Leptin, from fat to inflammation: old questions and new insights

Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.     

Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance

Lecithin-cholesterol acyltransferase deficiency is frequently associated with hypertriglyceridemia (HTG) in animal models and humans. We investigated the mechanism of HTG in the ldlr-/- x lcat-/- (double knockout (dko)) mice using the ldlr-/- x lcat+/+ (knock-out (ko)) littermates as control. Mean fasting triglyceride (TG) levels in the dko mice were elevated 1.75-fold compared with their controls (p < 0.002). Both the very low density lipoprotein and the low density lipoprotein/intermediate density lipoprotein fractions separated by fast protein liquid chromatography were TG-enriched in the dko mice. In vitro lipolysis assay revealed that the dko mouse very low density lipoprotein (d < 1.019 g/ml) fraction separated by ultracentrifugation was a more efficient substrate for lipolysis by exogenous bovine lipoprotein lipase. Post-heparin lipoprotein lipase activity was reduced by 61% in the dko mice. Hepatic TG production rate, determined after intravenous Triton WR1339 injection, was increased 8-fold in the dko mice. Hepatic mRNA levels of sterol regulatory element binding protein-1 (srebp-1) and its target genes acetyl-CoA carboxylase-1 (acc-1), fatty acid synthase (fas), and stearoyl-CoA desaturase-1 (scd-1) were significantly elevated in the dko mice compared with the ko control. The hepatic mRNA levels of LXRalpha (lxralpha) and its target genes including angiopoietin-like protein 3 (angptl-3) in the dko mice were unchanged. Fasting glucose and insulin levels were reduced by 31 and 42%, respectively in the dko mice, in conjunction with a 49% reduction in hepatic pepck-1 mRNA (p = 0.014). Both the HTG and the improved fasting glucose phenotype seen in the dko mice are at least in part attributable to an up-regulation of the hepatic srebp-1c gene.     

Microscopic and macroscopic study of the interaction betweenAlternaria alternata (Fr.) Keissler andNigrospora oryzae (Berk. & Broome) Petch.

Light Microscopy and Cryo-Scanning Electron Microscopy techniques were used to analyse the interaction betweenAlternaria alternata andNigrospora oryzae at different temperatures (15 and 25°C) and water activities (0.85, 0.90, 0.95, 0.98 and 0.995). Each interaction was given a numerical value to obtain the Index of Dominance (I) based on the variations observed in fungus growth when the environmental conditions changed. For a better understanding of the process, each species was studied individually anysing the effects of abiotic and biotic factors on their growth. In the tests performed, none of the two fungus species analysed was dominant over the other since both species presented mutual intermingling both in Rice Extract agar and in rice grains and no interaction between hyphae and the reproductive structures was observed.Alternaria alternata andN. oryzae presented their highest growth both individually and dually at 0.995 water activity and 25°CAlternaria alternata sporulated at all temperatures and water activity values, except at 0.85, whereasN. oryzae sporulated only at 0.98 and 0.995 at 25°C, presenting no changes as the strains interacted. Finally, temperature and water activity significantly affected fungal growth.     

Hog1 mitogen-activated protein kinase plays conserved and distinct roles in the osmotolerant yeast Torulaspora delbrueckii

Torulaspora delbrueckii has emerged during evolution as one of the most osmotolerant yeasts. However, the molecular mechanisms underlying this unusual stress resistance are poorly understood. In this study, we have characterized the functional role of the high-osmolarity glycerol (HOG) mitogen-activated protein kinase pathway in mediating the osmotic stress response, among others, in T. delbrueckii. We show that the T. delbrueckii Hog1p homologue TdHog1p is phosphorylated after cell transfer to NaCl- or sorbitol-containing medium. However, TdHog1p plays a minor role in tolerance to conditions of moderate osmotic stress, a trait related mainly with the osmotic balance. In consonance with this, the absence of TdHog1p produced only a weak defect in the timing of the osmostress-induced glycerol and GPD1 mRNA overaccumulation. Tdhog1Delta mutants also failed to display aberrant morphology changes in response to osmotic stress. Furthermore, our data indicate that the T. delbrueckii HOG pathway has evolved to respond to specific environmental conditions and to play a pivotal role in the stress cross-protection mechanism.     

Production of aborted pollen in marsh species of Chenopodiaceae: evidence of partial male sterility in Suadeaea and Salsoleae species

The main objective of this study is to establish the level of pollen abortion prior to its release from the anther in species of Chenopodiaceae in marsh habitats and to compare this level among the taxons, locations and positions of the flowers in the dichasium and the relative positions of the anthers. We established the level of nonfunctional pollen formation in 39 samples belonging to 10 species, using lactophenol cotton blue staining. Aborted pollen grains were found to be significantly smaller than normal ones. The results revealed differences in the percentage of normal grains among different species and tribes studied: Atripliceae (56.1 ± 27.1%), Salicornieae (80.36 ± 16.52%), Suaedeae (54.7 ± 31.2%) and Salsoleae (32.5 ± 25.7%). In some species there were significant differences among the populations studied, but in species of Saliconieae we found no differences either between different positions in the dicasia or in the anther. In the tribes Suaedeae and Salsoleae, we postulate the existence of a system that maintains different levels of partial male sterility among individuals in the populations, which would reduce the autogamous fruit set rate and favor the cross-pollination rates of sterile male individuals. We base this on high intrapopulation variability at those levels, on the constancy with which they are presented in the different populations studied, and on the lack of interannual differences.     

Why change habits? Early modern medical innovation between medicalisation and medical culture

Based on a discussion of the concept of medicalisation and medical culture in Anglo-American, French-, and German-speaking historiography the paper argues that medical innovation in Europe from the sixteenth to the mid-nineteenth century should be approached in a different way. Instead of asking from the perspective of a too narrow concept of medicalisation why medical innovations were rejected by the population, (medical) historians should analyse medical culture and ask why people should have changed their health and illness behaviour. This conceptual argument is deduced from four empirical examples: the introduction of smallpox vaccination, "medical police," the problem of medical professionalization, and the questions arising around the relations between the healthy/sick and their practitioners.     

Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men

The APOA1/C3/A4/A5 gene cluster encodes important regulators of fasting lipids, but the majority of lipid metabolism takes place in the postprandial state and knowledge about gene regulation in this state is scarce. With the aim of characterizing possible regulators of lipid metabolism, we studied the effects of nine single nucleotide polymorphisms (SNPs) during postprandial lipid metabolism. Eighty-eight healthy young men were genotyped for APOA1 -2630 (rs613808), APOA1 -2803 (rs2727784), APOA1 -3012 (rs11216158), APOC3 -640 (rs2542052), APOC3 -2886 (rs2542051), APOC3 G34G (rs4520), APOA4 N147S (rs5104), APOA4 T29T (rs5092), and A4A5_inter (rs1263177) and were fed a saturated fatty acid-rich meal (1g fat/kg of weight with 60% fat, 15% protein and 25% carbohydrate). Serial blood samples were extracted for 11 h after the meal. Total cholesterol and fractions [HDL-cholesterol, LDL-cholesterol, trifacylglycerols (TGs) in plasma, TG-rich lipoproteins (TRLs) (large TRLs and small TRLs), apolipoprotein A-I and apolipoprotein B] were determined. APOA1 -2803 homozygotes for the minor allele and A4A5_inter carriers showed a limited degree of postprandial lipemia. Carriers of the rare alleles of APOA4 N147S and APOA4 T29T had lower APOA1 plasma concentration during this state. APOC3 -640 was associated with altered TG kinetics but not its magnitude. We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism.