Adipocyte最新文献

Sequestration of free fatty acids (FFA) inside white adipose tissue (WAT) may reduce plasma FFA levels and prevent lipotoxicity in other organs. However, it is poorly understood how WAT responds to this metabolic stress. As albumin promotes FFA release from WAT, and thus albumin deficiency should promote FFA sequestration, we studied albumin knockout (Alb^-/-) mice and their wildtype (WT) littermates (eight-week-old males). Transmission electron microscopy and molecular analyses were used for characterization. There was no significant difference between genotypes for WAT mass, adipocyte size or triacylglycerol (TAG) content. No signs of cell death were observed in Alb^-/- adipocytes, suggesting a tolerance to the metabolic challenge. Alb^-/- adipocytes exhibited a lower density of caveolae with smaller invagination depths, indicating a potential adaptation to reduce FFA transport. A significantly higher abundance of micro-lipid droplets was observed in Alb^-/- mice, which may result from a rapid substrate cycle with high lipolysis and re-esterification. In support of the ultrastructural phenotype, lipidomic analysis also demonstrated a significant difference between Alb^-/- and WT for TAG composition. Our results showed that when no albumin is present to facilitate FFA mobilization, WAT can chronically adapt to protect the adipocytes in both morphological and molecular manners.

Melanin-concentrating hormone signalling pathways in the central nervous system are of significant clinical interest in treating appetite, sleep, and mood disorders. However, with the additional discovery of active MCH signalling pathways in peripheral tissues, knowing the degree to which cellular context influence MCH receptor function is increasingly important. In this study, we discovered MCH-mediated signalling responses that demonstrated bell-shaped dose response curves in multiple assays using both pre- and post-adipocyte 3T3-L1 models. MCH facilitated cell adhesion in pre-adipocytes, increased both the number and size of lipid droplets and inhibited lipolysis in adipocytes, with a maximum effective dose at 1 nM MCH. We hypothesize that the concentration of MCH cells are exposed to influences G protein bias at MCHR1 and/or signal switching to an unidentified pathway. Furthermore, this study elucidates the importance of hormone concentration when measuring GPCR signalling pathways in cell culture and tissue models.

Cachexia is a complex syndrome that is often associated with cancer. Chemotherapy, one of the main cancer treatments, worsens weight loss in cancer-induced cachexia. In this context, it is thought that fat loss precedes muscle loss, and that alterations in adipose tissue are associated with tumours. However, the effect of cancer treatment on adipose tissue is not well understood. This study aimed to evaluate the impact of chemotherapy alone on mature 3T3-L1 adipocytes to identify the mechanisms contributing to adipose tissue alteration. The murine cell line 3T3-L1, a model of mature adipocytes, was used in this study. After differentiation, cells were treated for 48 h with a chemotherapy cocktail called FLOT composed of 5-fluorouracil, leucovorin, oxaliplatin and docetaxel at two concentrations (FLOT 1X and 0.1X). The control group was treated with the vehicle of the chemotherapy cocktail. Viability, mitochondrial function and dynamics, lipid metabolism, and cellular stress were also evaluated. FLOT 1X chemotherapy significantly reduced viability of mature 3T3-L1 cells and inhibited lipid accumulation. Interestingly, while FLOT 1X treatment downregulated lipogenesis markers, FLOT 0.1X treatment upregulated some of them. Although, the treatment showed no effect on mitochondrial respiration or density, it significantly increased expression of oxidative stress and inflammation markers in adipocytes.This in vitro study provides the first evidence of FLOT chemotherapy's direct effects on healthy mature adipocytes. The results demonstrate significant treatment-induced reductions in cell viability along with dysregulation of both lipogenic and lipolytic pathways. These findings elucidate previously unrecognized mechanisms underlying adipose tissue dysfunction in cancer cachexia.

CXCR7, an alternative receptor for the inflammatory chemokine SDF-1, is involved in cell proliferation and migration. Recent studies have reported that CXCR7 also plays a role in adipose tissue. However, evidence regarding the role of CXCR7 and its ligands in adipocyte differentiation is limited. In this study, we aimed to elucidate changes in CXCR7 expression during adipocyte differentiation and the role of the SDF-1/CXCR7/CXCR4 axis in adipogenesis using recombinant SDF-1, the CXCR7 ligand CCX771, and small interfering RNAs. The results indicated that the levels of SDF-1 and its receptors, CXCR7 and CXCR4, decreased during the early stages of adipogenesis. Treatment with recombinant SDF-1 and CCX771 inhibited adipogenesis and lipid accumulation by inducing β-arrestin2, Wnt expression, and AKT phosphorylation and downregulating C/EBPα, PPARγ, and FABP4 expression. In contrast, knockdown of SDF-1 and CXCR7 in preadipocytes downregulated the β-arrestin2/Wnt and AKT pathway, leading to the induction of adipogenesis. Meanwhile, knockdown of CXCR4 had no significant effect. In mice, basal gene expression levels of SDF-1 and CXCR7 were higher in the stromal vascular fraction compared to mature adipocytes and were significantly upregulated by a high-fat diet. Our results provide new insights into the local role of the SDF-1-CXCR7 axis in adipocytes and offer additional benefits for the prevention of obesity-related metabolic disorders.

