Physiological and metabolomic consequences of reduced expression of the Drosophila brummer triglyceride Lipase

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer (bmm), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

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Physiological and Metabolomic Consequences of Reduced Expression of the Drosophila brummer Triglyceride Lipase

10.1101/2021.08.04.455099 ◽

2021 ◽

Author(s):

Nestor Nazario Yepiz ◽

Jaime Fernandez Sobaberas ◽

Roberta Lyman ◽

Marion Campbell ◽

Vijay Shankar ◽

...

Keyword(s):

Fatty Acids ◽

Locomotor Activity ◽

Saturated Fatty Acids ◽

Intermediary Metabolism ◽

Sleep Patterns ◽

Triglyceride Lipase ◽

Genetic Manipulations ◽

Metabolic States ◽

Drosophila Model ◽

Long Chain

Disruption of lipolysis has widespread effects on intermediary metabolism and organismal phenotypes. Defects in lipolysis can be modeled in Drosophila melanogaster through genetic manipulations of brummer ( bmm ), which encodes a triglyceride lipase orthologous to mammalian Adipose Triglyceride Lipase. RNAi-mediated knock-down of bmm in all tissues or metabolic specific tissues results in reduced locomotor activity, altered sleep patterns and reduced lifespan. Metabolomic analysis on flies in which bmm is downregulated reveals a marked reduction in medium chain fatty acids, long chain saturated fatty acids and long chain monounsaturated and polyunsaturated fatty acids, and an increase in diacylglycerol levels. Elevated carbohydrate metabolites and tricarboxylic acid intermediates indicate that impairment of fatty acid mobilization as an energy source may result in upregulation of compensatory carbohydrate catabolism. bmm downregulation also results in elevated levels of serotonin and dopamine neurotransmitters, possibly accounting for the impairment of locomotor activity and sleep patterns. Physiological phenotypes and metabolomic changes upon reduction of bmm expression show extensive sexual dimorphism. Altered metabolic states in the Drosophila model are relevant for understanding human metabolic disorders, since pathways of intermediary metabolism are conserved across phyla.

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Long-chain saturated fatty acids in breast milk are associated with the pathogenesis of atopic dermatitis via induction of inflammatory ILC3s

Scientific Reports ◽

10.1038/s41598-021-92282-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Weng Sheng Kong ◽

Naohiro Tsuyama ◽

Hiroko Inoue ◽

Yun Guo ◽

Sho Mokuda ◽

...

Keyword(s):

Fatty Acids ◽

Atopic Dermatitis ◽

Breast Milk ◽

Saturated Fatty Acids ◽

Lymphoid Cells ◽

Interleukin 17 ◽

Immune System Development ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Long Chain

AbstractBreastfeeding influences the immune system development in infants and may even affect various immunological responses later in life. Breast milk provides a rich source of early nutrition for infant growth and development. However, the presence of certain compounds in breast milk, related to an unhealthy lifestyle or the diet of lactating mothers, may negatively impact infants. Based on a cohort study of atopic dermatitis (AD), we find the presence of damage-associated molecular patterns (DAMPs) activity in the mother’s milk. By non-targeted metabolomic analysis, we identify the long-chain saturated fatty acids (LCSFA) as a biomarker DAMPs (+) breast milk samples. Similarly, a mouse model in which breastfed offspring are fed milk high in LCSFA show AD onset later in life. We prove that LCSFA are a type of damage-associated molecular patterns, which initiate a series of inflammatory events in the gut involving type 3 innate lymphoid cells (ILC3s). A remarkable increase in inflammatory ILC3s is observed in the gut, and the migration of these ILC3s to the skin may be potential triggers of AD. Gene expression analysis of ILC3s isolated from the gut reveal upregulation of genes that increase ILC3s and chemokines/chemokine receptors, which may play a role in ILC migration to the skin. Even in the absence of adaptive immunity, Rag1 knockout mice fed a high-LCSFA milk diet develop eczema, accompanied by increased gut ILC3s. We also present that gut microbiota of AD-prone PA milk-fed mice is different from non-AD OA/ND milk-fed mice. Here, we propose that early exposure to LCSFAs in infants may affect the balance of intestinal innate immunity, inducing a highly inflammatory environment with the proliferation of ILC3s and production of interleukin-17 and interleukin-22, these factors may be potential triggers or worsening factors of AD.

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Abstract MP014: Very Long Chain Saturated Fatty Acids and Diabetes Risk: Meta-Analysis of Cohort Studies in the FORCE Consortium

Circulation ◽

10.1161/circ.135.suppl_1.mp014 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Amanda Fretts ◽

Fumiaki Imamura ◽

Chaoyu Yu ◽

Alexis C Frazier-Wood ◽

Maria Lankinen ◽

...

