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Coordination of GPR40 and Ketogenesis Signaling by Medium Chain Fatty Acids Regulates Beta Cell Function.

ABSTRACT: Diabetes prevalence increases with age, and ?-cell dysfunction contributes to the incidence of the disease. Dietary lipids have been recognized as contributory factors in the development and progression of the disease. Unlike long chain triglycerides, medium chain triglycerides (MCT) increase fat burning in animal and human subjects as well as serum C-peptide in type 2 diabetes patients. We evaluated the beneficial effects of MCT on ?-cells in vivo and in vitro. MCT improved glycemia in aged rats via ?-cell function assessed by measuring insulin secretion and content. In ?-cells, medium chain fatty acid (MCFA)-C10 activated fatty acid receptor 1 FFAR1/GPR40, while MCFA-C8 induced mitochondrial ketogenesis and the C8:C10 mixture improved ? cell function. We showed that GPR40 signaling positively impacts ketone body production in ?-cells, and chronic treatment with ?-hydroxybutyrate (BHB) improves ?-cell function. We also showed that BHB and MCFA help ?-cells recover from lipotoxic stress by improving mitochondrial function and increasing the expression of genes involved in ?-cell function and insulin biogenesis, such as Glut2, MafA, and NeuroD1 in primary human islets. MCFA offers a therapeutic advantage in the preservation of ?-cell function as part of a preventative strategy against diabetes in at risk populations.

SUBMITTER: Pujol JB

PROVIDER: S-EPMC5946258 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Coordination of GPR40 and Ketogenesis Signaling by Medium Chain Fatty Acids Regulates Beta Cell Function.

Pujol Julien Benjamin JB Christinat Nicolas N Ratinaud Yann Y Savoia Claudia C Mitchell Siobhan E SE Dioum El Hadji M EHM

Nutrients 20180412 4

Diabetes prevalence increases with age, and β-cell dysfunction contributes to the incidence of the disease. Dietary lipids have been recognized as contributory factors in the development and progression of the disease. Unlike long chain triglycerides, medium chain triglycerides (MCT) increase fat burning in animal and human subjects as well as serum C-peptide in type 2 diabetes patients. We evaluated the beneficial effects of MCT on β-cells in vivo and in vitro. MCT improved glycemia in aged rat ...[more]

PMID: 29649104

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Project description:Concerns about global warming, fossil-fuel depletion, food security, and human health have promoted metabolic engineers to develop tools/strategies to overproduce microbial functional oils directly from renewable resources. Medium-chain fatty acids (MCFAs, C8-C12) have been shown to be important sources due to their diverse biotechnological importance, providing benefits ranging from functional lipids to uses in bio-fuel production. However, oleaginous microbes do not carry native pathways for the production of MCFAs, and therefore, diverse approaches have been adapted to compensate for the requirements of industrial demand. Mucor circinelloides is a promising organism for lipid production (15-36% cell dry weight; CDW) and the investigation of mechanisms of lipid accumulation; however, it mostly produces long-chain fatty acids (LCFAs). To address this challenge, we genetically modified strain M. circinelloides MU758, first by integrating heterologous acyl-ACP thioesterase (TE) into fatty acid synthase (FAS) complex and subsequently by modifying the ?-oxidation pathway by disrupting the acyl-CoA oxidase (ACOX) and/or acyl-CoA thioesterase (ACOT) genes with a preference for medium-chain acyl-CoAs, to elevate the yield of MCFAs. The resultant mutant strains (M-1, M-2, and M-3, respectively) showed a significant increase in lipid production in comparison to the wild-type strain (WT). MCFAs in M-1 (47.45%) was sharply increased compared to the wild type strain (2.25%), and it was further increased in M-2 (60.09%) suggesting a negative role of ACOX in MCFAs production. However, MCFAs in M-3 were much decreased compared to M-1,suggesting a positive role of ACOT in MCFAs production. The M-2 strain showed maximum lipid productivity (~1800 milligram per liter per day or mg/L.d) and MCFAs productivity (~1100 mg/L.d). Taken together, this study elaborates on how the combination of two multidimensional approaches, TE gene over-expression and modification of the ?-oxidation pathway via substantial knockout of specific ACOX gene, significantly increased the production of MCFAs. This synergistic approach ultimately offers a novel opportunity for synthetic/industrial biologists to increase the content of MCFAs.

