BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

• Keywords
• Adipose tissue, Ether lipids, Heart failure, Inflammation, Sodium-glucose cotransporter 2 inhibitors,
• MeSH
• Anti-Inflammatory Agents therapeutic use   pharmacology   MeSH
• Biomarkers blood   MeSH
• Diabetes Mellitus, Type 2 drug therapy   metabolism   diagnosis   MeSH
• Epicardial Adipose Tissue MeSH
• Ventricular Function, Left drug effects   MeSH
• Sodium-Glucose Transporter 2 Inhibitors * therapeutic use   pharmacology   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Inflammation Mediators * metabolism   MeSH
• Metabolomics MeSH
• Pericardium * metabolism   drug effects   MeSH
• Heart Failure * metabolism   physiopathology   drug therapy   MeSH
• Severity of Illness Index * MeSH
• Stroke Volume drug effects   MeSH
• Adipose Tissue * drug effects   metabolism   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Biomarkers MeSH
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Inflammation Mediators * MeSH

Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.

• Keywords
• Adtrp, FAHFA, adipose tissue, female, lipokines, male,
• Publication type
• Journal Article MeSH
• Preprint MeSH

With the increasing number of lipidomic studies, there is a need for an efficient and automated analysis of lipidomic data. One of the challenges faced by most existing approaches to lipidomic data analysis is lipid nomenclature. The systematic nomenclature of lipids contains all available information about the molecule, including its hierarchical representation, which can be used for statistical evaluation. The Lipid Over-Representation Analysis (LORA) web application (https://lora.metabolomics.fgu.cas.cz) analyzes this information using the Java-based Goslin framework, which translates lipid names into a standardized nomenclature. Goslin provides the level of lipid hierarchy, including information on headgroups, acyl chains, and their modifications, up to the "complete structure" level. LORA allows the user to upload the experimental query and reference data sets, select a grammar for lipid name normalization, and then process the data. The user can then interactively explore the results and perform lipid over-representation analysis based on selected criteria. The results are graphically visualized according to the lipidome hierarchy. The lipids present in the most over-represented terms (lipids with the highest number of enriched shared structural features) are defined as Very Important Lipids (VILs). For example, the main result of a demo data set is the information that the query is significantly enriched with "glycerophospholipids" containing "acyl 20:4" at the "sn-2 position". These terms define a set of VILs (e.g., PC 18:2/20:4;O and PE 16:0/20:4(5,8,10,14);OH). All results, graphs, and visualizations are summarized in a report. LORA is a tool focused on the smart mining of epilipidomics data sets to facilitate their interpretation at the molecular level.

• MeSH
• Glycerophospholipids * chemistry   MeSH
• Lipidomics MeSH
• Lipids * analysis   MeSH
• Software MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Glycerophospholipids * MeSH
• Lipids * MeSH

Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.

• Keywords
• ATGL, FAHFA, HSL, lipokine,
• MeSH
• Adipose Tissue, White metabolism   MeSH
• Esters chemistry   MeSH
• HEK293 Cells MeSH
• Palmitic Acid metabolism   MeSH
• Stearic Acids metabolism   MeSH
• Humans MeSH
• Lipase metabolism   MeSH
• Lipolysis physiology   MeSH
• Fatty Acids metabolism   MeSH
• Metabolism physiology   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Sterol Esterase metabolism   MeSH
• Triglycerides metabolism   MeSH
• Adipose Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Esters MeSH
• Palmitic Acid MeSH
• Stearic Acids MeSH
• Lipase MeSH
• Fatty Acids MeSH
• stearic acid MeSH Browser
• Sterol Esterase MeSH
• Triglycerides MeSH

Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.

• MeSH
• Adipose Tissue, White metabolism   MeSH
• Glucose metabolism   MeSH
• Carbon Isotopes MeSH
• Palmitic Acid metabolism   MeSH
• Stearic Acids metabolism   MeSH
• Lipase genetics   metabolism   MeSH
• Lipogenesis genetics   MeSH
• Lipolysis MeSH
• Fatty Acids metabolism   MeSH
• Metabolomics MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Cold Temperature MeSH
• Deuterium Oxide MeSH
• Triglycerides metabolism   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
• Names of Substances
• 5-PAHSA MeSH Browser
• 9-PAHSA MeSH Browser
• Glucose MeSH
• Carbon Isotopes MeSH
• Palmitic Acid MeSH
• Stearic Acids MeSH
• Lipase MeSH
• Fatty Acids MeSH
• Deuterium Oxide MeSH
• PNPLA2 protein, mouse MeSH Browser
• Triglycerides MeSH

Fatty acid esters of hydroxy fatty acids (FAHFAs) are lipid mediators with promising antidiabetic and anti-inflammatory properties that are formed in white adipose tissue (WAT) via de novo lipogenesis, but their biosynthetic enzymes are unknown. Using a combination of lipidomics in WAT, quantitative trait locus mapping, and correlation analyses in rat BXH/HXB recombinant inbred strains, as well as response to oxidative stress in murine models, we elucidated the potential pathway of biosynthesis of several FAHFAs. Comprehensive analysis of WAT samples identified ∼160 regioisomers, documenting the complexity of this lipid class. The linkage analysis highlighted several members of the nuclear factor, erythroid 2 like 2 (Nrf2)-mediated antioxidant defense system (Prdx6, Mgst1, Mgst3), lipid-handling proteins (Cd36, Scd6, Acnat1, Acnat2, Baat), and the family of flavin containing monooxygenases (Fmo) as the positional candidate genes. Transgenic expression of Nrf2 and deletion of Prdx6 genes resulted in reduction of palmitic acid ester of 9-hydroxystearic acid (9-PAHSA) and 11-PAHSA levels, while oxidative stress induced by an inhibitor of glutathione synthesis increased PAHSA levels nonspecifically. Our results indicate that the synthesis of FAHFAs via carbohydrate-responsive element-binding protein-driven de novo lipogenesis depends on the adaptive antioxidant system and suggest that FAHFAs may link activity of this system with insulin sensitivity in peripheral tissues.

• MeSH
• Adipose Tissue, White enzymology   metabolism   MeSH
• Biomarkers metabolism   MeSH
• Esters chemistry   metabolism   MeSH
• NF-E2-Related Factor 2 genetics   metabolism   MeSH
• Rats MeSH
• Palmitic Acid chemistry   metabolism   MeSH
• Stearic Acids chemistry   metabolism   MeSH
• Metabolomics methods   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Random Allocation MeSH
• Oxidative Stress * MeSH
• Peroxiredoxin VI genetics   metabolism   MeSH
• Rats, Inbred BN MeSH
• Rats, Inbred SHR MeSH
• Rats, Transgenic MeSH
• Gene Expression Regulation, Enzymologic * MeSH
• Gene Expression Profiling MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 9-hydroxystearic acid MeSH Browser
• Biomarkers MeSH
• Esters MeSH
• NF-E2-Related Factor 2 MeSH
• Palmitic Acid MeSH
• Stearic Acids MeSH
• Nfe2l2 protein, mouse MeSH Browser
• Nfe2l2 protein, rat MeSH Browser
• Peroxiredoxin VI MeSH
• Prdx6 protein, mouse MeSH Browser