A single historical substitution drives an increase in acetylcholine receptor complexity.

Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from four different, but evolutionarily related, subunits. These subunits assemble with a precise stoichiometry and arrangement such that two chemically distinct agonist-binding sites are formed between specific subunit pairs. How this subunit complexity evolved and became entrenched is unclear. Here we show that a single historical amino acid substitution is able to constrain the subunit stoichiometry of functional acetylcholine receptors. Using a combination of ancestral sequence reconstruction, single-channel electrophysiology, and concatenated subunits, we reveal that an ancestral ß-subunit can not only replace the extant ß-subunit but can also supplant the neighboring δ-subunit. By forward evolving the ancestral ß-subunit with a single amino acid substitution, we restore the requirement for a δ-subunit for functional channels. These findings reveal that a single historical substitution necessitates an increase in acetylcholine receptor complexity and, more generally, that simple stepwise mutations can drive subunit entrenchment in this model heteromeric protein.

Back to the future: Rational maps for exploring acetylcholine receptor space and time.

Global functions of nicotinic acetylcholine receptors, such as subunit cooperativity and compatibility, likely emerge from a network of amino acid residues distributed across the entire pentameric complex. Identification of such networks has stymied traditional approaches to acetylcholine receptor structure and function, likely due to the cryptic interdependency of their underlying amino acid residues. An emerging evolutionary biochemistry approach, which traces the evolutionary history of acetylcholine receptor subunits, allows for rational mapping of acetylcholine receptor sequence space, and offers new hope for uncovering the amino acid origins of these enigmatic properties.

pUdOs: Concise Plasmids for Bacterial and Mammalian Cells.

The plasmids from the Université d'Ottawa (pUdOs) are 28 small plasmids each comprising one of four origins of replication and one of seven selection markers, which together afford flexible use in Escherichia coli and several related gram-negative bacteria. The promoterless multicloning site is insulated from upstream spurious promoters by strong transcription terminators and contains type IIP or IIS restriction sites for conventional or Golden Gate cloning. pUdOs can be converted into efficient expression vectors through the insertion of a promoter at the user's discretion. For example, we demonstrate the utility of pUdOs as the backbone for an improved version of a Type III Secretion System reporter in Shigella. In addition, we derive a series of pUdO-based mammalian expression vectors, affording distinct levels of expression and transfection efficiency comparable to commonly used mammalian expression plasmids. Thus, pUdOs could advantageously replace traditional plasmids in a wide variety of cell types and applications.

Derepression may masquerade as activation in ligand-gated ion channels.

Agonists are ligands that bind to receptors and activate them. In the case of ligand-gated ion channels, such as the muscle-type nicotinic acetylcholine receptor, mechanisms of agonist activation have been studied for decades. Taking advantage of a reconstructed ancestral muscle-type ß-subunit that forms spontaneously activating homopentamers, here we show that incorporation of human muscle-type α-subunits appears to repress spontaneous activity, and furthermore that the presence of agonist relieves this apparent α-subunit-dependent repression. Our results demonstrate that rather than provoking channel activation/opening, agonists may instead 'inhibit the inhibition' of intrinsic spontaneous activity. Thus, agonist activation may be the apparent manifestation of agonist-induced derepression. These results provide insight into intermediate states that precede channel opening and have implications for the interpretation of agonism in ligand-gated ion channels.

The metabolic cascade leading to eicosanoid precursors--desaturases, elongases, and phospholipases A2--is altered in Zucker fatty rats.

Metabolic syndrome characterized by insulin resistance and obesity is accompanied by severe lipid metabolism perturbations and chronic low-grade inflammation. However, many unresolved questions remained regarding the regulation that underlie dyslipidemia, particularly the regulation of the metabolic cascade (synthesis and release) leading to eicosanoid precursors release. This study was undertaken to investigate the regulation of desaturases/elongases and phospholipases A(2) during the establishment of metabolic syndrome. Our results showed that delta-6 desaturase as well as elongase-6 expressions were upregulated in 3-month-old Zucker fatty rats as compared to lean littermates, independently of SREBP-1c activation. We also demonstrated for the first time an increase of liver group VII phospholipase A(2) gene expression in the obese animals together with a strong specific inhibition of type IVA and VIA phospholipases A(2). These results suggest that the regulation of unsaturated fatty acids biosynthesis and signalling cascade could contribute to the development of liver lipid dysregulation related to metabolic syndrome and may be considered as new potential targets in such pathological conditions.

On the interaction of acetone with electrophilic metallocavitands having extended cavities.