Project description:BackgroundMedium-chain fatty acids are molecules with applications in different industries and with growing demand. However, the current methods for their extraction are not environmentally sustainable. The reverse β-oxidation pathway is an energy-efficient pathway that produces medium-chain fatty acids in microorganisms, and its use in Saccharomyces cerevisiae, a broadly used industrial microorganism, is desired. However, the application of this pathway in this organism has so far either led to low titers or to the predominant production of short-chain fatty acids.ResultsWe genetically engineered Saccharomyces cerevisiae to produce the medium-chain fatty acids hexanoic and octanoic acid using novel variants of the reverse β-oxidation pathway. We first knocked out glycerolphosphate dehydrogenase GPD2 in an alcohol dehydrogenases knock-out strain (△adh1-5) to increase the NADH availability for the pathway, which significantly increased the production of butyric acid (78 mg/L) and hexanoic acid (2 mg/L) when the pathway was expressed from a plasmid with BktB as thiolase. Then, we tested different enzymes for the subsequent pathway reactions: the 3-hydroxyacyl-CoA dehydrogenase PaaH1 increased hexanoic acid production to 33 mg/L, and the expression of enoyl-CoA hydratases Crt2 or Ech was critical to producing octanoic acid, reaching titers of 40 mg/L in both cases. In all cases, Ter from Treponema denticola was the preferred trans-enoyl-CoA reductase. The titers of hexanoic acid and octanoic acid were further increased to almost 75 mg/L and 60 mg/L, respectively, when the pathway expression cassette was integrated into the genome and the fermentation was performed in a highly buffered YPD medium. We also co-expressed a butyryl-CoA pathway variant to increase the butyryl-CoA pool and support the chain extension. However, this mainly increased the titers of butyric acid and only slightly increased that of hexanoic acid. Finally, we also tested the deletion of two potential medium-chain acyl-CoA depleting reactions catalyzed by the thioesterase Tes1 and the medium-chain fatty acyl CoA synthase Faa2. However, their deletion did not affect the production titers.ConclusionsBy engineering the NADH metabolism and testing different reverse β-oxidation pathway variants, we extended the product spectrum and obtained the highest titers of octanoic acid and hexanoic acid reported in S. cerevisiae. Product toxicity and enzyme specificity must be addressed for the industrial application of the pathway in this organism.

Project description:Background & aimsKetogenic medium-chain fatty acids (MCFAs) with profound health benefits are commonly found in dairy products, palm kernel oil and coconut oil. We hypothesize that magnesium (Mg) supplementation leads to enhanced gut microbial production of MCFAs and, in turn, increased circulating MCFAs levels.MethodsWe tested this hypothesis in the Personalized Prevention of Colorectal Cancer Trial (PPCCT) (NCT01105169), a double-blind 2 × 2 factorial randomized controlled trial enrolling 240 participants. Six 24-h dietary recalls were performed for all participants at the baseline and during the intervention period. Based on the baseline 24-h dietary recalls, the Mg treatment used a personalized dose of Mg supplementation that would reduce the calcium (Ca): Mg intake ratio to around 2.3. We measured plasma MCFAs, sugars, ketone bodies and tricarboxylic acid cycle (TCA cycle) metabolites using the Metabolon's global Precision Metabolomics™ LC-MS platform. Whole-genome shotgun metagenomics (WGS) sequencing was performed to assess microbiota in stool samples, rectal swabs, and rectal biopsies.ResultsPersonalized Mg treatment (mean dose 205.58 mg/day with a range from 77.25 to 389.55 mg/day) significantly increased the plasma levels of C7:0, C8:0, and combined C7:0 and C8:0 by 18.45%, 25.28%, and 24.20%, respectively, compared to 14.15%, 10.12%, and 12.62% decreases in the placebo arm. The effects remain significant after adjusting for age, sex, race and baseline level (P = 0.0126, P = 0.0162, and P = 0.0031, respectively) and FDR correction at 0.05 (q = 0.0324 for both C7:0 and C8:0). Mg treatment significantly reduced the plasma level of sucrose compared to the placebo arm (P = 0.0036 for multivariable-adjusted and P = 0.0216 for additional FDR correction model) whereas alterations in daily intakes of sucrose, fructose, glucose, maltose and C8:0 from baseline to the end of trial did not differ between two arms. Mediation analysis showed that combined C7:0 and C8:0 partially mediated the effects of Mg treatment on total and individual ketone bodies (P for indirect effect = 0.0045, 0.0043, and 0.03, respectively). The changes in plasma levels of C7:0 and C8:0 were significantly and positively correlated with the alterations in stool microbiome α diversity (r = 0.51, p = 0.0023 and r = 0.34, p = 0.0497, respectively) as well as in stool abundance for the signatures of MCFAs-related microbiota with acyl-ACP thioesterase gene producing C7:0 (r = 0.46, p = 0.0067) and C8:0 (r = 0.49, p = 0.003), respectively, following Mg treatment.ConclusionsOptimizing Ca:Mg intake ratios to around 2.3 through 12-week personalized Mg supplementation leads to increased circulating levels of MCFAs (i.e. C7:0 and C8:0), which is attributed to enhanced production from gut microbial fermentation and, maybe, sucrose consumption.

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Coordination of GPR40 and Ketogenesis Signaling by Medium Chain Fatty Acids Regulates Beta Cell Function.

Publications

Coordination of GPR40 and Ketogenesis Signaling by Medium Chain Fatty Acids Regulates Beta Cell Function.

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