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

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GeneXX:an online tool for the exploration of transcript changes in skeletal muscle associated with exercise

Exercise stimulates a wide array of biological processes, but the mechanisms involved are incompletely understood. Many previous studies have adopted transcriptomic analyses of skeletal muscle to address particular research questions, a process that ultimately results in the collection of large amounts of publicly available data that has not been fully integrated or interrogated. To maximize the use of these available transcriptomic exercise data sets, we have downloaded and reanalyzed them and formulated the data into a searchable online tool, geneXX. GeneXX is highly intuitive and free and provides immediate information regarding the response of a transcript of interest to exercise in skeletal muscle. To demonstrate its utility, we carried out a meta-analysis on the included data sets and show transcript changes in skeletal muscle that persist regardless of sex, exercise mode, and duration, some of which have had minimal attention in the context of exercise. We also demonstrate how geneXX can be used to formulate novel hypotheses on the complex effects of exercise, using preliminary data already generated. This resource represents a valuable tool for researchers with interests in human skeletal muscle adaptation to exercise. </jats:p

Biological Evaluations, NMR Analyses, Molecular Modeling Studies, and Overview of the Synthesis of the Marine Natural Product (−)-Mucosin

Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (−)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (−)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (−)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (−)-mucosin (1) is also presented

The effect of acute and long‐term physical activity on extracellular matrix and serglycin in human skeletal muscle

Remodeling of extracellular matrix (ECM), including regulation of proteoglycans in skeletal muscle can be important for physiological adaptation to exercise. To investigate the effects of acute and long‐term exercise on the expression of ECM‐related genes and proteoglycans in particular, 26 middle‐aged, sedentary men underwent a 12 weeks supervised endurance and strength training intervention and two acute, 45 min bicycle tests (70% VO2max), one at baseline and one after 12 weeks of training. Total gene expression in biopsies from m. vastus lateralis was measured with deep mRNA sequencing. After 45 min of bicycling approximately 550 gene transcripts were >50% upregulated. Of these, 28 genes (5%) were directly related to ECM. In response to long‐term exercise of 12 weeks 289 genes exhibited enhanced expression (>50%) and 20% of them were ECM related. Further analyses of proteoglycan mRNA expression revealed that more than half of the proteoglycans expressed in muscle were significantly enhanced after 12 weeks intervention. The proteoglycan serglycin (SRGN) has not been studied in skeletal muscle and was one of few proteoglycans that showed increased expression after acute (2.2‐fold, P < 0.001) as well as long‐term exercise (1.4‐fold, P < 0.001). Cultured, primary human skeletal muscle cells expressed and secreted SRGN. When the expression of SRGN was knocked down, the expression and secretion of serpin E1 (SERPINE1) increased. In conclusion, acute and especially long‐term exercise promotes enhanced expression of several ECM components and proteoglycans. SRGN is a novel exercise‐regulated proteoglycan in skeletal muscle with a potential role in exercise adaptatio

Postprandial Effects of Salmon Fishmeal and Whey on Metabolic Markers in Serum and Gene Expression in Liver Cells

Fish is considered an important part of a healthy diet, in part due to the content of long chain omega-3 fatty acids. However, both lean and fatty fish have beneficial health effects, suggesting that micronutrients and proteins may play a role. In a randomised, controlled, cross-over trial, five healthy male participants consumed 5.2 g of protein from either salmon fishmeal or whey. Blood samples were taken before and 30 and 60 min after intake. The concentration of glucose, lipids, hormones and metabolites, including 28 different amino acids and derivatives, were measured in serum or plasma. Cultured HepG2 cells were incubated with or without serum from the participants, and transcriptomic profiling was performed using RNA sequencing. The ingestion of both salmon fishmeal and whey reduced the glucose and triglyceride levels in serum. Protein intake, independent of the source, increased the concentration of 22 amino acids and derivatives in serum. Fishmeal increased the concentration of arginine, methionine, serine, glycine, cystathionine and 2-aminobutyric acid more than whey did. Incubation with postprandial serum resulted in large transcriptomic alterations in serum-fasted HepG2 cells, with the differential expression of >4500 protein coding genes. However, when comparing cells cultivated in fasting serum to postprandial serum after the ingestion of fishmeal and whey, we did not detect any differentially regulated genes, neither with respect to the protein source nor with respect to the time after the meal. The comparable nutrigenomic effects of fishmeal and whey do not change the relevance of fish by-products as an alternative food source

