CD36 Inhibitors Reduce Postprandial Hypertriglyceridemia and Protect against Diabetic Dyslipidemia and Atherosclerosis

CD36 is recognized as a lipid and fatty acid receptor and plays an important role in the metabolic syndrome and associated cardiac events. The pleiotropic activity and the multiple molecular associations of this scavenger receptor with membrane associated molecules in different cells and tissues have however questioned its potential as a therapeutic target. The present study shows that it is possible to identify low molecular weight chemicals that can block the CD36 binding and uptake functions. These inhibitors were able to reduce arterial lipid deposition, fatty acid intestinal transit, plasma concentration of triglycerides and glucose, to improve insulin sensitivity, glucose tolerance and to reduce the plasma concentration of HbAc1 in different and independent rodent models. Correlation between the anti-CD36 activity of these inhibitors and the known pathophysiological activity of this scavenger receptor in the development of atherosclerosis and diabetes were observed at pharmacological doses. Thus, CD36 might represent an attractive therapeutic target

Necdin Controls Proliferation of White Adipocyte Progenitor Cells

White adipose tissues are composed mainly of white fat cells (adipocytes), which play a key role in energy storage and metabolism. White adipocytes are terminally differentiated postmitotic cells and arise from their progenitor cells (preadipocytes) or mesenchymal stem cells residing in white adipose tissues. Thus, white adipocyte number is most likely controlled by the rate of preadipocyte proliferation, which may contribute to the etiology of obesity. However, little is known about the molecular mechanisms that regulate preadipocyte proliferation during adipose tissue development. Necdin, which is expressed predominantly in postmitotic neurons, is a pleiotropic protein that possesses anti-mitotic and pro-survival activities. Here we show that necdin functions as an intrinsic regulator of white preadipocyte proliferation in developing adipose tissues. Necdin is expressed in early preadipocytes or mesenchymal stem cells residing in the stromal compartment of white adipose tissues in juvenile mice. Lentivirus-mediated knockdown of endogenous necdin expression in vivo in adipose tissues markedly increases fat mass in juvenile mice fed a high-fat diet until adulthood. Furthermore, necdin-null mutant mice exhibit a greater expansion of adipose tissues due to adipocyte hyperplasia than wild-type mice when fed the high-fat diet during the juvenile and adult periods. Adipose stromal-vascular cells prepared from necdin-null mice differentiate in vitro into a significantly larger number of adipocytes in response to adipogenic inducers than those from wild-type mice. These results suggest that necdin prevents excessive preadipocyte proliferation induced by adipogenic stimulation to control white adipocyte number during adipose tissue development

The dispersion state of milk fat influences triglyceride metablism in the rat A13CO2 breath test study

Background Milk fat, which has different structures in the various dairy products, is a major and controversial lipid source in the Western diet. However, information about the digestion fate of milk fat depending on its supramolecular structure for a given composition is scarce. Aim of the study In this study, 13CO2 breath tests were performed with fasted rats force–fed different dairy preparations of similar composition but differing in fat suprastructure in order to highlight differences of general lipid metabolism. Methods Each preparation consisted of a NaCl solution, anhydrous milk fat labelled with a 13C mixed triacylglycerol, casein (as native phosphocaseinate powder with some lactose), and dipalmitoylphosphatidylcholine. Milk fat was either fed (i) unemulsified consecutively to the aqueous phase, or emulsified as (ii) coarse droplets of ∼10 µm covered mainly with the phospholipid, or (iii–iv) fine droplets of ∼1 µm covered mainly with casein, force–fed either in the liquid state or in a semi–crystallized state. 13C abundance in expired air samples was measured by isotope ratio mass spectrometry; results were expressed as 13C enrichment and were submitted to an ANOVA analysis. Results The 13CO2 excretion curves of the unemulsified preparation and the coarse emulsion were similar and presented a sharp peak, both significantly different from the fine emulsion curves characterized by a nearly linear cumulative recovery. The crystalline state of the fine emulsion droplets and the viscosity of these emulsions did not affect significantly their excretion curves. The lipid metabolization (indicated by the 13C recovery) was significantly slower for the fine droplets coated with casein than for the large droplets coated with the phospholipid and the unemulsified fat. For the latter, a single 13C peak rapidly appeared, while for small droplets coated with caseins, 13C excretion was continuous up to 6 h. Conclusions Global lipid metabolism based on oxidation to CO2 was decreased with smaller compared to larger emulsified milk fat particles with different coatings. These data support the concept that dairy products with different fat suprastructures are digested and metabolized differently

Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun-Dexmedetomidine, Clonidine? A Minireview

Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a "central" compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock. Counterintuitively, α 2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show that α 2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

Obesity is linked to adipose tissue hypertrophy (increased adipocyte cell size) and hyperplasia (increased cell number). Comparative analyses of gene datasets allowed us to identify 1426 genes which may represent common adipose phenotype in humans and mice. Among them we identified several adipocyte-specific genes dysregulated in obese adipose tissue, involved in either fatty acid storage (acyl CoA synthase ACSL1, hormone-sensitive lipase LIPE, aquaporin 7 AQP7, perilipin PLIN) or cell adhesion (fibronectin FN1, collagens COL1A1, COL1A3, metalloprotein MMP9, or both (scavenger receptor FAT/CD36). Using real-time analysis of cell surface occupancy on xCELLigence system we developed a new method to study lipid uptake and differentiation of mouse 3T3L1 fibroblasts and human adipose stem cells. Both processes are regulated by insulin and fatty acids such as oleic acid. We showed that fatty acid addition to culture media increased the differentiation rate and was required for full differentiation into unilocular adipocytes. Significant activation of lipogenesis, i.e. lipid accumulation, by either insulin or oleic acid was monitored in times ranging from 1 to 24 h, depending on differentiation state, whereas significant effects on adipogenesis, i.e., surperimposed lipid accumulation and gene transcriptional regulations were measured after 3 to 4 d. Combination of selected times for analysis of lipid contents, cell counts, size fractionations, and gene transcriptional regulations showed that FAT/CD36 specific inhibitor AP5258 significantly increased cell survival of oleic acid-treated mouse and human adipocytes, and partially restored the transcriptional response to oleic acid in the presence of insulin through JNK pathway. Taken together, these data open new perspectives to study the molecular mechanisms commonly dysregulated in mouse and human obesity at the level of lipogenesis linked to hypertrophy and adipogenesis linked to hyperplasia

Impact of chemical ageing on the toxicity of biogenic and anthropogenic organic aerosols using model cells

SSCI-VIDE+CARE+STO:DLI:SPR:MRV:CGOInternational audienceA large subset of PM2.5 is identified as organic matter (OM) and ranges from 20 to 60 % of the fine aerosol mass. The OM originates from both primary (directly emitted) and secondary sources (formed from gas-to-particle conversion). This last fraction, also called secondary organic aerosol (SOA) represents the main component of OM as it could account for 20 to 80 % of its mass. While representing subset of atmospheric particle load, very little is known about the health effect of SOA. The aim of this work was to study the impact of aerosol ageing on cell viability. Both, biogenic (from limonene) and anthropogenic (from naphthalene) SOA were generated with different oxidation ageing (related to different atmospheric residence time) using a potential aerosol mass (PAM) chamber, to simulate different aerosol age. SOA were collected, extracted and model cells (mouse fibroplast cells, 3T3-L1) were exposed to the extracts. Cell proliferation was measured over time in order to evaluate their viability. The results shown that both aged and fresh SOA inhibit cell proliferation (after media washout) and this inhibition was increased as a function of SOA ageing. These results were associated with chemical characterization, using high-resolution mass spectrometry in order to link chemical composition and cell mortality. This work shows that SOA can influence cell viability and that ageing is an important factor to take into consideration when evaluating the effect of aerosol on health. This work will be applied to a more realistic and complex biological system (e.g., lung cells)