In aging, the capacity of subcutaneous adipose tissue (SAT) to store lipids decreases and this results in metabolically unfavorable fat redistribution. Triggers of this age-related SAT dysfunction may include cellular senescence or endoplasmic reticulum (ER) stress. Therefore, we compared lipogenic capacity of SAT between young and older women and investigated its relation to senescence and ER stress markers. Samples of SAT and corresponding SAT-derived primary preadipocytes were obtained from two groups of women differing in age (36 vs. 72 years, n = 15 each) but matched for fat mass. mRNA levels of selected genes (lipogenesis: ACACA, FASN, SCD1, DGAT2, ELOVL6; senescence: p16, p21, NOX4, GDF15; ER stress-ATF4, XBP1s, PERK, HSPA5, GADD34, HYOU1, CHOP, EDEM1, DNAJC3) were assessed by qPCR, protein levels of GDF15 by ELISA, and mitochondrial function by the Seahorse Analyzer. Compared to the young, SAT and in vitro differentiated adipocytes from older women exhibited reduced mRNA expression of lipogenic enzymes. Out of analyzed senescence and ER stress markers, the only gene, whose expression correlated negatively with the expression of lipogenic enzymes in both SAT and adipocytes, was GDF15, a marker of not only senescence but also mitochondrial dysfunction. In line with this, inhibition of mitochondrial ATP synthase in adipocytes strongly upregulated GDF15 while reduced expression of lipogenic enzymes. Moreover, adipocytes from older women had a tendency for diminished mitochondrial capacity. Thus, a reduced lipogenic capacity of adipocytes in aged SAT appears to be linked to mitochondrial dysfunction rather than to ER stress or accumulation of senescent cells.

• Keywords
• Aging, Lipogenesis, Mitochondrial dysfunction, Senescence, Stress of endoplasmic reticulum, Subcutaneous adipose tissue,
• MeSH
• Biomarkers metabolism   MeSH
• Cell Differentiation MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• Adult MeSH
• Humans MeSH
• Lipogenesis * MeSH
• Mitochondria metabolism   MeSH
• Subcutaneous Fat metabolism   MeSH
• Growth Differentiation Factor 15 metabolism   MeSH
• Aged MeSH
• Cellular Senescence MeSH
• Aging metabolism   MeSH
• Endoplasmic Reticulum Stress MeSH
• Adipocytes metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Biomarkers MeSH
• Endoplasmic Reticulum Chaperone BiP MeSH
• GDF15 protein, human MeSH Browser
• HSPA5 protein, human MeSH Browser
• Growth Differentiation Factor 15 MeSH

BACKGROUND/OBJECTIVES: OxLDL-β2GPI complex has been suggested to have a role in the development of atherosclerosis and other inflammatory diseases. The aim of this study was to investigate the possible association of circulating oxLDL-β2GPI with obesity-induced inflammatory state of adipose tissue and related comorbidities as metabolic syndrome development. SUBJECTS/METHODS: Two cohorts of subjects were examined in the study. Cohort I: 36 women with wide range of body mass index (17-48 kg m-2) and metabolic status (with or without metabolic syndrome (MS); cohort II: 20 obese women undergoing a dietary intervention (DI) consisting of 1-month very-low-calorie diet, and 5 months of weight-stabilization period. Serum levels of oxLDL-β2GPI were measured by enzyme-linked immunosorbent assay. Insulin sensitivity was evaluated by hyperinsulinemic-euglycemic clamp and homeostasis model assessment of insulin resistance. mRNA expression of macrophage markers was determined in both subcutaneous (SAT) and visceral (VAT) adipose tissue in cohort I and in SAT in cohort II. RESULTS: Serum oxLDL-β2GPI levels were increased in obese subjects with MS compared to lean or obese without MS (obese with MS: 26.6±5.0 vs lean: 15.17±1.97, P<0.001; vs obese without MS: 16.36±2.89, P<0.05). Serum oxLDL-β2GPI correlated with MS indices (glucose, high-density lipoprotein, triglyceride and ureic acid) and with mRNA expression of macrophage markers in VAT. Weight-reducing DI decreased serum oxLDL-β2GPI levels together with lipid parameters and the mRNA expression of inflammatory markers in SAT. CONCLUSIONS: OxLDL-β2GPI seems to be an important marker of visceral adipose tissue inflammation and possibly a factor contributing to insulin resistance and metabolic syndrome development in obese patients.

• MeSH
• beta 2-Glycoprotein I blood   chemistry   metabolism   MeSH
• Biomarkers blood   MeSH
• Adult MeSH
• Cohort Studies MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipoproteins, LDL blood   chemistry   metabolism   MeSH
• Metabolic Syndrome blood   physiopathology   MeSH
• Multiprotein Complexes MeSH
• Obesity * blood   metabolism   physiopathology   MeSH
• Adipose Tissue metabolism   physiopathology   MeSH
• Inflammation blood   physiopathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• beta 2-Glycoprotein I MeSH
• Biomarkers MeSH
• Lipoproteins, LDL MeSH
• Multiprotein Complexes MeSH
• oxidized low density lipoprotein MeSH Browser

Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinflammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specific lipid mediators with anti-inflammatory properties are released from adipocytes undergoing lipolysis to induce macrophage migration. In the present study, we showed that conditioned medium (CM) from adipocytes treated with forskolin to stimulate lipolysis can induce migration of RAW 264.7 macrophages. In addition to FFAs, lipolytic stimulation increased release of prostaglandin E2(PGE2) and prostaglandin D2(PGD2), reflecting cytosolic phospholipase A2α activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-inflammatory PGE2potently induced macrophage migration while different FFAs and PGD2had modest effects. The ability of CM to induce macrophage migration was abolished by treating adipocytes with the COX2 inhibitor sc236 or by treating macrophages with the prostaglandin E receptor 4 antagonist AH23848. In fasted mice, macrophage accumulation in adipose tissue coincided with increases of PGE2levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE2with inflammation suppressive properties plays a significant role in mediating ATM accumulation during lipolysis.