Keyword(s):

Fatty Acids ◽

Palmitic Acid ◽

Lower Risk ◽

Fixed Effects ◽

Meta Analysis ◽

Arachidic Acid ◽

Saturated Fatty Acids ◽

Diabetes Risk ◽

Incident Diabetes ◽

Long Chain

Background: Circulating saturated fatty acids are biomarkers of diet and metabolism that may influence the pathogenesis of diabetes. Unlike palmitic acid (16:0), which has been extensively studied, little is known of the relationship of very long-chain saturated fatty acids (VLSFAs), with 20 carbons or more, to diabetes risk. Objective: To investigate the associations of circulating levels of VLSFA with incident diabetes. Methods: A meta-analysis was conducted within a consortium of prospective (cohort or nested case-control) studies having circulating measures of one or more VLSFAs, including arachidic acid (20:0), behenic acid (22:0) and lignoceric acid (24:0). Standardized analysis was conducted in each study using pre-specified models, exposures, outcomes, and covariates. Study-specific estimates were pooled using fixed effects meta-analysis. Results: Current findings were based on 9 participating studies, including 46,549 total participants and 13,750 incident diabetes. In multivariable-adjusted analyses, higher levels of all 3 VLSFAs were associated with lower risk of incident diabetes. Pooled RRs (95% CI) per interquintile range were 0.80 (0.71-0.90) for 20:0; 0.83 (0.76-0.91) for 22:0; and 0.70 (0.63-0.79) for 24:0, after adjustment for demographics, lifestyle factors and clinical conditions. Additional adjustments for circulating palmitic acid and triglyceride levels moved the RRs toward the null (illustrated for 24:0, in model 3 of the Figure ). Conclusions: Based on meta-analysis of results from several studies around the world, biomarker levels of VLSFA are associated with lower risk of incident diabetes, potentially mediated by effects on circulating triglycerides and 16:0.

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Nrf2 affects the efficiency of mitochondrial fatty acid oxidation

Biochemical Journal ◽

10.1042/bj20130863 ◽

2014 ◽

Vol 457 (3) ◽

pp. 415-424 ◽

Cited By ~ 116

Author(s):

Marthe H. R. Ludtmann ◽

Plamena R. Angelova ◽

Ying Zhang ◽

Andrey Y. Abramov ◽

Albena T. Dinkova-Kostova

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Saturated Fatty Acids ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Atp Production ◽

Mitochondrial Fatty Acid ◽

Mitochondrial Oxidation ◽

Long Chain

Transcription factor Nrf2 affects fatty acid oxidation; the mitochondrial oxidation of long-chain (palmitic) and short-chain (hexanoic) saturated fatty acids is depressed in the absence of Nrf2 and accelerated when Nrf2 is constitutively activated, affecting ATP production and FADH2 utilization.

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Plasma Ceramides and Sphingomyelins in Relation to Atrial Fibrillation Risk: The Cardiovascular Health Study

Journal of the American Heart Association ◽

10.1161/jaha.119.012853 ◽

2020 ◽

Vol 9 (4) ◽

Author(s):

Paul N. Jensen ◽

Amanda M. Fretts ◽

Andrew N. Hoofnagle ◽

Colleen M. Sitlani ◽

Barbara McKnight ◽

...

Keyword(s):

Atrial Fibrillation ◽

Fatty Acids ◽

Palmitic Acid ◽

Cardiovascular Health ◽

Saturated Fatty Acids ◽

Behenic Acid ◽

Hazard Ratio ◽

Health Study ◽

Cardiovascular Health Study ◽

Long Chain

Background Ceramides exhibit multiple biological activities that may influence the pathophysiological characteristics of atrial fibrillation (AF). Whether the length of the saturated fatty acid carried by the ceramide or their sphingomyelin precursors are associated with AF risk is not known. Methods and Results Among 4206 CHS (Cardiovascular Health Study) participants (mean age, 76 years; 40% men) who were free of prevalent AF at baseline, we identified 1198 incident AF cases over a median 8.7 years of follow‐up. We examined 8 sphingolipid species: ceramide and sphingomyelin species with palmitic acid and species with very‐long‐chain saturated fatty acids: arachidic; behenic; and lignoceric. In adjusted Cox regression analyses, ceramides and sphingomyelins with very‐long‐chain saturated fatty acids were associated with reduced AF risk (ie, per 2‐fold higher ceramide with behenic acid hazard ratio, 0.71; 95% CI, 0.59–0.86; sphingomyelin with behenic acid hazard ratio, 0.60; 95% CI, 0.46–0.77). In contrast, ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (ceramide with palmitic acid hazard ratio, 1.31; 95% CI, 1.03–1.66; sphingomyelin with palmitic acid hazard ratio, 1.73; 95% CI, 1.18–2.55). Associations were attenuated with adjustment for NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), but did not differ significantly by age, sex, race, body mass index, or history of coronary heart disease. Conclusions Our findings suggest that several ceramide and sphingomyelin species are associated with incident AF, and that these associations differ on the basis of the fatty acid. Ceramides and sphingomyelins with palmitic acid were associated with increased AF risk, whereas ceramides and sphingomyelins with very‐long‐chain saturated fatty acids were associated with reduced AF risk.

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