We report the synthesis and characterization of tantalum-boronate trimetallic clusters of general formula {[Cp*Ta](3)(µ(2)-RB(O)(2))(3)(µ(2)-OH)(µ(2)-O)(2)(µ(3)-OH)} (R= 4-(C(6)H(5))(C(6)H(4)) (Ta(3)-4Ph), 4-(C(6)H(5)O)(C(6)H(4)) (Ta(3)-4OPh), 4-(C(7)H(7)O)(C(6)H(4)) (Ta(3)-4OBn), 4-(C(8)H(5))(C(6)H(4)) (Ta(3)-4PhEt), and 4-(C(12)H(7))(C(6)H(4)) (Ta(3)-4Napht)). All complexes have been characterized by NMR spectroscopy and X-ray diffraction. The trimetallic species feature a large Lewis acid type cavity allowing for substrate binding in both the solid and the liquid state using a unique electrostatic interaction and a hydrogen bond. ΔH° and ΔS° values for association of acetone with the complexes vary between -2.0 and -4.1 kcal·mol(-1) and -3 and 2 cal·mol(-1)·K(-1), respectively, showing weaker binding than smaller cavitands of the same type. The barrier for acetone exchange at equilibrium is similar for all complexes, and ΔH(‡) values vary between 8.2 and 11.4 kcal·mol(-1).

Ancestral acetylcholine receptor ß-subunit forms homopentamers that prime before opening spontaneously.

Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from two α-subunits, and one each of the ß-, δ-, and ε-subunits. To form functional channels, the subunits must assemble with one another in a precise stoichiometry and arrangement. Despite being different, the four subunits share a common ancestor that is presumed to have formed homopentamers. The extent to which the properties of the modern-day receptor result from its subunit complexity is unknown. Here, we discover that a reconstructed ancestral muscle-type ß-subunit can form homopentameric ion channels. These homopentamers open spontaneously and display single-channel hallmarks of muscle-type acetylcholine receptor activity. Our findings attest to the homopentameric origin of the muscle-type acetylcholine receptor, and demonstrate that signature features of its function are both independent of agonist and do not necessitate the complex heteropentameric architecture of the modern-day protein.

Altered adipose tissue metabolism in offspring of dietary obese rat dams.

To investigate further the mechanisms of developmental programming, we analysed the effects of maternal overnutrition and of postnatal high-fat feeding on adipose tissue metabolism in the offspring. Postnatal changes in serum adiponectin, leptin and TAG [triacylglycerol (triglyceride)] levels, adipose tissue TAGs, fatty acids and enzyme activities were determined in offspring of cafeteria-diet-fed dams during gestation and lactation, weaned on to standard chow or on to cafeteria diet. Obese rats showed higher adiposity (+35% to 85%) as well as a significant increase in serum glucose, insulin, leptin, adiponectin and TAG levels (P<0.01) and adipose tissue LPL (lipoprotein lipase) and GPDH (glycerol-3-phosphate dehydrogenase) activities (P<0.01), compared with control pups at weaning (day 21) and at adulthood (day 90). Adipose HSL (hormone-sensitive lipase) activity was increased only at day 90 (P<0.05), and FAS (fatty acid synthase) activity remained unchanged. The proportions of SFAs (saturated fatty acids) and MUFAs (mono-unsaturated fatty acids) and the Δ(9)-desaturation index were significantly increased (P<0.05), whereas PUFAs (polyunsaturated fatty acids) were decreased (P<0.01) in serum and adipose TAGs of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal overnutrition induced permanent changes in adipose tissue metabolism of the offspring. These pre-existing alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Consequently, adipose adipokines and enzymes could provide a potential therapeutic target, and new investigations in this field could constitute strategies to improve the impact of early-life overnutrition.

Limitations in the characterisation of cigarette products using different machine smoking regimes.

It is recognised that no single machine smoking regime can represent the different behaviours of individual human smokers. It has been argued that the current ISO standard regime provides machine yields that are somewhat low for certain cigarette designs compared to human intake. Various cigarette machine smoking regimes have been proposed as options for regulatory use to provide data that reflect "average" or "maximum" yields as related to human intake. Some public health representatives have proposed that the intense regime mandated for testing in Canada with 100% of the ventilation holes in the cigarette filter blocked, should be used for product characterisation and that it is not necessary that it should reflect general human smoking behaviour. We believe that this is a flawed approach because our studies and those of other workers demonstrate that the conditions generated in the cigarette when using this intense machine smoking regime are extreme in comparison to the conditions found for regimes based more realistically on human smoking. In this paper, we provide data to show that smokers modify their smoking intensity over the course of smoking in response to changes in draw resistance, smoke concentrations and smoke temperatures. We compare changes in and interactions between these parameters during puffing when smoking cigarettes of different designs. Cigarettes were smoked using various machine smoking regimes previously proposed for smoke testing as well as a regime based on human smoking data from an 'in-house' study. Puffing parameters were derived from this study to represent the 'average smoker' under laboratory conditions and equivalent to the 90th percentile when the studied smokers smoked under natural conditions. Biomarker data from human uptake studies have shown that ventilation is an effective cigarette design tool to reduce total smoke constituent uptake in humans so demonstrating that any blocking of filter ventilation is far from 100%. Likewise, this current work also shows how smokers modify their smoking behaviour in ways not well reflected by the 100% ventilation blocking regime. It seems logical that any machine smoking regime chosen for future product regulation should reflect these findings for it to have valid public health relevance. In addition, it seems misguided to discourage product design features, such as ventilation, which clearly can provide products with reduced human smoke exposure, just to maintain the dogma, counter to the scientific evidence, that there must be a regulatory regime with 100% ventilation blocking.

