The findings indicate a less successful outcome for obese patients with psychiatric disorders (particularly adjustment disorders, depression and/or personality disorders), compared to patients not mentally ill. An eating disorder preceding surgery, however, was not a negative predictor of success following bariatric surgery. To improve outcome of bariatric surgery in obese patients with psychiatric disorders, more individual psychosocial intervention strategies are necessary.

Medullary thymic epithelial cells (mTEC) play an important and unique role in central tolerance, expressing tissue-restricted Ags (TRA) which delete thymocytes autoreactive to peripheral organs. Since deficiencies in this cell type or activity can lead to devastating autoimmune diseases, it is important to understand the factors which regulate mTEC differentiation and function. Lymphotoxin (LT) ligands and the LTβR have been recently shown to be important regulators of mTEC biology; however, the precise role of this pathway in the thymus is not clear. In this study, we have investigated the impact of this signaling pathway in greater detail, focusing not only on mTEC but also on other thymic stromal cell subsets. LTβR expression was found in all TEC subsets, but the highest levels were detected in MTS-15+ thymic fibroblasts. Rather than directing the expression of the autoimmune regulator Aire in mTEC, we found LTβR signals were important for TRA expression in a distinct population of mTEC characterized by low levels of MHC class II (mTEClow), as well as maintenance of MTS-15+ fibroblasts. In addition, thymic stromal cell subsets from LT-deficient mice exhibit defects in chemokine production similar to that found in peripheral lymphoid organs of Lta−/− and Ltbr−/− mice. Thus, we propose a broader role for LTα1β2-LTβR signaling in the maintenance of the thymic microenvironments, specifically by regulating TRA and chemokine expression in mTEClow for efficient induction of central tolerance.

The main physiological function of adipose-derived stromal/progenitor cells (ASC) is to differentiate into adipocytes. ASC are most likely localized at perivascular sites in adipose tissues and retain the capacity to differentiate into multiple cell types. Although cell surface markers for ASC have been described, there is no complete consensus on the antigen expression pattern that will precisely define these cells. DLK1(PREF1) is an established marker for mouse adipocyte progenitors which inhibits adipogenesis. This suggests that DLK1(PREF1) could be a useful marker to characterize human ASC. The DLK1(PREF1) status of human ASC is however unknown. In the present study we isolated ASC from the heterogeneous stromal vascular fraction of subcutaneous abdominal fat pats of adult women. These cells were selected by their plastic adherence and expanded to passage 5. The ASC were characterized as relatively homogenous cell population with the capacity to differentiate in vitro into adipocytes, chondrocytes, and osteoblasts and the immunophenotype CD105⁺/CD90⁺/CD34⁺/CD31⁻/FABP4⁻. The ASC were positive for DLK1(PREF1) which was well expressed in proliferating and density arrested cells but downregulated in the course of adipogenic differentiation. To investigate whether DLK1(PREF1) plays a role in the regulation of adipogenesis in these cells RNAi-mediated knockdown experiments were conducted. Knockdown of DLK1(PREF1) in differentiating ASC resulted in a significant increase of the expression of the adipogenic key regulator PPARγ2 and of the terminal adipogenic differentiation marker FABP4. We conclude that DLK1(PREF1) is well expressed in human ASC and acts as a negative regulator of adipogenesis. Moreover, DLK1(PREF1) could be a functional marker contributing to the characterization of human ASC.

Long-term weight-loss (WL) interventions reduce insulin serum levels, protect from obesity, and postpone age-associated diseases. The impact of long-term WL on adipose-derived stromal/progenitor cells (ASCs) is unknown. We identified DIRAS3 and IGF-1 as long-term WL target genes up-regulated in ASCs in subcutaneous white adipose tissue of formerly obese donors (WLDs). We show that DIRAS3 negatively regulates Akt, mTOR and ERK1/2 signaling in ASCs undergoing adipogenesis and acts as a negative regulator of this pathway and an activator of autophagy. Studying the IGF-1–DIRAS3 interaction in ASCs of WLDs, we demonstrate that IGF-1, although strongly up-regulated in these cells, hardly activates Akt, while ERK1/2 and S6K1 phosphorylation is activated by IGF-1. Overexpression of DIRAS3 in WLD ASCs completely inhibits Akt phosphorylation also in the presence of IGF-1. Phosphorylation of ERK1/2 and S6K1 is lesser reduced under these conditions. In conclusion, our key findings are that DIRAS3 down-regulates Akt–mTOR signaling in ASCs of WLDs. Moreover, DIRAS3 inhibits adipogenesis and activates autophagy in these cells.

We demonstrate that adipose-derived stromal/progenitor cells isolated from abdominal subcutaneous fat pads of adult donors successively enter replicative senescence after long-term cultivation. This is characterized by enlarged cell size, flattened morphology, and upregulated senescence-associated β-galactosidase activity. Moreover, the senescence- associated cyclin-dependent kinase inhibitors p16(Ink4A) and p21(Cip1) were induced correlating with activation of the G1/S cell cycle inhibitor retinoblastoma protein and terminal proliferation arrest. The number of cells in the adipose-derived stromal/progenitor cell population with high adipogenic capacity declined inversely with the increase of senescent cells. Adipogenic hormone cocktail induced expression of the adipogenic key regulators peroxisome proliferator-activated receptor-γ2 and CCAAT/enhancer-binding protein α was significantly reduced in senescent adipose-derived stromal/ progenitor cells. Furthermore, the expression of the adipogenic differentiation genes fatty acid binding protein-4, adiponectin, and leptin and the formation of fat droplets were impaired. We conclude cellular senescence contributes to dysfunctions in adipose-derived stromal/progenitor cell replication, adipogenesis, triglyceride storage, and adipokine secretion.