Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and a severe threat to pregnant people and offspring health. The molecular origins of GDM, and in particular the placental responses, are not fully known. The present study aimed to perform a comprehensive characterisation of the lipid species in placentas from pregnancies complicated with GDM using high-resolution MS lipidomics, with a particular focus on sphingolipids and acylcarnitines in a semi-targeted approach. The results indicated that despite no major disruption in lipid metabolism, placentas from GDM pregnancies showed significant alterations in sphingolipids, mostly lower abundance of total ceramides. Additionally, very long-chain ceramides and sphingomyelins with twenty-four carbons were lower, and glucosylceramides with sixteen carbons were higher in placentas from GDM pregnancies. Semi-targeted lipidomics revealed the strong impact of GDM on the placental acylcarnitine profile, particularly lower contents of medium and long-chain fatty-acyl carnitine species. The lower contents of sphingolipids may affect the secretory function of the placenta, and lower contents of long-chain fatty acylcarnitines is suggestive of mitochondrial dysfunction. These alterations in placental lipid metabolism may have consequences for fetal growth and development.

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, insulin resistance (IR) and dyslipidaemia. Consumption of a high-fat diet (HFD) enriched in SFA leads to the accumulation of ceramide (Cer), the central molecule in sphingolipid metabolism. Elevations in plasma and tissue Cer are found in obese individuals, and there is evidence to suggest that Cer lipotoxicity contributes to the MetS. EPA and DHA have shown to improve MetS parameters including IR, inflammation and hypertriacylglycerolaemia; however, whether these improvements are related to Cer is currently unknown. This review examines the potential of EPA and DHA to improve Cer lipotoxicity and MetS parameters including IR, inflammation and dyslipidaemia in vitro and in vivo. Current evidence from cell culture and animal studies indicates that EPA and DHA attenuate palmitate- or HFD-induced Cer lipotoxicity and IR, whereas evidence in humans is greatly lacking. Overall, there is intriguing potential for EPA and DHA to improve Cer lipotoxicity and related MetS parameters, but more research is warranted.

Coordinated changes in energy metabolism develop to support gestation and lactation in the periparturient dairy cow. Maternal physiology involves the partitioning of nutrients (i.e. glucose, amino acids and fatty acids (FA)) for fetal growth and milk synthesis. However, the inability of the dairy cow to successfully adapt to a productive lactation may trigger metabolic stress characterized by uncontrolled adipose tissue lipolysis and reduced insulin sensitivity. A consequence is lipotoxicity and hepatic triglyceride deposition that favors the development of fatty liver disease (FLD) and ketosis. This review describes contemporary perspectives pertaining to FA surfeit and complex lipid metabolism in the transition dairy cow. The role of saturated and unsaturated FA as bioactive signaling molecules capable of modulating insulin secretion and sensitivity is explored. Moreover, the metabolic fate of FA as influenced by mitochondrial function is considered. This includes the influence of inadequate mitochondrial oxidation on acylcarnitine status and the use of FA for lipid mediator synthesis. Lipid mediators, including the sphingolipid ceramide and diacylglycerol, are evaluated considering their established ability to inhibit insulin signaling and glucose transport in non-ruminant diabetics. The mechanisms of FLD in the transition cow are revisited with attention centered on glycerophospholipid phosphatidylcholine and triglyceride secretion. The relationship between oxidative stress and oxylipids within the context of insulin antagonism, hepatic steatosis and inflammation is also reviewed. Lastly, peripartal hormonal involvement or lack thereof of adipokines (i.e. leptin, adiponectin) and hepatokines (i.e. fibroblast growth factor-21) is described. Similarities and differences in ruminant and non-ruminant physiology are routinely showcased. Unraveling the lipidome of the dairy cow has generated breakthroughs in our understanding of periparturient lipid biology. Therapeutic approaches that target FA and complex lipid metabolism holds promise to enhance cow health, well-being and productive lifespan.