Time course of changes in serum oxidant/antioxidant status in overfed obese rats and their offspring.

The aim of the present study was to determine the time course of changes in oxidant/antioxidant status, as well as serum glucose, insulin, leptin and lipid levels, liver adipose tissue and muscle lipid and protein contents, in cafeteria-diet-fed dams during gestation and lactation, and in their offspring throughout adulthood. Food intake was also evaluated. The cafeteria diet induced a significant increase in maternal body and relative adipose tissue weights, daily energy intake, and plasma glucose, insulin, leptin and lipid levels at parturition (day 0) and at the end of lactation (day 21). Plasma total antioxidant status [ORAC (oxygen radical absorbance capacity)], erythrocyte catalase and SOD (superoxide dismutase) activities were lower, whereas plasma hydroperoxide and carbonyl protein levels were higher in cafeteria-diet-fed mothers compared with control mothers at days 0 and 21. Pups from cafeteria-diet-fed dams, both males and females, also had consistently higher body and relative adipose tissue weights, and plasma glucose, insulin, leptin, triacylglycerol (triglyceride) and cholesterol levels at birth (day 0), weaning (day 21) and 3 months of age (day 90). These offspring had significantly lower ORAC and catalase activity, and higher plasma hydroperoxide and carbonyl protein levels and SOD activity at birth, at days 21 and 90 compared with control offspring. In conclusion, excessive maternal fat and energy intake can play an important role in the development of metabolic disorders in the offspring. Maternal oxidative stress may be among the responsible factors. Fetal oxidative stress may present an additional confounding influence and probably contributes to additional disorders, aggravating features of the metabolic syndrome. An improvement in maternal oxidant/antioxidant status during pregnancy and lactation, with adequate nutrition, could have beneficial effects on the progeny.

cis-Bis[(1-adamantylmeth-yl)amine-κN]-dichloridoplatinum(II) N,N-dimethyl-formamide solvate.

The asymmetric unit of the title compound {systematic name: cis-dichloridobis[(3,7-dimethylbicyclo-[3.3.1]non-1-ylmeth-yl)-amine-κN]platinum(II) N,N-dimethyl-formamide solvate}, [PtCl(2)(C(11)H(19)N)(2)]·C(3)H(7)NO, consists of two metrically similar Pt complexes and two dimethyl-formamide solvent mol-ecules. Each Pt(II) center is coordinated by the amine groups of two (1-adamantylmeth-yl)amine ligands and two Cl atoms in a cis-square-planar arrangement. The Pt(II) centers lie slightly outside [0.031 (4) and 0.038 (4) Å] the coordination planes. The N-Pt-N and Cl-Pt-Cl angles [92.1 (4)-92.30 (11)°] are slightly more open than the N-Pt-Cl angles [87.3 (3)-88.3 (3)°]. N-H⋯O and N-H⋯Cl inter-molecular hydrogen bonds are observed, forming two discrete pairs of complexes and solvent mol-ecules.

Roles of survival and dispersal in reintroduction success of Griffon vulture (Gyps fulvus).

The success of reintroduction programs greatly depends on the amount of mortality and dispersal of the released individuals. Although local environmental pressures are likely to play an important role in these processes, they have rarely been investigated because of the lack of spatial replicates of reintroduction. In the present study, we analyzed a 25-year data set encompassing 272 individuals released in five reintroduction programs of Griffon Vultures (Gyps fulvus) in France to examine the respective roles of survival and dispersal in program successes and failures. We use recent developments in multi-strata capture-recapture models to take into account tag loss in survival estimates and to consider and estimate dispersal among release areas. We also examined the effects of sex, age, time, area, and release status on survival, and we tested whether dispersal patterns among release areas were consistent with habitat selection theories. Results indicated that the survival of released adults was reduced during the first year after release, with no difference between sexes. Taking into account local observations only, we found that early survival rates varied across sites. However when we distinguished dispersal from mortality, early survival rates became equal across release sites. It thus appears that among reintroduction programs difference in failure and success was due to differential dispersal among release sites. We revealed asymmetrical patterns of dispersal due to conspecific attraction: dispersers selected the closest and the largest population. We showed that mortality can be homogeneous from one program to another while, on the contrary, dispersal is highly dependent on the matrix of established populations. Dispersal behavior is thus of major interest for metapopulation restoration and should be taken into account in planning reintroduction designs.

