Adipose tissue is composed of adipocytes and cells from the stromal vascular fraction. In this issue of Cell Metabolism, Bäckdahl et al. (2021) use spatial transcriptomics to provide a first glimpse at the architecture of human adipose tissue. The authors identify distinct adipocyte subpopulations with specific metabolic features.
- MeSH
- Humans MeSH
- Transcriptome * genetics MeSH
- Adipose Tissue MeSH
- Adipocytes * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Comment MeSH
- Research Support, Non-U.S. Gov't MeSH
Hormone-sensitive lipase (HSL) was initially characterized as the hormonally regulated neutral lipase activity responsible for the breakdown of triacylglycerols into fatty acids in adipose tissue. This review aims at providing up-to-date information on structural properties, regulation of expression, activity and function as well as therapeutic potential. The lipase is expressed as different isoforms produced from tissue-specific alternative promoters. All isoforms are composed of an N-terminal domain and a C-terminal catalytic domain within which a regulatory domain containing the phosphorylation sites is embedded. Some isoforms possess additional N-terminal regions. The catalytic domain shares similarities with bacteria, fungus and vascular plant proteins but not with other mammalian lipases. HSL singularity is provided by regulatory and N-terminal domains sharing no homology with other proteins. HSL has a broad substrate specificity compared to other neutral lipases. It hydrolyzes acylglycerols, cholesteryl and retinyl esters among other substrates. A novel role of HSL, independent of its enzymatic function, has recently been described in adipocytes. Clinical studies revealed dysregulations of HSL expression and activity in disorders, such as lipodystrophy, obesity, type 2 diabetes and cancer-associated cachexia. Development of specific inhibitors positions HSL as a pharmacological target for the treatment of metabolic complications.
Obesity is a multisystem disorder associated with cardiovascular and metabolic complications. According to recent studies, it is characterized as a condition of low-grade inflammation with altered adipose tissue function and secretion of various adipokines. One of the strategies in obesity treatment is dietary intervention (DI) that could modulate cytokine levels in a favourable way. The aim of this review was to summarize the results of studies performed in the last 13 years investigating DI programmes accompanied with weight loss in relation to profile of adipokines at different level (adipose tissue mRNA, adipose tissue secretion and circulating level) and identify whether modulations of adipokines are implicated in the positive effects of DIs. The overall finding is that DIs leading to 5-10% weight loss modulate production of certain adipokines and generally induce improvement of clinical parameters, e.g. insulin sensitivity, but the amelioration of obesity complications is not coherent with the pattern of adipokine regulation, except maybe for leptin. Global analysis of the adipose tissue secretome and measurement of panels of adipokines may prove more informative than studies on individual molecules.
- MeSH
- Adipokines metabolism MeSH
- Weight Loss MeSH
- Humans MeSH
- Obesity diet therapy metabolism MeSH
- Diet, Reducing MeSH
- Adipose Tissue metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.
- MeSH
- Adipocytes, White metabolism MeSH
- Homeostasis MeSH
- Humans MeSH
- Disease Management * MeSH
- Lipid Metabolism physiology MeSH
- Obesity metabolism therapy MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
OBJECTIVE: Hypoadiponectinemia observed in obesity is associated with insulin resistance, diabetes and atherosclerosis. The aim of the present study was to investigate secretion of adiponectin and its multimeric isoforms by explants derived from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese and non-obese subjects. DESIGN: Paired samples of SAT and VAT and blood samples were obtained from 23 subjects (10 non-obese and 13 obese) undergoing elective abdominal surgery. Total adiponectin quantities and adiponectin isoforms were measured in conditioned media of explants derived from SAT and VAT using enzyme-linked immunosorbent assay and non-denaturing western blot, respectively. RESULTS: Total adiponectin plasma levels were lower in obese than in non-obese subjects (P<0.05). Secretion of total adiponectin in adipose tissue (AT) explants was lower in obese than in non-obese subjects in SAT (P<0.05) but not in VAT. In both, SAT and VAT, the most abundant isoform released into conditioned media was the high-molecular weight (HMW) form. Its relative proportion in relation to total adiponectin was higher in conditioned media of explants from both fat depots when compared with plasma (P<0.001). The proportion of secreted HMW vs total adiponectin was higher in VAT than in SAT explants in the group of non-obese individuals (49.3±3.1% in VAT vs 40.6±2.8% in SAT; P<0.01), whereas no difference between the two depots was found in obese subjects (46.2±3.0 % in VAT vs 46.0±2.4 % in SAT). CONCLUSION: Obesity is associated with the decrease of total adiponectin secretion in SAT. The profile of adiponectin isoforms secreted by SAT and VAT explants differs from that in plasma. Secretion of total adiponectin and HMW isoform of adiponectin are different in obese and non-obese subjects in relation to AT depot.
