ABSTRACT
Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.
Subject(s)
Insulin Resistance , Obesity , Male , Mice , Animals , Obesity/complications , Obesity/genetics , Adipose Tissue/metabolism , Inflammation/metabolism , Diet, High-Fat/adverse effects , Lysosomes/metabolism , Lipids , Macrophages/metabolism , Mice, Inbred C57BLABSTRACT
STUDY DESIGN: Human nucleus pulposus cells from intervertebral disc specimens were cultured to study the effects of tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 on the focal adhesion kinase (FAK) expression by these cells. The effect of co-stimulation with dexamethasone on the FAK expression by nucleus pulposus cells was also studied. OBJECTIVES: To evaluate the possible role of activated FAK expressed by the human nucleus pulposus cells and its correlation with inflammatory cytokines (TNF-alpha, IL-8) and dexamethasone. SUMMARY OF BACKGROUND DATA: There have been no reported studies showing the correlation between the activated FAK expression by human nucleus pulposus cells with inflammatory cytokines and dexamethasone. METHODS: The FAK expression in cultured human nucleus pulposus cells was studied, and Western blot and immunofluorescence analysis were performed to assess its relation to TNF-alpha, IL-8, and dexamethasone. RESULTS: Treatments of TNF-alpha and IL-8 up-regulated the activated FAK expression. Dexamethasone attenuated the cytokine-induced FAK expression. The effects of inflammatory cytokines on the FAK expression were found to be concentration dependent, with greater correlation shown by IL-8 than TNF-alpha. CONCLUSION: TNF-alpha and IL-8 stimulation up-regulated the FAK expression of human nucleus pulposus cells, and the coadministration of dexamethasone attenuated it.
Subject(s)
Dexamethasone/pharmacology , Focal Adhesion Protein-Tyrosine Kinases/biosynthesis , Gene Expression Regulation, Enzymologic/physiology , Interleukin-8/physiology , Intervertebral Disc/enzymology , Tumor Necrosis Factor-alpha/physiology , Cells, Cultured , Focal Adhesion Protein-Tyrosine Kinases/genetics , Gene Expression Regulation, Enzymologic/drug effects , Humans , Interleukin-8/pharmacology , Intervertebral Disc/cytology , Intervertebral Disc/drug effects , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
We conducted a study on the mechanism of KAI1/CD82-mediated suppression of tumor invasiveness and metastasis, and examined its effect on MMP-9 activity and the TIMP1 levels in H1299 human non-small cell lung carcinoma cells. The H1299 human lung carcinoma cells were transfected with pcDNA3.1-CD82 and stable transfectant clones that had a high KAI1/CD82 expression were obtained. We performed Western blot analysis, cell invasion assay, gelatin zymography, and RT-PCR to assess the KAI1/CD82 expression and tumor invasiveness, the MMP-9 activity, the MMP-9 mRNA and protein levels, and the TIMP1 levels in the H1299/CD82 transfectant cells and compared the results with those of the control groups. The H1299/CD82 transfectants exhibited significant suppression of cell invasion, reduced MMP9 enzyme activity, elevated MMP9 mRNA and MMP-9 protein levels, and elevated TIMP1 levels. It may be postulated that KAI1/CD82 over-expression in the H1299 non-small cell lung carcinoma cells suppresses the tumor invasiveness and metastatic potential by inducing MMP9 inactivation via the up-regulation of TIMP1.
