TY  - JOUR
AB  -  Phosphatase and tensin homolog (PTEN) hamartoma tumour syndrome (PHTS) is a rare disorder caused by germline mutations in the tumour suppressor gene PTEN, a key negative regulator of phosphatidylinositol 3-kinase (PI3K)/AKT signalling. Children with PHTS often develop lipomas, for which only surgical resection is available as treatment. We investigated the effects of the selective PI3K-inhibitor alpelisib on Pten-deficient lipomas. After incubation with alpelisib or the non-selective PI3K inhibitor wortmannin, we analysed histology, gene expression, and Pi3k pathway in lipoma and control epididymal adipose tissue (epiWAT). Alpelisib increased adipocyte area in lipomas compared to epiWAT. Baseline gene expression showed higher levels of markers for proliferation (Pcna), fibrosis (Tgfb1), and adipogenesis (Pparg) in lipomas, while hormone-sensitive lipase expression was lower than in epiWAT. Following alpelisib incubation, target genes of Pi3k signalling and extracellular matrix factors were reduced. We confirmed Pi3k inhibition through detecting decreased Akt levels compared to control treatment. Human lipoma samples treated with alpelisib showed variable lipolysis responses, suggesting variability in therapeutic outcomes. We established an ex vivo model to study alpelisib effects on Pten-deficient lipomas. These results underscore the therapeutic potential of targeted PI3K inhibition in the treatment of PHTS-associated lipomas, particularly in cases that are inoperable.
AU  - Merz, L.M.*
AU  - Winter, K.*
AU  - Richter, S.*
AU  - Kallendrusch, S.*
AU  - Horn, A.*
AU  - Grunewald, S.*
AU  - Klöting, N.
AU  - Krause, K.*
AU  - Kiess, W.*
AU  - Le Duc, D.*
AU  - Garten, A.*
C1  - 73402
C2  - 56993
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Effects of alpelisib treatment on murine Pten-deficient lipomas.
JO  - Adipocyte
VL  - 14
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2025
SN  - 2162-3945
ER  - 

TY  - JOUR
AB  - S-adenosyl-homocysteine-hydrolase (AHCY) plays an important role in the methionine cycle regulating cellular methylation levels. AHCY has been reported to influence proliferation and differentiation processes in different cell types, e.g. in cancer cells and mouse embryonic stem cells. In the development of adipose tissue, both the proliferation and differentiation of adipocyte progenitor cells (APCs) are important processes, which in the context of obesity are often dysregulated. To assess whether AHCY might also be involved in cell proliferation and differentiation of APCs, we investigated the effect of reduced AHCY activity on human and mouse APCs in vitro. We show that the inhibition of AHCY using adenosine dialdehyde (AdOx) and the knockdown of AHCY using gene-specific siRNAs reduced APC proliferation and number. Inhibition of AHCY further reduced APC differentiation into mature adipocytes and the expression of adipogenic differentiation markers. Global DNA methylation profiling in human APCs revealed that inhibition of AHCY is associated with alterations in CpG methylation levels of genes involved in fat cell differentiation and pathways related to cellular growth. Our findings suggest that AHCY is necessary for the maintenance of APC proliferation and differentiation and inhibition of AHCY alters DNA methylation processes leading to a dysregulation of the expression of genes involved in the regulation of these processes.
AU  - Boczki, P.*
AU  - Colombo, M.*
AU  - Weiner, J.*
AU  - Rapöhn, I.
AU  - Lacher, M.*
AU  - Kiess, W.*
AU  - Hanschkow, M.*
AU  - Körner, A.
AU  - Landgraf, K.*
C1  - 68934
C2  - 53776
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Inhibition of AHCY impedes proliferation and differentiation of mouse and human adipocyte progenitor cells.
JO  - Adipocyte
VL  - 13
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2024
SN  - 2162-3945
ER  - 