Dogs suffer from skin associated issues with a disproportionate frequency, with consequent interest in providing nutrition to optimize their skin's natural defences. Linoleic acid (LA) is known as an essential nutrient in dogs and plays a critical part in the lipid component of skin barrier formation. Minimum requirements have been defined, primarily based on eliminating signs of deficiencies such as dry, flaky skin and inflammation. Zn has been shown as an important nutrient for maintaining epidermal health. This pilot study investigated whether there are skin barrier benefits from feeding both linoleic acid and Zn at levels significantly in excess of published minimum requirements. Eight Labrador retrievers were fed a diet containing 3.8 g/Mcal LA, 21 mg/Mcal Zn for 12 weeks to establish baseline conditions for all dogs (basal diet). After this period, for a further 12 weeks, the dogs were switched onto a diet containing 7.9 g/Mcal LA and 50 mg/Mcal Zn (test diet). Transepidermal water loss (TEWL measurements) were used as a measure of skin quality and integrity and were taken at the end of the initial feeding period, and at 6 and 12 weeks of the test feeding period. TEWL was reduced by 8.11 g/m2/h (P < 0.001) six weeks after instigation of the test diet, and by 7.52 g/m2/h (P < 0.005) at 12 weeks, compared to the levels (14.73 g/m2/h) at the end of the basal feeding trial period. The results showed evidence of improved barrier properties as TEWL when feeding higher levels of LA and Zn for six and 12 weeks.

Vitamin A is an essential micronutrient for life and the phytochemical β-carotene, also known as pro-vitamin A, is an important dietary source of this vitamin. Vitamin A (retinol) is the parent compound of all bioactive retinoids but it is retinoic acid (RA) that is the active metabolite of vitamin A. The plasma concentration of retinol is maintained in a narrow range and its normal biological activities strictly regulated since excessive intake can lead to toxicity and thus also be detrimental to life. The present review will give an overview of how vitamin A homeostasis is maintained and move on to focus on the link between circulating vitamin A and metabolic disease states. Finally, we will examine how pharmacological or genetic alterations in vitamin A homeostasis and RA-signalling can influence body fat and blood glucose levels including a novel link to the liver secreted hormone fibroblast growth factor 21, an important metabolic regulator.

Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the de novo synthesis or the degradation pathways has been shown to have detrimental effects. The earlier identification of selective inhibitors of fungal SL biosynthesis promised potent broad-spectrum anti-fungal agents, which later encouraged testing some of those agents against protozoan parasites. In this review we focus on the key enzymes of the SL de novo biosynthetic pathway in protozoan parasites of the Apicomplexa and Kinetoplastidae, outlining the divergence and interconnection between host and pathogen metabolism. The druggability of the SL biosynthesis is considered, alongside recent technology advances that will enable the dissection and analyses of this pathway in the parasitic protozoa. The future impact of these advances for the development of new therapeutics for both globally threatening and neglected infectious diseases is potentially profound.

The follicle destiny towards ovulation or atresia is multi-factorial in nature and involves outcries, paracrine and endocrine factors that promote cell proliferation and survival (development) or unchain apoptosis as part of the atresia process. In several types of cells, sphingosine-1-phospate (S1P) promotes cellular proliferation and survival, whereas ceramide (CER) triggers cell death, and the S1P/CER ratio may determine the fate of the cell. The aim of present study was to quantify S1P and CER concentrations and their ratio in bovine antral follicles of 8 to 17 mm classified as healthy and atretic antral follicles. Follicles were dissected from cow ovaries collected from a local abattoir. The theca cell layer, the granulosa cells and follicular fluid were separated, and 17β-estradiol (E2) and progesterone (P4) concentrations were measured in the follicular fluid by radioimmunoassay. Based on the E2/P4 ratio, the follicles were classified as healthy (2.2±0.3) or atretic (0.2±0.3). In both follicular compartments (granulosa and theca cell layer), sphingolipids were extracted and S1P and CER concentrations were quantified by HPLC (XTerra RP18; 5 µm, 3.0×150 mm column). Results showed that in both follicular compartments, S1P concentrations were higher in healthy antral follicles than in atretic antral follicles (P<0.05). The concentration of CER in the granulosa cells was higher in atretic antral follicles than in healthy antral follicles, but no differences were observed in the theca cell layer. The S1P/CER ratio in both follicular compartments was also higher in healthy antral follicles. Interestingly, in these follicles, there was a 45-fold greater concentration of S1P than CER in the granulosa cells (P<0.05), whereas in the theca cell layer, S1P had only a 14-fold greater concentration than CER when compared with atretic antral follicles. These results suggest that S1P plays a role in follicle health, increasing cellular proliferation and survival. In contrast, reduction of S1P and the S1P/CER in the antral follicle could trigger cellular death and atresia.

