dihydroceramide and Obesity

Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3-ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1-phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest.

Topics: Animals; Apoptosis; Autophagy; Cardiovascular Diseases; Ceramides; Diabetes Mellitus, Type 2; Humans; Molecular Structure; Obesity; Sphingolipids

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. Serum ceramides were not significantly different within groups but, using all ceramide data relative to insulin sensitivity as a continuous variable, we observed significant inverse relationships between C18:0, C20:0, and C22:0 species and insulin sensitivity. Interestingly, we found that total serum dihydroceramides and individual species were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals, with C18:0 species showing the strongest inverse relationship to insulin sensitivity. Finally, we administered a physiological mix of dihydroceramides to primary myotubes and found decreased insulin sensitivity in vitro without changing the overall intracellular sphingolipid content, suggesting a direct effect on insulin resistance. These data extend what is known regarding serum sphingolipids and insulin resistance and show the importance of serum dihydroceramides to predict and promote insulin resistance in humans.

Topics: Ceramides; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Obesity; Sphingolipids; Triglycerides

Leuconostoc pseudomesenteroides is widely isolated from fermented foods; however, the underlying molecular mechanism behind its anti-obesity function has rarely been studied. This study aims to explore the role of alterations in gut microbes and liver metabolites mediated by Leuconostoc pseudomesenteroides (Tu) in obese mice for a period of 8 weeks through UPLC/Q-TOF-MS and 16S rRNA sequencing. Our results showed that Tu administration at a dosage of 1 × 10

Topics: Animals; Anti-Obesity Agents; Ceramides; Diet, High-Fat; Dysbiosis; Fermented Foods; Firmicutes; Gastrointestinal Microbiome; Leuconostoc; Liver; Mice; Mice, Obese; Obesity; Proteobacteria; RNA, Ribosomal, 16S

Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue, White; Adult; Animals; Cell Cycle; Cell Death; Ceramides; Fatty Acid Desaturases; Female; Humans; Insulin; Lipolysis; Male; Mice; Middle Aged; Obesity; Oxidative Stress; Signal Transduction

Waist circumference (WC), the clinical marker of central obesity, is gaining popularity as a screening tool for type 2 diabetes (T2D). While there is epidemiologic evidence favoring the WC-T2D association, its biological substantiation is generally weak. Our objective was to determine the independent association of plasma lipid repertoire with WC.. Samples and data from the San Antonio Family Heart Study of 1208 Mexican Americans from 42 extended families were used. Association of plasma lipidomic profiles with the cross-sectionally assessed WC was determined. Plasma lipidomic profiling entailed liquid chromatography with mass spectrometry. Statistical analyses included multivariable polygenic regression models and bivariate trait analyses using the SOLAR software.. After adjusting for age and sex interactions, body mass index, homeostasis model of assessment-insulin resistance, total cholesterol, triglycerides, high density lipoproteins and use of lipid lowering drugs, dihydroceramides as a class were associated with WC. Dihydroceramide species 18:0, 20:0, 22:0, and 24:1 were significantly associated and genetically correlated with WC. Two sphingomyelin species (31:1 and 41:1) were also associated with WC.. Plasma dihydroceramide levels independently associate with WC. Thus, high resolution plasma lipidomic studies can provide further credence to the biological underpinnings of the association of WC with T2D.

Topics: Adult; Blood Glucose; Cardiovascular Diseases; Ceramides; Cholesterol; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Male; Mexican Americans; Middle Aged; Multivariate Analysis; Obesity; Prevalence; Surveys and Questionnaires; Texas; Triglycerides; Waist Circumference; Young Adult