• Keywords
• adipose tissue, cyclooxygenase, eicosanoids, extracellular signal-regulated kinase, fatty acid, inflammation, lipase,
• MeSH
• Enzyme Activation MeSH
• 3T3-L1 Cells MeSH
• Chemotaxis * MeSH
• Cyclooxygenase 1 genetics   MeSH
• Cyclooxygenase 2 genetics   MeSH
• Dinoprostone metabolism   MeSH
• Group IV Phospholipases A2 metabolism   MeSH
• Arachidonic Acid metabolism   MeSH
• Lipolysis * MeSH
• Macrophages cytology   MeSH
• Mice MeSH
• Fasting MeSH
• RAW 264.7 Cells MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Adipocytes metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Cyclooxygenase 1 MeSH
• Cyclooxygenase 2 MeSH
• Dinoprostone MeSH
• Group IV Phospholipases A2 MeSH
• Arachidonic Acid MeSH

Nutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial effects of weight loss.

• MeSH
• Adult MeSH
• Gene Regulatory Networks genetics   MeSH
• Weight Loss genetics   physiology   MeSH
• Caloric Restriction * MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Obesity metabolism   MeSH
• Gene Expression Profiling MeSH
• Adipose Tissue metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Calorie restriction-induced weight loss is accompanied by profound changes in adipose tissue characteristics. To determine the effect of weight loss on differentiation of preadipocytes and secretory capacity of in vitro differentiated adipocytes, we established cultures of these cells from paired subcutaneous adipose tissue biopsies obtained before and at the end of weight-reducing dietary intervention (DI) in 23 obese women. Based on lipid accumulation and the expression of differentiation markers, in vitro adipogenesis increased after weight loss and it was accompanied by enhanced expression of genes involved in de novo lipogenesis. This effect of weight loss was not driven by changes of peroxisome proliferator-activated receptor γ sensitivity to rosiglitazone. Weight loss also enhanced the expression of adiponectin and leptin while reducing that of monocyte chemoattractant protein 1 and interleukin-8 by cultured adipocytes. Thus, the weight-reducing (DI) increased adipogenic capacity of preadipocytes and shifted their secretion toward lower inflammatory profile. Reprogramming of preadipocytes could represent an adaptation to weight loss leading to partial restoration of preobese adipose tissue traits and thus contribute to the improvement of metabolic status. However, enhanced adipogenesis could also contribute to the unwanted weight regain after initial weight loss.

• MeSH
• Adipogenesis genetics   physiology   MeSH
• Adiponectin metabolism   MeSH
• Chemokine CCL2 metabolism   MeSH
• Cytokines metabolism   MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Weight Loss genetics   physiology   MeSH
• Interleukin-8 metabolism   MeSH
• Cells, Cultured MeSH
• Leptin metabolism   MeSH
• Humans MeSH
• Obesity MeSH
• PPAR gamma metabolism   MeSH
• Rosiglitazone MeSH
• Thiazolidinediones pharmacology   MeSH
• Adipocytes cytology   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adiponectin MeSH
• Chemokine CCL2 MeSH
• Cytokines MeSH
• Interleukin-8 MeSH
• Leptin MeSH
• PPAR gamma MeSH
• Rosiglitazone MeSH
• Thiazolidinediones MeSH

AIMS/HYPOTHESIS: Our goal was to identify a set of human adipose tissue macrophage (ATM)-specific markers and investigate whether their gene expression in subcutaneous adipose tissue (SAT) as well as in visceral adipose tissue (VAT) is related to obesity and to the occurrence of the metabolic syndrome. METHODS: ATM-specific markers were identified by DNA microarray analysis of adipose tissue cell types isolated from SAT of lean and obese individuals. We then analysed gene expression of these markers by reverse transcription quantitative PCR in paired samples of SAT and VAT from 53 women stratified into four groups (lean, overweight, obese and obese with the metabolic syndrome). Anthropometric measurements, euglycaemic-hyperinsulinaemic clamp, blood analysis and computed tomography scans were performed. RESULTS: A panel of 24 genes was selected as ATM-specific markers based on overexpression in ATM compared with other adipose tissue cell types. In SAT and VAT, gene expression of ATM markers was lowest in lean and highest in the metabolic syndrome group. mRNA levels in the two fat depots were negatively correlated with glucose disposal rate and positively associated with indices of adiposity and the metabolic syndrome. CONCLUSIONS/INTERPRETATION: In humans, expression of ATM-specific genes increases with the degree of adiposity and correlates with markers of insulin resistance and the metabolic syndrome to a similar degree in SAT and in VAT.

• MeSH
• Adult MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Macrophages metabolism   MeSH
• Metabolic Syndrome metabolism   MeSH
• Young Adult MeSH
• Overweight metabolism   MeSH
• Intra-Abdominal Fat cytology   metabolism   MeSH
• Obesity metabolism   MeSH
• Subcutaneous Fat cytology   metabolism   MeSH
• Aged MeSH
• Adipose Tissue cytology   metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH