Independent mechanisms underlie the protective effect of dietary polyunsaturated fatty acid supplementation and Gαz deficiency on the early type 1 diabetes phenotype of Non-obese diabetic (NOD) mice

AbstractNon-obese diabetic (NOD) mice deficient in Gz alpha subunit (Gαz) are protected from developing hyperglycemia, even with early islet insulitis similar to wild-type mice. Similarly, wild-type (WT) NOD mice are protected from glucose intolerance when fed a diet enriched in eicosapentaneoic acid (EPA). In the beta-cell, Prostaglandin EP3 receptor (EP3), whose primary endogenous ligand is the arachidonic acid (AA) metabolite, prostaglandin E2, is specifically coupled to Gαz. In this work, we tested whether dietary EPA supplementation, thereby reducing systemic PGE2 levels, would complement Gαz loss in the NOD mouse model. WT and Gαz-null NOD mice were fed an AA-enriched diet, EPA-enriched diet, or control diet upon weaning. After 12 weeks of diet feeding, glucose tolerance tests were performed and pancreatic islets and whole pancreas collected for ex vivo analyses, with the longer-term effect of an EPA-enriched diet on splenic T-cell populations quantified via flow cytometry. Our results reveal a polyunsaturated fatty acid-enriched diet, whether AA or EPA, improves wild-type NOD glucose tolerance by the same magnitude as Gαz loss, but through almost completely different physiological and cellular mechanisms. Our results shed critical light on future research into novel pharmacological and dietary adjuvant therapies for T1D.

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Carrageenan-induced granuloma and iron status in rats with dietary polyunsaturated fatty acid deficiency

British Journal Of Nutrition ◽

10.1079/bjn19910108 ◽

1991 ◽

Vol 65 (3) ◽

pp. 497-503 ◽

Cited By ~ 5

Author(s):

T. Carbonell ◽

M. P. Saiz ◽

M. T. Mitjavila ◽

P. Puig-Parellada ◽

C. Cambon-Gros ◽

...

Keyword(s):

Lipid Peroxidation ◽

Fatty Acid ◽

Polyunsaturated Fatty Acid ◽

Iron Status ◽

Control Diet ◽

Fe Deficiency ◽

Prostaglandin E ◽

Sprague Dawley ◽

Deficient Diet ◽

Dietary Polyunsaturated Fatty Acid

Sprague–Dawley rats were fed for 4 months on a control diet or a polyunsaturated-fatty-acid (PUFA)-deficient diet. The combined effects of iron overload (Fe dextran) or Fe deficiency (desferrioxamine) on carrageenan-induced granuloma were studied. PUFA deficiency induced changes in Fe metabolism, but no alterations in lipid peroxidation variables were observed. Inflammation implied an increase in lipid peroxidation, Fe storage and caeruloplasmin concentration, together with symptoms of anaemia. PUFA deficiency in inflamed rats gave rise to a lower inflammatory response (granuloma weight and prostaglandin E2concentration) and ethane exhalation. Fe overload potentiated inflammatory and lipid peroxidation processes, whereas Fe deficiency decreased them.

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Naringenin Prevents Obesity, Hepatic Steatosis, and Glucose Intolerance in Male Mice Independent of Fibroblast Growth Factor 21

Endocrinology ◽

10.1210/en.2014-2003 ◽

2015 ◽

Vol 156 (6) ◽

pp. 2087-2102 ◽

Cited By ~ 46

Author(s):

Julia M. Assini ◽

Erin E. Mulvihill ◽

Amy C. Burke ◽

Brian G. Sutherland ◽

Dawn E. Telford ◽

...

Keyword(s):

Fatty Acid ◽

Growth Factor ◽

Glucose Tolerance ◽

Fibroblast Growth Factor ◽

Hepatic Steatosis ◽

Metabolic Adaptation ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Wild Type ◽

Metabolic Dysregulation

Abstract The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21−/−) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21−/− mice. HFD-fed Fgf21−/− mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.