TY  - JOUR
AB  - BACKGROUND: Mature adipocytes are notoriously difficult to study ex vivo and alternative cell culture systems have therefore been developed. One of the most common models are human adipose progenitor cells (hAPCs). Unfortunately, these display replicative senescence after prolonged culture conditions, which limits their use in mechanistic studies. METHODS: Herein, we knocked in human telomerase reverse transcriptase (TERT) into the AAVS1 locus of CD55+ hAPCs derived from abdominal subcutaneous adipose tissue and characterized the cells before and after differentiation into adipocytes. RESULTS: Immortalized TERT-hAPCs retained proliferative and adipogenic capacities comparable to those of early-passage wild type hAPCs for > 80 passages. In line with this, our integrative transcriptomic and proteomic analyses revealed that TERT-hAPCs displayed robust adipocyte expression profiles in comparison to wild type hAPCs. This was confirmed by functional analyses of lipid turnover where TERT-hAPCs exhibited pronounced responses to insulin and pro-lipolytic stimuli such as isoprenaline, dibutyrul cAMP and tumour necrosis factor alpha. In addition, TERT-hAPCs could be readily cultured in both standard 2D and 3D-cultures and proteomic analyses revealed that the spheroid culture conditions improved adipogenesis. CONCLUSION: Through descriptive and functional studies, we demonstrate that immortalization of human CD55+ hAPCs is feasible and results in cells with stable proliferative and adipogenic capacities over multiple passages. As these cells are cryopreservable, they provide the additional advantage over primary cells of allowing repeated studies in both 2D and 3D model systems with the same genetic background. (234/250).
AU  - Couchet, M.*
AU  - Gao, H.*
AU  - Klingelhuber, F.
AU  - Jalkanen, J.*
AU  - De Castro Barbosa, T.*
AU  - Omar-Hmeadi, M.*
AU  - Massier, L.*
AU  - Krahmer, N.
AU  - Mejhert, N.*
AU  - Rydén, M.*
C1  - 68918
C2  - 53770
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
TI  - Adipogenic characterization of immortalized CD55+ progenitor cells from human white adipose tissue.
JO  - Adipocyte
VL  - 14
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2023
SN  - 2162-3945
ER  - 

TY  - JOUR
AB  - Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP), regulate growth and metabolic pathways. Here, we asked if serum levels of these factors are altered with overweight/obesity and if this is related to adipose tissue (AT) expression and/or increased fat mass. Furthermore, we hypothesized that expression of GHR, IGF-1 and IGFBP-3 is associated with AT function. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio obesity-related elevations were detectable until early puberty. Circulating levels did not correlate with AT expression of these factors, which was decreased with overweight/obesity. Independent from obesity, expression of GHR, IGF-1 and IGFBP-3 was related to AT dysfunction,and increased insulin levels. Serum GHBP was associated with liver fat percentage and transaminase levels. We conclude that obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased AT mass and elevations in GHBP are more closely related to liver status in children. The diminished AT expression of these factors with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.
AU  - Kempf, E.*
AU  - Landgraf, K.*
AU  - Vogel, T.*
AU  - Spielau, U.*
AU  - Stein, R.
AU  - Raschpichler, M.*
AU  - Kratzsch, J.*
AU  - Kiess, W.*
AU  - Stanik, J.*
AU  - Körner, A.
C1  - 66757
C2  - 53292
SP  - 630-642
TI  - Associations of GHR, IGF-1 and IGFBP-3 expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children.
JO  - Adipocyte
VL  - 11
IS  - 1
PY  - 2022
SN  - 2162-3945
ER  - 