- MeSH
- Adiponectin blood MeSH
- Atherosclerosis blood physiopathology prevention & control MeSH
- Diabetes Mellitus, Type 2 blood physiopathology prevention & control MeSH
- Adult MeSH
- Enzyme-Linked Immunosorbent Assay MeSH
- Insulin Resistance MeSH
- Middle Aged MeSH
- Humans MeSH
- Intra-Abdominal Fat metabolism MeSH
- Obesity blood complications metabolism physiopathology MeSH
- Subcutaneous Fat metabolism MeSH
- Protein Isoforms blood MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: Adipocytes are cells specialized for storage of neutral lipids. This storage capacity is dependent on lipogenesis and is diminished in obesity. The reason for the decline in lipogenic activity of adipocytes in obesity remains unknown. Recent data show that lipogenesis in liver is regulated by pathways initiated by endoplasmic reticulum stress (ERS). Thus, we aimed at investigating the effect of ERS on lipogenesis in adipose cells. METHODS: Preadipocytes were isolated from subcutaneous abdominal adipose tissue from obese volunteers and in vitro differentiated into adipocytes. ERS was induced pharmacologically by thapsigargin (TG) or tunicamycin (TM). Activation of Unfolded Protein Response pathway (UPR) was monitored on the level of eIF2α phosphorylation and mRNA expression of downstream targets of UPR sensors. Adipogenic and lipogenic capacity was evaluated by Oil Red O staining, measurement of incorporation of radio-labelled glucose or acetic acid into lipids and mRNA analysis of adipogenic/lipogenic markers. RESULTS: Exposition of adipocytes to high doses of TG (100 nM) and TM (1 μg/ml) for 1-24 h enhanced expression of several UPR markers (HSPA5, EDEM1, ATF4, XBP1s) and phosphorylation of eIF2α. This acute ERS substantially inhibited expression of lipogenic genes (DGAT2, FASN, SCD1) and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to low dose of TG (2.5 nM) during the early phases of adipogenic conversion of preadipocytes impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in mature adipocytes. CONCLUSIONS: Acute ERS weakened a capacity of mature adipocytes to store lipids and chronic ERS diminished adipogenic potential of preadipocytes.
- MeSH
- Cell Differentiation * MeSH
- Endoplasmic Reticulum drug effects metabolism MeSH
- Phosphorylation MeSH
- Stress, Physiological * MeSH
- Humans MeSH
- Lipids biosynthesis MeSH
- Unfolded Protein Response MeSH
- Thapsigargin pharmacology MeSH
- Adipocytes cytology MeSH
- Tunicamycin pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
- MeSH
- Biomarkers metabolism MeSH
- Cell Differentiation 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
BACKGROUND: Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. METHODS: SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. RESULTS: Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. CONCLUSION: This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression.
- MeSH
- Cell Differentiation genetics MeSH
- Fatty Acid Desaturases genetics metabolism MeSH
- Adult MeSH
- Gene Expression MeSH
- Genotype MeSH
- Immune System MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Linear Models MeSH
- Fatty Acids genetics MeSH
- Lipid Metabolism genetics MeSH
- Multigene Family genetics MeSH
- Multivariate Analysis MeSH
- Obesity genetics MeSH
- Subcutaneous Fat metabolism MeSH
- Inflammation genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Abdomen MeSH
- Adult MeSH
- Energy Intake MeSH
- Gene Expression MeSH
- Research Support as Topic MeSH
- Cardiovascular Diseases etiology MeSH
- Humans MeSH
- Obesity diet therapy physiopathology MeSH
- Diet, Reducing MeSH
- Adipose Tissue metabolism pathology MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female 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