In the present study, the effect of long-term fructose feeding on skeletal muscle mitochondrial energetics was investigated. Measurements in isolated tissue were coupled with the determination of whole-body energy expenditure and insulin sensitivity. A significant increase in plasma NEFA, as well as in skeletal muscle TAG and ceramide, was found in fructose-fed rats compared with the controls, together with a significantly higher plasma insulin response to a glucose load, while no significant variation in plasma glucose levels was found. Significantly lower RMR values were found in fructose-fed rats starting from week 4 of the dietary treatment. Skeletal muscle mitochondrial mass and degree of coupling were found to be significantly higher in fructose-fed rats compared with the controls. Significantly higher lipid peroxidation was found in fructose-fed rats, together with a significant decrease in superoxide dismutase activity. Phosphorylated Akt levels normalised to plasma insulin levels were significantly lower in fructose-fed rats compared with the controls. In conclusion, a fructose-rich diet has a deep impact on a metabolically relevant tissue such as skeletal muscle. In this tissue, the consequences of high fructose feeding are altered glucose tolerance, elevated mitochondrial biogenesis and increased mitochondrial coupling. This latter modification could have a detrimental metabolic effect by causing oxidative stress and energy sparing that contribute to the high metabolic efficiency of fructose-fed rats.

The properties of 4 fluorescent lipid compounds in the surface membrane of adult male Schistosoma mansoni worms were examined by fluorescent microscopy and fluorescent recovery after photobleaching (FRAP). The data suggest that the probes N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl) sphingosine (BODIPY FL ceramide) and PKH2 pass through the outer membrane and enter structures in or below the membrane. In contrast 5-(N-octadecanoyl)aminofluorescein (AF18) and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl) sphingosylphosphocholine (BODIPY FL sphingomyelin) insert into the outer monolayer. The DL values of these latter 2 compounds, 8·83 ± 2·35 × 10−9 cm2 s−1 and 2·76 ± 0·53 × 10−9cm2 s−1, respectively, suggest that they enter different domains. Furthermore, it was observed that both BODIPY FL ceramide and BODIPY FL sphingomyelin entered particular structures in or under the surface membrane. The possible nature of these particles is discussed.

Cancer develops from overlapping events that tend to deregulate the metabolism and unbalance the homeostasis of cells. Sphingolipids, major components of biological membranes, are also mediators of intracellular signalling. Their metabolism can be influenced by diverse stimuli and the accumulation or deficiency of intermediates may trigger proliferation and/or impair the ability of damaged cells to undergo apoptosis. Many sphingolipid-regulated functions are implicated in tumour initiation, promotion, progression and responsiveness to chemotherapy. In this review, evidence of the alteration of sphingolipids metabolism and signalling will be discussed in breast cancer prevention and therapy.

Various lipidic molecules serve as second messengers for transducing signals from the cell surface to the cell interior and trigger specific cellular responses. Sphingolipids represent a complex group of lipids that have recently emerged as new transducers in eukaryotic cells. Several sphingolipid molecules are able to modulate cell growth, differentiation and death. This review summarises current knowledge of the signalling functions of sphingolipids, especially in the regulation of tumour necrosis factor α (TNF-α)-mediated cytotoxic effects. TNF-α is a multifaceted cytokine that controls a wide range of immune responses in mammals, including induction of programmed cell death (also called apoptosis). On the basis of recent observations, a working model is proposed for the molecular mechanisms underlying regulation of sphingolipid generation following TNF-α receptor 1 activation. The implications of these findings for the development of future pharmacological strategies to prevent the cytotoxic TNF-α response and subsequent cellular dysfunctions (as seen in various human diseases) are discussed.