FABP4
Fatty acid-binding protein, adipocyte (Adipocyte lipid-binding protein) (ALBP) (Adipocyte-type fatty acid-binding protein) (A-FABP) (AFABP) (Fatty acid-binding protein 4)
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Adipose tissue (AT) dysfunction associated with obesity or aging is a major cause for lipid redistribution and the progression of cardiometabolic disorders. Our goal is to decipher the contribution of human AT microvascular endothelial cells (ECs) in the maintenance of fatty acid (FA) fluxes and the impact of senescence on their function. We used freshly isolated primary microvascular ECs from human AT. Our data identified the endothelial FA handling machinery including FATPs (FA transport proteins) FATP1, FATP3, FATP4, and CD36 as well as FABP4 (FA binding protein 4). We showed that PPARγ (peroxisome proliferator-activated receptor gamma) regulates the expression of FATP1, CD36, and FABP4 and is a major regulator of FA uptake in human AT EC (hATEC). We provided evidence that endothelial PPARγ activity is modulated by senescence. Indeed, the positive regulation of FA transport by PPARγ agonist was abolished, whereas the emergence of an inflammatory response was favored in senescent hATEC. This was associated with the retention of nuclear FOXO1 (forkhead box protein O1), whereas nuclear PPARγ translocation was impaired. These data support the notion that PPARγ is a key regulator of primary hATEC function including FA handling and inflammatory response. However, the outcome of PPARγ activation is modulated by senescence, a phenomenon that may impact the ability of hATEC to properly respond to and handle lipid fluxes. Finally, our work highlights the role of hATEC in the regulation of FA fluxes and reveals that dysfunction of these cells with accelerated aging is likely to participate to AT dysfunction and the redistribution of lipids.
MeSH Terms
- Abdominal Fat
- Active Transport, Cell Nucleus
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Endothelial Cells
- Fatty Acid-Binding Proteins
- Fatty Acids
- Female
- Forkhead Box Protein O1
- Humans
- Inflammation
- Microvessels
- PPAR gamma
- Signal Transduction
Keywords
- adipose tissue
- cellular senescence
- endothelial cells
- fatty acids
- inflammation
- peroxisome proliferator-activated receptors
Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of [i]Aplnr[/i] ([i]Aplnr[/i] ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the [i]Apln[/i] and [i]Aplnr[/i] mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial [i]Foxo1[/i] deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the [i]Apln[/i] mice. The impaired glucose utilization in the [i]Aplnr[/i] mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.
MeSH Terms
- Aging
- Animals
- Apelin
- Apelin Receptors
- Endothelium
- Fatty Acid-Binding Proteins
- Fatty Acids
- Forkhead Box Protein O1
- Glucose
- Human Umbilical Vein Endothelial Cells
- Humans
- Male
- Mice, Knockout
- Signal Transduction
Sarcopenia, the aging-related deterioration of skeletal muscle, is a disease that is directly associated with quality of life. Given the trend of an increasing aging population worldwide, the prevention of aging-related diseases such as sarcopenia has become ever more important and urgent. To identify potential therapeutic targets for this disease. we used a bioinformatics approach of combining cDNA microarray analysis and protein-protein interaction prediction. We found 673 significant differentially expressed genes (128 upregulated and 545 downregulated) in sarcopenia patients of over 60 years of age. Most of the upregulated genes were involved in metabolic processes such as the PPAR signaling pathway. In particular, FABP4, PLIN1, and ADIPOQ were related to fatty acid and lipid metabolism. Some of the downregulated genes were located in the mitochondrial matrix. Additionally, through the protein interaction network analysis, we found two key molecules (MAP1LC3B and HSP90AB1) that were associated with autophagy. These results suggest that mitochondrial dysfunction and lipid metabolism are associated with sarcopenia.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- DNA, Mitochondrial
- Female
- Humans
- Male
- Microarray Analysis
- Middle Aged
- Muscle Strength
- Muscle, Skeletal
- Sarcopenia
Keywords
- Alzheimer’s disease
- aging
- microarray
- protein–protein interaction
A key effect of prolonged reducing diets and bariatric surgeries in formerly obese people is long-term caloric restriction (CR). The analysis of the impact of these interventions on specific tissues will contribute to a better understanding of their mechanisms of action. The physiological functions of subcutaneous white adipose tissues are mainly fulfilled by adipocytes arising out of adipose-derived stromal/progenitor cells (ASCs), which are crucial for adipose tissue homeostasis. In the present study we analyzed ASC from age-matched long-term calorically restricted formerly obese (CRD), obese (OD) and normal weight donors (NWDs). We demonstrate that ASC derived from CRD has a significant longer replicative lifespan than ASC isolated from OD and NWD. This correlated with strongly reduced DNA-damage and improved survival of the CRD ASC, both are hallmarks of CR. The adipogenic capacity was significantly lower in ASC derived from CRD than that from OD, as shown by reduced expression of the adipogenic key regulator PPARγ2 and the differentiation marker FABP4. The adipogenic capacity of ASCs from CRD and NWD differed only slightly. In conclusion, we provide evidence that bariatric surgery and diet-induced long-term CR substantially reprogram ASCs in formerly obese humans, comprising reduced DNA-damage, improved viability, extended replicative lifespan and reduced adipogenic differentiation potential.
