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Diet-MEF2 Interactions Shape Lipid Droplet Diversification in Muscle to Influence Drosophila Lifespan

ABSTRACT: The number, size, and composition of lipid droplets can be influenced by dietary changes that shift energy substrate availability. This diversification of lipid droplets can promote metabolic flexibility and shape cellular stress responses in unique tissues with distinctive metabolic roles. Using Drosophila, we uncovered a role for myocyte enhancer-factor 2 (MEF2) in modulating diet-dependent lipid droplet diversification within adult striated muscle, impacting mortality rates. Muscle-specific attenuation of MEF2, whose chronic activation maintains glucose and mitochondrial homeostasis, leads to the accumulation of large, cholesterol ester-enriched intramuscular lipid droplets in response to high calorie, carbohydrate sufficient diets. The diet-dependent accumulation of these lipid droplets also correlates with both enhanced stress protection in muscle and increases in organismal lifespan. Furthermore, MEF2 attenuation releases an antagonistic regulation of cell cycle gene expression programs, and up-regulation of Cyclin E is required for diet-and-MEF2 dependent diversification of intramuscular lipid droplets. The integration of MEF2-regulated gene expression networks with dietary responses thus plays a critical role in shaping muscle metabolism and function, further influencing organismal lifespan. Together, these results highlight a potential protective role for intramuscular lipid droplets during dietary adaptation.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE147676 | GEO | 2020/08/11

REPOSITORIES: GEO

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Diet-MEF2 Interactions Shape Lipid Droplet Diversification in Muscle to Influence Drosophila Lifespan

Project description:Diet-MEF2 Interactions Shape Lipid Droplet Diversification in Muscle to Influence Drosophila Lifespan

| PRJNA616015 | ENA

Short-term low calorie diet remodels skeletal muscle lipid profile and metabolic gene expression in obese adults

Project description:OBJECTIVE Diet intervention in obese adults is the first strategy to induce weight loss and to improve insulin sensitivity. We hypothesized that improvements in insulin sensitivity after weight loss from a short-term dietary intervention tracks with alterations in expression of metabolic genes and abundance of specific lipid species. RESEARCH DESIGN AND METHODS Eight obese, insulin resistant, non-diabetic adults were recruited to participate in a three-week low calorie diet intervention study (1000 kcal/day). Fasting blood samples and vastus lateralis skeletal muscle biopsies were obtained before and after the dietary intervention. Clinical chemistry and measures of insulin sensitivity were determined. Unbiased microarray gene expression and targeted lipidomic analysis of skeletal muscle was performed. RESULTS Body weight was reduced, insulin sensitivity (HOMA-IR) was enhanced, and serum insulin concentration and blood lipid (triglyceride, cholesterol, LDL and HDL) levels were improved after dietary intervention. Gene set enrichment analysis of skeletal muscle revealed that oxidative phosphorylation and inflammatory processes were among the most enriched KEGG-pathways identified after dietary intervention. mRNA expression of PDK4 and MLYCD increased, while SCD decreased in skeletal muscle after dietary intervention. Dietary intervention altered the intramuscular lipid profile of skeletal muscle, with changes in content of phosphatidylcholine and triglyceride species among the pronounced. CONCLUSIONS Short-term diet intervention and weight loss in obese adults alters metabolic gene expression and reduces specific phosphatidylcholine and triglyceride species in skeletal muscle, concomitant with improvements in clinical outcomes and enhanced insulin sensitivity.

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Heterozygous midnolin knockout attenuates severity of nonalcoholic fatty liver disease in mice fed a Western-style diet high in fat, cholesterol, and fructose

Project description:We found that global heterozygous midnolin knockout attenuated the severity of nonalnonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose. This attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.