TY  - JOUR
AB  - Vaspin expression and function is related to metabolic disorders and comorbidities of obesity. In various cellular and animal models of obesity, diabetes and atherosclerosis vaspin has shown beneficial, protective and/or compensatory action. While testing proteases for inhibition by vaspin, we noticed specific cleavage within the vaspin N-terminus and sequence analysis predicted cell-penetrating activity for the released peptides. These findings raised the question whether these proteolytic peptides exhibit biological activity.We synthesized various N-terminal vaspin peptides to investigate cell-penetrating activity and analyse uptake mechanisms. Focusing on adipocytes, we performed microarray analysis and functional assays to elucidate biological activities of the vaspin-derived peptide, which is released by KLK7 cleavage (vaspin residues 21-30; VaspinN). Our study provides first evidence that proteolytic processing of the vaspin N-terminus releases cell-penetrating and bioactive peptides with effects on adipocyte biology. The VaspinN peptide increased preadipocyte proliferation, interfered with clonal expansion during the early stage of adipogenesis and blunted adrenergic cAMP-signalling, downstream lipolysis as well as insulin signalling in mature adipocytes.Protease-mediated release of functional N-terminal peptides presents an additional facet of vaspin action. Future studies will address the mechanisms underlying the biological activities and clarify, if vaspin-derived peptides may have potential as therapeutic agents for the treatment of metabolic diseases.
AU  - Tindall, C.*
AU  - Erkner, E.*
AU  - Stichel, J.*
AU  - Beck-Sickinger, A.G.*
AU  - Hoffmann, A.
AU  - Weiner, J.*
AU  - Heiker, J.T.
C1  - 61836
C2  - 50481
CY  - 530 Walnut Street, Ste 850, Philadelphia, Pa 19106 Usa
SP  - 216-231
TI  - Cleavage of the vaspin N-terminus releases cell-penetrating peptides that affect early stages of adipogenesis and inhibit lipolysis in mature adipocytes.
JO  - Adipocyte
VL  - 10
IS  - 1
PB  - Taylor & Francis Inc
PY  - 2021
SN  - 2162-3945
ER  - 

TY  - JOUR
AB  - PKCl, an atypical member of the multifunctional protein kinase C family, has been implicated in the regulation of insulinstimulated glucose transport and of the intracellular immune response. To further elucidate the role of this cellular regulator in diet-induced obesity and insulin resistance, we generated both liver (PKC-Alb) and adipose tissue (PKC-Ap2) specific knockout mice. Body weight, fat mass, food intake, glucose homeostasis and energy expenditure were evaluated in mice maintained on either chow or high fat diet (HFD). Ablation of PKCl from the adipose tissue resulted in mice that were indistinguishable from their wild-type littermates. However, PKC-Alb mice were resistant to diet-induced obesity (DIO). Surprisingly this DIO resistance was not associated with either a reduction in caloric intake or an increase in energy expenditure as compared with their wild-type littermates. Furthermore, these mice displayed an improvement in glucose tolerance. When maintained on chow diet, these mice were similar to wild types in respect to body weight and fat mass, yet insulin sensitivity was impaired compared with wt littermates. Taken together these data suggest that hepatic PKCl is modulating insulin-mediated glucose turnover and response to high fat diet feeding, thus offering a deeper understanding of an important target for anti-obesity therapeutics.
AU  - Habegger, K.M.*
AU  - Matzke, D.*
AU  - Ottaway, N.*
AU  - Hembree, J.*
AU  - Holland, J.*
AU  - Raver, C.*
AU  - Mansfeld, J.*
AU  - Müller, T.D.
AU  - Perez-Tilve, D.*
AU  - Pfluger, P.T.
AU  - Lee, S. J.*
AU  - Diaz-Meco, M.*
AU  - Moscat, J.*
AU  - Leitges, M.*
AU  - Tschöp, M.H.
AU  - Hofmann, S.M.
C1  - 10679
C2  - 30326
SP  - 203-214
TI  - Role of adipose and hepatic atypical protein kinase C lambda (PKCλ) in the development of obesity and glucose intolerance.
JO  - Adipocyte
VL  - 1
IS  - 4
PB  - Landes Bioscience
PY  - 2012
SN  - 2162-3945
ER  -