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Polyunsaturated fatty acid‐derived I Ks channel activators shorten the QT interval ex‐vivo and in‐vivo

Acta Physiologica ◽

10.1111/apha.13471 ◽

2020 ◽

Vol 229 (4) ◽

Cited By ~ 3

Author(s):

Mark A. Skarsfeldt ◽

Sara I. Liin ◽

Hans P. Larsson ◽

Bo H. Bentzen

Keyword(s):

Fatty Acid ◽

Polyunsaturated Fatty Acid ◽

Qt Interval ◽

Ex Vivo

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Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00010.2021 ◽

2021 ◽

Author(s):

Cody D. Smith ◽

Chein-Te Lin ◽

Shawna L. McMillin ◽

Luke A. Weyrauch ◽

Cameron Alan Schmidt ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Glucose Tolerance ◽

Glucose Intolerance ◽

High Fat Diet ◽

Whole Body ◽

Acid Oxidation ◽

Wild Type ◽

High Fat ◽

Redox Environment

Elevated mitochondrial H2O2 emission and an oxidative shift in cytosolic redox environment have been linked to high fat diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle β-oxidation flux were studied. In mice overexpressing peroxisome proliferator activated receptor-α in muscle (MCK-PPARα), lipid supported mitochondrial respiration, membrane potential (ΔΨm) and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole-body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1 deficient, fatty-liver dystrophic mice, another model characterized by increased β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondrial-targeted catalase) with MCK-PPARα mice normalized JH2O2 production, redox environment and glucose tolerance, but surprisingly both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high fat diet MCK-PPARα mice were characterized by much lower whole body, fat and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in attempt to restore bioenergetic homeostasis.

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Ketoacylsynthase Domains of a Polyunsaturated Fatty Acid Synthase in Thraustochytrium sp. Strain ATCC 26185 Can Effectively Function as Stand-Alone Enzymes in Escherichia coli

Applied and Environmental Microbiology ◽

10.1128/aem.03133-16 ◽

2017 ◽

Vol 83 (9) ◽

Cited By ~ 8

Author(s):

Xi Xie ◽

Dauenpen Meesapyodsuk ◽

Xiao Qiu

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Polyunsaturated Fatty Acid ◽

Strain Atcc ◽

Wild Type ◽

Fatty Acid Production ◽

Content Type ◽

E Coli ◽

Catalytic Domains ◽

Long Chain

ABSTRACT Thraustochytrium sp. strain ATCC 26185 accumulates a high level of docosahexaenoic acid (DHA), a nutritionally important ω-3 very-long-chain polyunsaturated fatty acid (VLCPUFA) synthesized primarily by polyunsaturated fatty acid (PUFA) synthase, a type I polyketide synthase-like megaenzyme. The PUFA synthase in this species comprises three large subunits, each with multiple catalytic domains. It was hypothesized that among these domains, ketoacylsynthase (KS) domains might be critical for catalyzing the condensation of specific unsaturated acyl-acyl carrier proteins (ACPs) with malonyl-ACP, thereby retaining double bonds in an extended acyl chain. To investigate the functions of these putative KS domains, two segment sequences from subunit A (KS-A) and subunit B (KS-B) of the PUFA synthase were dissected and then expressed as stand-alone enzymes in Escherichia coli. The results showed that both KS-A and KS-B domains could complement the defective phenotypes of both E. coli fabB and fabF mutants. Overexpression of these domains in wild-type E. coli led to increases in total fatty acid production. KS-B produced a higher ratio of unsaturated fatty acids (UFAs) to saturated fatty acids (SFAs), while KS-A could improve the overall production of fatty acids more effectively, particularly for the production of SFAs, implying that KS-A is more comparable to FabF, while KS-B is more similar to FabB in catalytic functions. Successful complementation and functional expression of the embedded KS domains in E. coli are the first step forward in studying the molecular mechanism of the PUFA synthase for the biosynthesis of VLCPUFAs in Thraustochytrium. IMPORTANCE Very-long-chain polyunsaturated fatty acids (VLCPUFAs) are important for human health. They can be biosynthesized in either an aerobic pathway or an anaerobic pathway in nature. However, abundant VLCPUFAs in marine microorganisms are primarily synthesized by polyunsaturated fatty acid (PUFA) synthase, a megaenzyme with multiple subunits, each with multiple catalytic domains. Furthermore, the fundamental mechanism for this enzyme to synthesize these fatty acids still remains unknown. This report started with dissecting the embedded KS domains of the PUFA synthase from marine protist Thraustochytrium sp. strain ATCC 26185 and then expressing them in wild-type E. coli and mutants defective in condensation of acyl-ACP with malonyl-ACP. Successful complementation of the mutants and improved fatty acid production in the overexpression experiments indicate that these KS domains can effectively function as stand-alone enzymes in E. coli. This result has paved the way for further studying of molecular mechanisms of the PUFA synthase for the biosynthesis of VLCPUFAs.