MeSH Terms
- Adipogenesis
- Adult
- Bariatric Surgery
- Caloric Restriction
- Case-Control Studies
- Cell Proliferation
- Cell Survival
- Cells, Cultured
- Cellular Senescence
- DNA Damage
- Diet, Reducing
- Fatty Acid-Binding Proteins
- Female
- Humans
- Middle Aged
- Nutritional Status
- Obesity
- PPAR gamma
- Stem Cells
- Stromal Cells
- Subcutaneous Fat
- Time Factors
Keywords
- Adipose-derived stem cells
- Caloric restriction
- DNA damage
- Humans
- Senescence
- Survival
Aging negatively affects angiogenesis which is found to be linked to declined vascular endothelial growth factor (VEGF) production. Adult human thymus degenerates into fat tissue (thymus adipose tissue (TAT)). Recently, we described that TAT from cardiomyopathy ischemic subjects has angiogenic properties. The goal of our study was to analyze whether aging could also impair angiogenic properties in TAT as in other adipose tissue such as subcutaneous (subcutaneous adipose tissue (SAT)). SAT and TAT specimens were obtained from 35 patients undergoing cardiac surgery, making these tissues readily available as a prime source of adipose tissue. Patients were separated into two age-dependent groups; middle-aged (n = 18) and elderly (n = 17). Angiogenic, endothelial, and adipogenic expression markers were analyzed in both tissues from each group and correlations were examined between these parameters and also with age. There were no significant differences in subjects from either group in clinical or biological variables. Angiogenic markers VEGF-A, B, C, and D and adipogenic parameters, peroxisome proliferator-activated receptors (PPARγ2), FABP4, and ADRP showed elevated expression levels in TAT from elderly patients compared to the middle-aged group, while in SAT, expression levels of these isoforms were significantly decreased in elderly patients. VEGF-R1, VEGF-R2, VEGF-R3, Thy1, CD31, CD29, and VLA1 showed increased levels in TAT from the elderly compared to the middle-aged, while in SAT these levels displayed a decline with aging. Also, in TAT, angiogenic and endothelial parameters exhibited strong positive correlations with age. TAT appears to be the most appropriate source of angiogenic and endothelial factors in elderly cardiomyopathy subjects compared to SAT.
MeSH Terms
- Adipose Tissue
- Aged
- Aging
- Angiogenesis Inducing Agents
- Blotting, Western
- Female
- Flow Cytometry
- Follow-Up Studies
- Humans
- Male
- Middle Aged
- Myocardial Ischemia
- Thymus Gland
Lipin 1 is a bifunctional protein that regulates gene transcription and, as a Mg(2 )-dependent phosphatidic acid phosphatase (PAP), is a key enzyme in the biosynthesis of phospholipids and triacylglycerol. We describe here the functional interaction between lipin 1 and the nuclear factor of activated T cells c4 (NFATc4). Lipin 1 represses NFATc4 transcriptional activity through protein-protein interaction, and lipin 1 is present at the promoters of NFATc4 transcriptional targets in vivo. Catalytically active and inactive lipin 1 can suppress NFATc4 transcriptional activity, and this suppression may involve recruitment of histone deacetylases to target promoters. In fat pads from mice deficient for lipin 1 (fld mice) and in 3T3-L1 adipocytes depleted of lipin 1 there is increased expression of several NFAT target genes including tumor necrosis factor alpha, resistin, FABP4, and PPARgamma. Finally, both lipin 1 protein and total PAP activity are decreased with increasing adiposity in the visceral, but not subcutaneous, fat pads of ob/ob mice. These observations place lipin 1 as a potentially important link between triacylglycerol synthesis and adipose tissue inflammation.