Obesity and type 2 diabetes mellitus are global public health challenges. Activating thermogenic adipose tissues, such as brown adipose tissue and beige adipose tissue, could be a promising strategy to combat obesity and consequently obesity-related diabetes. Both peroxisome proliferator-activated receptor-γ (PPARγ) and retinoid X receptor γ (RXRγ) play significant roles in the regulation of adipogenic differentiation. However, the underlying mechanisms and interactions between these receptors during adipogenic differentiation remain unclear. In this study, we conducted a comprehensive analysis of a transcriptome sequencing dataset sourced from the GEO database, encompassing samples of white and brown adipose tissues from 15 healthy individuals. Our findings reveal that RXRγ expression is significantly elevated in brown adipose tissue relative to white adipose tissue (p = 0.041). Furthermore, co-immunoprecipitation assays validated that RXRγ can be co-precipitated with PPARγ. Subsequent luciferase assays demonstrated that the interaction between RXRγ and PPARγ significantly enhances the transcriptional activity of uncoupling protein 1 (UCP1) compared to the overexpression of PPARγ alone (3.4-fold vs. 1.5-fold, p < 0.001). Notably, in human preadipocytes, the co-overexpression of RXRγ with PPARγ resulted in a significant increase in UCP1 transcriptional activity compared to the overexpression of PPARγ alone (3.4-fold vs. 2.0-fold, p < 0.05). In summary, our findings suggest that RXRγ serves as a novel cofactor for PPARγ, promoting the browning of adipose tissue through the upregulation of UCP1 transcription.

 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.

Inflammatory changes in perivascular adipose tissue are associated with atherosclerotic lesions in the adjacent artery and can also be used as a marker in patient workup. While adipocyte size is known to be closely related to adipose tissue dysfunction and inflammation, it has not been widely studied in perivascular adipose tissue obtained from healthy human subjects without clinical atherosclerosis. In this cross-sectional study, we addressed this issue by measuring adipocyte size and defining its relationship to cardiovascular risk factors in a healthy cohort of living kidney donors. The presence of cardiovascular risk factors was established by a standardized questionnaire, clinical measurements and body composition analyses. Adipocyte size was measured in the perivascular depot. The proportions of various macrophage subtypes were determined by flow cytometry. To confirm the results, the proportion of CD68  +  macrophages was additionally assessed by immunohistochemistry. A correlation and principal component analyses were performed to explore associations. Adipocyte size in perivascular adipose tissue correlated with markers of lipid metabolism, inflammation, and glucose metabolism. Further, the positive correlation with the pro-inflammatory subpopulation of macrophages suggests a strong local effect of perivascular adipose tissue. Perivascular adipocyte size was associated with cardiovascular risk factors and markers of inflammation in a healthy cohort of living kidney donors. This further supports the local role of adipose tissue dysfunction and inflammation in early atherosclerosis development and detection.

microRNAs (miRNAs), a subclass of noncoding short RNAs, direct cells fate decisions that are important for cell proliferation and cell lineage decisions. Adipogenic differentiation contributes greatly to the development of white adipose tissue, involving of highly organized regulation by miRNAs. In the present study, we screened and identified 78 differently expressed miRNAs of porcine BMSCs during adipogenic differentiation. Of which, the role of miR-29c in regulating the proliferation and adipogenic differentiation was proved and detailed. Specifically, over-expression miR-29c inhibits the proliferation and adipogenic differentiation of BMSCs, which were reversed upon miR-29c inhibitor. Interference of IGF1 inhibits the proliferation and adipogenic differentiation of BMSCs. Mechanistically, miR-29c regulates the proliferation and adipogenic differentiation of BMSCs by targeting IGF1 and further regulating the MAPK pathway and the PI3K-AKT-mTOR pathway, respectively. In conclusion, we highlight the important role of miR-29c in regulating proliferation and adipogenic differentiation of BMSCs.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Background: Sepsis is a significant contributor to both intensive care unit (ICU) admissions and mortality among patients in ICU, with a rising prevalence of obesity. There is a lack of extensive research on the correlation between TyGI and findings in patients with sepsis, especially in obese patients.

Methods: This study used a retrospective cohort design and included patients with sepsis (≥18 years) from the Medical Information Mart for Intensive Care IV database. The association between TyGI and outcome was examined using multivariable logistic regression analysis.

Results: 8,840 patients with sepsis were included in the analysis. The in-ICU mortality rate was 9.7%. Non-survivors exhibited significantly greater TyGI levels than survivors [9.19(8.76-9.71) vs. 9.10(8.67-9.54), p < 0.001]. The adjusted multivariate regression model showed that elevated TyGI values were linked to a greater likelihood of death in ICU (odds ratio [OR] range 1.072-1.793, p < 0.001) and hospital (OR range 1.068-1.445, p = 0.005). Restricted Cubic Spline analysis revealed a nonlinear association between TyGI and in-ICU and in-hospital mortality risks within specified ranges. Subgroup analysis revealed interaction effects in the general obesity, abdominal obesity, and impaired fasting glucose subgroups (p = 0.014, 0.016, and < 0.001, respectively).

Conclusion: TyGI was associated with an increased sepsis-related short-term mortality risk and adverse outcomes after ICU admission.