2023-05-03 | GSE226810 | GEO

Transcriptome shifts triggered by vitamin A and SCD genotype interaction in Duroc pigs

Project description:Background The composition of intramuscular fat depends on genetic and environmental factors, including the diet. In pigs, we identified a haplotype of three SNP mutations in the steaoryl-coA desaturase (SCD) gene promoter associated with higher content of monounsaturated fatty acids in intramuscular fat. The second of these three SNPs (rs80912566, C>T) affected a putative retinol response element in the SCD promoter. The effect of dietary vitamin A restriction over intramuscular fat content is controversial in pigs as it seems to depend on the genetic line and the duration of the restriction. This study aims to investigate changes in the muscle transcriptome in SCD rs80912566_TT and CC pigs fed with and without vitamin A supplement during the fattening period. Results Vitamin A did not affect carcass fattening traits and fatty acid composition in muscle, but we observed an interaction between vitamin A and SCD genotype on the desaturation of muscle fatty acids. The diet without vitamin A supplement tended to enlarge the compositional differences between genotypes. The interaction between diet and genotype was also evident at the transcriptome level, the highest number of differentially expressed genes were detected between SCD rs80912566_TT pigs fed with the two diets. Conclusions Restricting dietary vitamin A during the fattening period did not improve intramuscular fat content despite relevant changes in muscle gene expression, both in coding and non-coding genes. Despite this, there was a significant interaction between the SCD genotype and the dietary vitamin A, which affected the quality of the meat through a change in the saturation index of intramuscular fat and activated general pathways of retinol response in a SCD genotype-dependant manner.

2021-09-12 | GSE183909 | GEO

Polyunsaturated fatty acids acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increases postprandial insulin sensitivity

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Project description:Obesity has emerged as a worldwide problem in human health. Dietary lipids are taken up and transported via lymphatics into the circulatory system. During this process, lipids pass the mesenteric lymph node (mLN). These organs filter the lymph fluid for foreign antigens to induce and control immune responses. Alteration of that function during obesity has only slightly been studied. Here, we characterize changes within the microarchitecture of the mLN during high levels of lipid transport and highlight the role of stromal cells. Microarray experiments detected gene probes expressed by mLN stromal cells. Transmission electron microscopy enabled us to identify lipid droplets in different stromal cells, and in macrophages. Sizes, numbers and intercellular distances increased after 10 weeks of a high-fat diet. Thus, we propose that changes in the microarchitecture and increased accumulation of lipid droplets in stromal cells and macrophages have an influence on the immunological function of the mLN.

2020-05-14 | GSE138594 | GEO

Dietary lipids accumulate in macrophages and stromal cells and change the microarchitecture of the mesenteric lymph node I

2020-05-14 | GSE138593 | GEO

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2023-06-30 | GSE213928 | GEO

Microarray analysis of gene expression in liver, adipose tissue and skeletal muscle in response to chronic dietary administration of NDGA to high-fructose fed dyslipidemic rats

Project description:A high-fructose diet (HFrD) fed rat model of hypertriglyceridemia, dyslipidemia, insulin resistance and hepatic steatosis was employed to investigate the global transcriptional changes in the lipid metabolizing pathways in three insulin sensitive tissues:, liver, skeletal muscle and adipose tissue in response to chronic dietary administration of NDGA.

2016-10-13 | GSE81346 | GEO

Altered hepatic lipid droplet morphology and lipid metabolism in fasted Plin2 null mice

Project description:Perilipin 2 (Plin2) binds to the surface of hepatic lipid droplets (LDs) with expression levels that correlate with triacylglyceride (TAG) content. We investigated if Plin2 is important for hepatic LD storage in fasted or high-fat diet-induced obese Plin2+/+ and Plin2-/- mice. Plin2-/- mice had comparable body weights, metabolic phenotype, glucose tolerance, and circulating TAG and total cholesterol levels compared to Plin2+/+ mice, regardless of the dietary regime. Both fasted and high-fat fed Plin2-/- mice stored reduced levels of hepatic TAG compared to Plin2+/+ mice. Fasted Plin2-/- mice stored fewer, but larger hepatic lipid droplets compared to Plin2+/+ mice. Detailed hepatic lipid analysis showed substantial reductions in accumulated TAG species in fasted Plin2-/- mice compared to Plin2+/+ mice, whereas cholesteryl esters and phosphatidylcholines were increased. RNA sequencing revealed minor differences in hepatic gene expression between fed Plin2+/+ and Plin2-/- mice, in contrast to marked differences in gene expression between fasted Plin2+/+ and Plin2-/- mice. Our findings demonstrate that Plin2 is required to regulate hepatic lipid droplet size and storage of neutral lipid species in the fasted state, while its role in obesity-induced steatosis is less clear.

2023-10-13 | GSE214064 | GEO

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