Combined diet and exercise training decreases serum lipids associated with insulin resistance.

Objective: Circulating lipids are linked with insulin resistance and increased cardiovascular disease risk. We previously reported that dihydroceramides, a specific type of sphingolipid, are elevated in insulin-resistant individuals; however, little is known regarding whether insulin-sensitizing lifestyle interventions can improve profiles of sphingolipids and other lipid species.

Methods: A total of 21 individuals with obesity participated in a 3-month lifestyle intervention of combined weight loss and exercise training.

SHIP1 modulation and proteome characterization of microglia.

Understanding microglial states in the aging brain has become crucial, especially with the discovery of numerous Alzheimer's disease (AD) risk and protective variants in genes such as INPP5D and TREM2, which are essential to microglia function in AD. Here we present a thorough examination of microglia-like cells and primary mouse microglia at the proteome and transcriptome levels to illuminate the roles these genes and the proteins they encode play in various cell states. First, we compared the proteome profiles of wildtype and INPP5D (SHIP1) knockout primary microglia.

Associations of plasma sphingolipids with measures of insulin sensitivity, β-cell function, and incident diabetes in Japanese Americans.

Background And Aims: To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, β-cell function, and incident diabetes in the Japanese American Community Diabetes Study.

Methods And Results: Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species.

Serum dihydroceramides correlate with insulin sensitivity in humans and decrease insulin sensitivity in vitro.

Serum ceramides, especially C16:0 and C18:0 species, are linked to CVD risk and insulin resistance, but details of this association are not well understood. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity and to determine if dihydroceramides cause insulin resistance in vitro. As expected, we found that serum triglycerides were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals.

A case report of primary pulmonary artery intimal sarcoma.

Primary pulmonary artery sarcoma is a rare tumor that mimics pulmonary embolism. Patients may present with cough, dyspnea, chest pain, and weight loss. The diagnosis is challenging.

Association of plasma ceramides with prevalent and incident type 2 diabetes mellitus in middle and older aged adults.

Aims: The role of ceramides in the pathogenesis of type 2 diabetes mellitus (T2DM) is incompletely characterized. Given that ceramides represent therapeutic targets to disrupt the euglycemia-T2DM transition, we aimed to characterize their association with prevalent and incident T2DM in a novel cohort.

Methods: We examined the cross-sectional and longitudinal association of baseline ceramides with prevalent and incident T2DM among 1423 adults (47% women; median (range) baseline age 72 (51-95) years) in the Mayo Clinic Study of Aging cohort.

Sex Differences in Insulin Sensitivity are Related to Muscle Tissue Acylcarnitine But Not Subcellular Lipid Distribution.

Objective: Sex differences in insulin sensitivity are present throughout the life-span, with men having a higher prevalence of insulin resistance and diabetes compared with women. Differences in lean mass, fat mass, and fat distribution-particularly ectopic fat-have all been postulated to contribute to the sexual dimorphism in diabetes risk. Emerging data suggest ectopic lipid composition and subcellular localization are most relevant; however, it is not known whether they explain sex differences in obesity-induced insulin resistance.

Associations Between Plasma Ceramides and Cerebral Microbleeds or Lacunes.

Objective: High plasma ceramide levels and ratios are associated with poor outcomes in individuals with cardiovascular disease; less is known about their relation to cerebral small vessel disease. We examined whether high plasma ceramide levels or ratios were associated with cerebral microbleeds (CMBs) and lacunes and whether associations differ by sex. Approach and Results: We included 548 participants enrolled in the MCSA (Mayo Clinic Study of Aging) with concurrent plasma ceramide assays and magnetic resonance imaging.

Associations between cerebrospinal fluid total phosphatidylcholines, neurodegeneration, cognitive decline, and risk of mild cognitive impairment in the Mayo Clinic Study of Aging.

It is unclear whether cerebrospinal fluid (CSF) phosphatidylcholines (PCs) are associated with neuroimaging measures of amyloid deposition and neurodegeneration (glucose metabolism, cortical thickness, and hippocampal volume), cognitive decline, or risk of mild cognitive impairment (MCI) among cognitively unimpaired older adults. This study investigated the associations of 19 individual CSF PC concentrations and their total sum with cross-sectional and longitudinal measures of amyloid deposition and neurodegeneration, global and domain-specific cognitive z-scores, and risk of MCI among 655 cognitively unimpaired participants, mean age of 71 years, enrolled in the Mayo Clinic Study of Aging. Neither the CSF total PC concentration nor individual CSF PCs were cross-sectionally or longitudinally associated with neuroimaging measures, cognition, or risk of MCI.

Nucleotides released from palmitate-activated murine macrophages attract neutrophils.

Obesity and elevation of circulating free fatty acids are associated with an accumulation and proinflammatory polarization of macrophages within metabolically active tissues, such as adipose tissue, muscle, liver, and pancreas. Beyond macrophages, neutrophils also accumulate in adipose and muscle tissues during high-fat diets and contribute to a state of local inflammation and insulin resistance. However, the mechanisms by which neutrophils are recruited to these tissues are largely unknown.

Elevated Plasma Ceramides Are Associated With Higher White Matter Hyperintensity Volume-Brief Report.