Intra-Individual Variations in How Insulin Sensitivity Responds to Long-Term Exercise: Predictions by Machine Learning Based on Large-Scale Serum Proteomics

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise (“non-responders”). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes

Plin2 deletion increases cholesteryl ester lipid droplet content and disturbs cholesterol balance in adrenal cortex

Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. Steroidogenic cells primarily store CEs in cytoplasmic lipid droplet (LD) organelles, as contrasted to the majority of mammalian cell types that predominantly store triacylglycerol (TAG) in LDs. The LD-binding Plin2 binds to both CE- and TAG-rich LDs, and although Plin2 is known to regulate degradation of TAG-rich LDs, its role for regulation of CE-rich LDs is unclear. To investigate the role of Plin2 in the regulation of CE-rich LDs, we performed histological and molecular characterization of adrenal glands from Plin2+/+ and Plin2−/− mice. Adrenal glands of Plin2−/− mice had significantly enlarged organ size, increased size and numbers of CE-rich LDs in cortical cells, elevated cellular unesterified cholesterol levels, and increased expression of macrophage markers and genes facilitating reverse cholesterol transport. Despite altered LD storage, mobilization of adrenal LDs and secretion of corticosterone induced by adrenocorticotropic hormone stimulation or starvation were similar in Plin2+/+ and Plin2−/− mice. Plin2−/− adrenals accumulated ceroid-like structures rich in multilamellar bodies in the adrenal cortex-medulla boundary, which increased with age, particularly in females. Finally, Plin2−/− mice displayed unexpectedly high levels of phosphatidylglycerols, which directly paralleled the accumulation of these ceroid-like structures. Our findings demonstrate an important role of Plin2 for regulation of CE-rich LDs and cellular cholesterol balance in the adrenal cortex

Plin2 deletion increases cholesteryl ester lipid droplet content and disturbs cholesterol balance in adrenal cortex

Cholesteryl esters (CEs) are the water-insoluble transport and storage form of cholesterol. Steroidogenic cells primarily store CEs in cytoplasmic lipid droplet (LD) organelles, as contrasted to the majority of mammalian cell types that predominantly store triacylglycerol (TAG) in LDs. The LD-binding Plin2 binds to both CE- and TAG-rich LDs, and although Plin2 is known to regulate degradation of TAG-rich LDs, its role for regulation of CE-rich LDs is unclear. To investigate the role of Plin2 in the regulation of CE-rich LDs, we performed histological and molecular characterization of adrenal glands from Plin2+/+ and Plin2−/− mice. Adrenal glands of Plin2−/− mice had significantly enlarged organ size, increased size and numbers of CE-rich LDs in cortical cells, elevated cellular unesterified cholesterol levels, and increased expression of macrophage markers and genes facilitating reverse cholesterol transport. Despite altered LD storage, mobilization of adrenal LDs and secretion of corticosterone induced by adrenocorticotropic hormone stimulation or starvation were similar in Plin2+/+ and Plin2−/− mice. Plin2−/− adrenals accumulated ceroid-like structures rich in multilamellar bodies in the adrenal cortex-medulla boundary, which increased with age, particularly in females. Finally, Plin2−/− mice displayed unexpectedly high levels of phosphatidylglycerols, which directly paralleled the accumulation of these ceroid-like structures. Our findings demonstrate an important role of Plin2 for regulation of CE-rich LDs and cellular cholesterol balance in the adrenal cortex