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Fatty and defatted herring scrap fed to mink (Mustela vison) in the reproduction and nursing periods

Canadian Journal of Animal Science ◽

10.4141/a98-093 ◽

1999 ◽

Vol 79 (4) ◽

pp. 457-465 ◽

Cited By ~ 1

Author(s):

Tove N. Clausen ◽

Birthe M. Damgaard ◽

Christian F. Børsting ◽

Carsten Hejlesen

Keyword(s):

Fatty Acid ◽

Vitamin E ◽

Energy Density ◽

Key Words ◽

Polyunsaturated Fatty Acid ◽

Dietary Fat ◽

Control Diet ◽

Dietary Group ◽

Negative Effects ◽

Acetic Acids

The use of fatty herring scrap and defatted herring scrap products for female mink in the reproduction and nursing periods was investigated in two experiments. In exp. 1, diets with 27% fatty herring scrap with 60 vs. 120 mg vitamin E kg−1 feed, and 10 vs. 19% defatted herring scrap ensiled with formic and acetic acids were compared with a control diet without fatty herring scrap or defatted herring scrap silage. Each dietary group consisted of 137 females. In exp. 2, diets with 20% fatty herring scrap with 63 vs. 78% of the dietary fat originating from fish, and diets containing 20 vs. 29% defatted herring scrap were compared with a control diet without fatty herring scrap or defatted herring scrap. Each dietary group consisted of 90 females. The results showed that fatty herring scrap, defatted herring scrap and defatted herring scrap silage can be used at these levels during the winter and reproduction periods until parturition, without any negative effects on the number of kits per female at parturition and weaning. However, use of defatted herring scrap silage in the nursing period resulted in lower kit weights at weaning. There were also some indications that high amounts of dietary fat from herring led to reduced kit weights at weaning; therefore, reducing the fat content in herring seemed to be appropriate in order to reduce the content of fish fat in the diet in the nursing period. The recommended addition of 60 mg vitamin E kg−1 wet feed, with an energy density of 5–6 MJ kg−1 during winter, reproduction and nursing periods, was sufficient according to the plasma content of α -tocopherol. Furthermore, there were no negative effects in the nursing period of feeding fatty or defatted herring scrap during the preceding rearing season of the females. Key words: Mink, marine lipid, polyunsaturated fatty acid, haematology, α -tocopherol, acid silage

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The effects of low-ratio n-6/n-3 PUFA on biomarkers of inflammation: a systematic review and meta-analysis

Food & Function ◽

10.1039/d0fo01976c ◽

2021 ◽

Author(s):

Yali Wei ◽

Yan Meng ◽

Na Li ◽

Qian Wang ◽

Liyong Chen

Keyword(s):

Systematic Review ◽

Fatty Acid ◽

Polyunsaturated Fatty Acid ◽

Meta Analysis ◽

Chain Polyunsaturated Fatty Acid ◽

Inflammation Markers ◽

Pufa Supplementation ◽

Long Chain

The purpose of the systematic review and meta-analysis was to determine if low-ratio n-6/n-3 long-chain polyunsaturated fatty acid (PUFA) supplementation affects serum inflammation markers based on current studies.

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