Objective: Sphingolipids, including S1P (sphingosine-1-phosphate) and ceramides, have been associated with vascular tone, blood pressure regulation, cardiovascular outcomes, and mortality. However, the relationship between plasma sphingolipids and cerebrovascular disease has not been examined. We aimed to assess the cross-sectional association between plasma sphingolipids and white matter hyperintensity (WMH) volume, which is a marker of cerebrovascular disease.

Rare variant significantly alters de novo ceramide synthesis pathway.

The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease.

Longitudinal association between phosphatidylcholines, neuroimaging measures of Alzheimer's disease pathophysiology, and cognition in the Mayo Clinic Study of Aging.

Plasma phosphatidylcholines (PCs) have been examined in the context of Alzheimer's disease dementia. However, their association with longitudinal changes in amyloid deposition remains unknown. This study investigated the associations of 8 plasma PC levels (PC aa [14:0_14:0], PC aa [16:0_16:0], PC aa [16:0_18:2], PC aa [16:0_22:6], PC aa [18:0_18:0], PC aa [18:0_18:1], PC aa [18:0_20:4], PC aa [18:1_18:1]) with cross-sectional and longitudinal measures of amyloid deposition, Alzheimer's disease-associated neurodegeneration (glucose metabolism and cortical thickness), and cognition (global- and domain-specific) of 1440 cognitively unimpaired participants (47% female, aged 50.

2-Hydroxy-oleic acid does not activate sphingomyelin synthase activity.

2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis. Previous studies have suggested that 2OHOA's anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. To confirm this phenomenon, in this study, we treated both A549 and U118 cells with 2OHOA and measured SMS activity.

Direct analysis of PI(3,4,5)P using liquid chromatography electrospray ionization tandem mass spectrometry.

Phosphatidylinositol (3,4,5) trisphosphate (PIP) is a biologically active membrane phospholipid that is essential for the growth and survival of all eukaryotic cells. We describe a new method that directly measures PIP and describe the HPLC separation and measurement of the positional isomers of phosphatidylinositol bisphosphate, PI(3,5)P, PI(3,4)P and PI(4,5)P. Mass spectrometric analyses were performed online using ultra-high performance liquid chromatography (UHPLC)-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative multiple-reaction monitoring (MRM) modes.

Intramuscular triglyceride synthesis: importance in muscle lipid partitioning in humans.

Intramuscular triglyceride (IMTG) concentration is elevated in insulin-resistant individuals and was once thought to promote insulin resistance. However, endurance-trained athletes have equivalent concentration of IMTG compared with individuals with type 2 diabetes, and have very low risk of diabetes, termed the "athlete's paradox." We now know that IMTG synthesis is positively related to insulin sensitivity, but the exact mechanisms for this are unclear.

Plasma Sphingolipids are Associated With Gait Parameters in the Mayo Clinic Study of Aging.

Background: Disrupted gait has been associated with an increased risk of frailty, disability, and death, but the causal molecular pathways are not well understood. Sphingolipids, including ceramides, are associated with multiple age-related diseases. Ceramides promote atrophy, necrosis, and proteolysis in cellular and animal models, and ceramide C16:0 levels are negatively correlated with muscle mass in men.

Liver serine palmitoyltransferase activity deficiency in early life impairs adherens junctions and promotes tumorigenesis.

Unlabelled: Serine palmitoyltransferase is the key enzyme in sphingolipid biosynthesis. Mice lacking serine palmitoyltransferase are embryonic lethal. We prepared liver-specific mice deficient in the serine palmitoyltransferase long chain base subunit 2 gene using an albumin-cyclization recombination approach and found that the deficient mice have severe jaundice.

Pharmacological Characterization of a Potent Inhibitor of Autotaxin in Animal Models of Inflammatory Bowel Disease and Multiple Sclerosis.

Autotaxin is a secreted enzyme that catalyzes the conversion of lysophosphatidyl choline into the bioactive lipid mediator lysophosphatidic acid (LPA). It is the primary enzyme responsible for LPA production in plasma. It is upregulated in inflammatory conditions and inhibition of autotaxin may have anti-inflammatory activity in a variety of inflammatory diseases.

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans.

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15).

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism.

Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specificLpcat3gene knock-out mice. We producedLpcat3-Flox/villin-Cre-ER(T2)mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to deleteLpcat3specifically in the small intestine.

Muscle sphingolipids during rest and exercise: a C18:0 signature for insulin resistance in humans.

Aims/hypotheses: Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise.

Methods: We measured basal relationships and the effect of acute exercise (1.

Deficiency in lysophosphatidylcholine acyltransferase 3 reduces plasma levels of lipids by reducing lipid absorption in mice.

Background & Aims: Phosphatidylcholines (PCs) are structural and functional constituents of cell membranes. The activity of acyltransferase (lysophosphatidylcholine acyltransferase [LPCAT]) is required for addition of polyunsaturated fatty acids to the sn-2 position of PCs and is therefore required to maintain cell membrane structure and function. LPCAT3 is the most abundant isoform of LPCAT in the small intestine and liver, which are important sites of plasma lipoprotein metabolism.