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

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

Parenteral nutrition (PN) is often associated with the deterioration of liver functions (PNALD). Omega-3 polyunsaturated fatty acids (PUFA) were reported to alleviate PNALD but the underlying mechanisms have not been fully unraveled yet. Using omics´ approach, we determined serum and liver lipidome, liver proteome, and liver bile acid profile as well as markers of inflammation and oxidative stress in rats administered either ω-6 PUFA based lipid emulsion (Intralipid) or ω-6/ω-3 PUFA blend (Intralipid/Omegaven) via the enteral or parenteral route. In general, we found that enteral administration of both lipid emulsions has less impact on the liver than the parenteral route. Compared with parenterally administered Intralipid, PN administration of ω-3 PUFA was associated with 1. increased content of eicosapentaenoic (EPA)- and docosahexaenoic (DHA) acids-containing lipid species; 2. higher abundance of CYP4A isoenzymes capable of bioactive lipid synthesis and the increased content of their potential products (oxidized EPA and DHA); 3. downregulation of enzymes involved CYP450 drug metabolism what may represent an adaptive mechanism counteracting the potential negative effects (enhanced ROS production) of PUFA metabolism; 4. normalized anti-oxidative capacity and 5. physiological BAs spectrum. All these findings may contribute to the explanation of ω-3 PUFA protective effects in the context of PN.

• MeSH
• Emulsions MeSH
• Enteral Nutrition methods   MeSH
• Phospholipids MeSH
• Liver metabolism   MeSH
• Rats MeSH
• Eicosapentaenoic Acid chemistry   MeSH
• Docosahexaenoic Acids chemistry   MeSH
• Oxygen metabolism   MeSH
• Lipidomics MeSH
• Lipids chemistry   MeSH
• Malondialdehyde metabolism   MeSH
• Metabolomics MeSH
• Fatty Acids, Unsaturated metabolism   MeSH
• Fatty Acids, Omega-3 chemistry   MeSH
• Oxidative Stress MeSH
• Parenteral Nutrition methods   MeSH
• Rats, Wistar MeSH
• Proteome metabolism   MeSH
• Reactive Oxygen Species metabolism   MeSH
• Fish Oils MeSH
• Soybean Oil MeSH
• Inflammation MeSH
• Bile Acids and Salts analysis   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Emulsions MeSH
• Phospholipids MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Oxygen MeSH
• Lipids MeSH
• Malondialdehyde MeSH
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 MeSH
• Proteome MeSH
• Reactive Oxygen Species MeSH
• Fish Oils MeSH
• Soybean Oil MeSH
• soybean oil, phospholipid emulsion MeSH Browser
• Bile Acids and Salts MeSH