on MI and whether silencing CTRP3 attenuated these effects. For gain-of-function analysis, MSCs overexpressing CTRP3 (LvC3-MSCs), control virus-transfected MSCs (LvNull-MSCs), MSCs alone, or phosphate-buffered saline (PBS) were injected into the peripheral areas of the infarction immediately after coronary artery ligation. For loss-of-function analysis, mice subjected to MI were randomized into groups and administered CTRP3-knockdown MSCs (LvshC3-MSCs), Lvshctrl-MSCs, MSCs, or PBS. Survival rates, cardiac function, and myocardial remodeling in mice were evaluated after 4 weeks. Injection of MSCs or LvNull-MSCs improved the left ventricular ejection fraction, inhibited cardiac fibrosis, and regulated cellular profiles of the infarction border zone 4 weeks after MI compared with those in the PBS group. Furthermore, overexpression of hCTRP3 promoted the efficacy of MSCs in the treatment of MI. However, knocking down CTRP3 impaired that. Coculture experiments confirmed that hCTRP3-enriched conditioned medium (CM) promoted MSCs migration and protected against H2O2-induced cell damage. Conversely, CM from C3-/- MSCs (CTRP3 knock out) significantly reduced the migration and antioxidative effects of MSCs. CTRP3 protein alone promoted MSCs proliferation and migration by upregulating matrix metalloproteinase 9 (MMP9) and protecting against oxidation by increasing superoxide dismutase 2 (SOD2) and metallothionein 1/2 (MT1/2) expression; and these effects were blocked by pretreatment with the extracellular signal-regulated kinase (ERK1/2) inhibitor U0126. Overexpression of CTRP3 significantly improved the MSCs-based efficacy on MI by increasing cell survival and retention via a mechanism involving ERK1/2-MMP9 and ERK1/2-SOD2/MT1/2 signaling.

Dataset Information

C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.

Publications

C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis.

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