MeSH Terms
- 3T3-L1 Cells
- Adipocytes
- Aging
- Animals
- Calcium Signaling
- DNA
- Gene Expression Regulation
- Histone Deacetylases
- Hydroxamic Acids
- Inflammation Mediators
- Mice
- NFATC Transcription Factors
- Nuclear Proteins
- Obesity
- PPAR alpha
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Phosphatidate Phosphatase
- Promoter Regions, Genetic
- Protein Binding
- RNA, Messenger
- Repressor Proteins
- Trans-Activators
- Transcription Factors
- Transcription, Genetic
- Tumor Necrosis Factor-alpha
Mesenchymal stem cells (MSC) are pluripotent cells, present in the bone marrow and other tissues that can differentiate into cells of all germ layers and may be involved in tissue maintenance and repair in adult organisms. Because of their plasticity and accessibility these cells are also prime candidates for regenerative medicine. The contribution of stem cell aging to organismal aging is under debate and one theory is that reparative processes deteriorate as a consequence of stem cell aging and/or decrease in number. Age has been linked with changes in osteogenic and adipogenic potential of MSCs. Here we report on changes in global gene expression of cultured MSCs isolated from the bone marrow of mice at ages 2, 8, and 26-months. Microarray analyses revealed significant changes in the expression of more than 8000 genes with stage-specific changes of multiple differentiation, cell cycle and growth factor genes. Key markers of adipogenesis including lipoprotein lipase, FABP4, and Itm2a displayed age-dependent declines. Expression of the master cell cycle regulators p53 and p21 and growth factors HGF and VEGF also declined significantly at 26 months. These changes were evident despite multiple cell divisions in vitro after bone marrow isolation. The results suggest that MSCs are subject to molecular genetic changes during aging that are conserved during passage in culture. These changes may affect the physiological functions and the potential of autologous MSCs for stem cell therapy.
MeSH Terms
- Aging
- Animals
- Apoptosis
- Bone Marrow Cells
- Cell Cycle
- Cells, Cultured
- Gene Expression
- Intercellular Signaling Peptides and Proteins
- Mesenchymal Stem Cells
- Mice
- Mice, Inbred C57BL
Wnts comprise a family of secreted signaling proteins that regulate diverse developmental processes. Activation of Wnt signaling by Wnt10b inhibits differentiation of preadipocytes and blocks adipose tissue development; however, the effect of Wnt10b on other mesenchymal lineages has not been defined. To explore the physiological role of Wnt signaling in bone development, we analyzed FABP4-Wnt10b mice, which express the Wnt10b transgene in marrow. Femurs from FABP4-Wnt10b mice have almost four times as much bone in the distal metaphyses and are mechanically stronger. These mice maintain elevated bone mass at least through 23 months of age. In addition, FABP4-Wnt10b mice are protected from the bone loss characteristic of estrogen deficiency. We used pharmacological and genetic approaches to demonstrate that canonical Wnt signaling stimulates osteoblastogenesis and inhibits adipogenesis of bipotential mesenchymal precursors. Wnt10b shifts cell fate toward the osteoblast lineage by induction of the osteoblastogenic transcription factors Runx2, Dlx5, and osterix and suppression of the adipogenic transcription factors C/EBPalpha and PPARgamma. One mechanism whereby Wnt10b promotes osteoblastogenesis is suppression of PPARgamma expression. Finally, Wnt10b-/- mice have decreased trabecular bone and serum osteocalcin, confirming that Wnt10b is an endogenous regulator of bone formation.
MeSH Terms
- Aging
- Animals
- Bone Density
- Cell Division
- Female
- Mice
- Mice, Knockout
- Osteoblasts
- Ovariectomy
- Proto-Oncogene Proteins
- Wnt Proteins