Decidual prolactin silences the expression of genes detrimental to pregnancy.

Although the main role of prolactin (PRL) in pregnant rodents is to sustain progesterone production by the corpus luteum, progesterone treatment of PRL or PRL receptor (PRL-R) null mice is unable to prevent fetal loss. We have previously shown that the rat decidua is a site of PRL production and action. In this report, we examined the hypothesis, using PRL null mice and rat decidual cell culture, that the absence of this hormone leads to the expression in the decidua of genes detrimental to pregnancy. The results show that decidual growth is normal in PRL null mice treated with PRL, progesterone, or their combination. However, the decidua of mice treated with progesterone starts expressing IL-6 and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), two proteins absent from the decidua of wild-type mice and involved, respectively, in inflammation and progesterone catabolism. The expression of both IL-6 and 20alpha-HSD is prevented by PRL treatment. Our results further suggest that PRL inhibition of 20alpha-HSD expression is at the level of transcription and that decidual PRL (dPRL) inhibits 20alpha-HSD promoter activity. Inhibitors of Janus kinase 2 (Jak2) but not other kinases prevent dPRL down-regulation of the 20alpha-HSD promoter. Furthermore, cotransfection of the 20alpha-HSD promoter with expression vectors of constitutively active PRL-R, Jak2, or signal transducer and activator of transcription 5b (Stat5b) leads to substantial inhibition of promoter activity. Taken together, our investigation provides an explanation for the inability of progesterone to sustain pregnancy in PRL null mice and suggests that dPRL plays an important role in pregnancy by repressing the expression of IL-6 and 20alpha-HSD in the decidua. The study also demonstrates that PRL signals through the Jak2/Stat5 pathway to down-regulate 20alpha-HSD expression in the decidua.

Ancestral Reconstruction Approach to Acetylcholine Receptor Structure and Function.

Acetylcholine receptors (AChRs) are members of a superfamily of proteins called pentameric ligand-gated ion channels, which are found in almost all forms of life and thus have a rich evolutionary history. Muscle-type AChRs are heteropentameric complexes assembled from four related subunits (α, ß, δ, and ɛ). Here we reconstruct the amino acid sequence of a ß subunit ancestor shared by humans and cartilaginous fishes (i.e., Torpedo). Then, by resurrecting this ancestral ß subunit and co-expressing it with human α, δ, and ɛ subunits, we show that despite 132 substitutions, the ancestral subunit is capable of forming human/ancestral hybrid AChRs. Whole-cell currents demonstrate that the agonist acetylcholine has reduced potency for hybrid receptors, while single-channel recordings reveal that hybrid receptors display reduced conductance and open probability. Our results outline a promising strategy for studies of AChR evolution aimed at identifying the amino acid origins of AChR structure and function.

In situ hybridization of dihydroxyacetone phosphate acyltransferase, the regulating enzyme involved in plasmalogen biosynthesis.

In situ hybridization can be carried out using different methods. The experimenter has to choose various parameters: the type of tissue fixation, the time of incubation, and the duration of the exposure time. All these parameters are determinant for the sensitivity and the resolution of this technique. This publication of technical aspects described different experiments performed for in situ hybridization on liver tissue. We may conclude on the parameters to optimize each step of the hybridization procedure. Moreover, this technique could be transposed to the brain and applied to little structures with a light expression of DHAP-AT.

Implication of three isoforms of PLA(2) in human T-cell proliferation.

We observed that human (Jurkat) T-cells constitutively expressed the mRNA, encoding for the four isoforms of phospholipase A(2) (PLA(2)), i.e. two secretory (type IB and type V), and two cytosolic (type IV, Ca(2+)-dependent and type VI, Ca(2+)-independent). In order to assess whether these PLA(2) isoforms are active, we labeled Jurkat T-cells with [(3)H]arachidonic acid ([(3)H]AA) and determined its release into the extracellular medium in the presence of phorbol 12-myristate 13-acetate (PMA) and ionomycin. The three PLA(2) isoforms seem functional as aristolochic acid and bromoenol lactone (BEL), the respective inhibitors of type IB/type V and type VI PLA(2)s, significantly inhibited the release of free [(3)H]AA. On the other hand, arachidonyl trifluoromethyl ketone (AACOCF(3)), an inhibitor of type IV PLA(2), failed to curtail significantly the release of free [(3)H]AA into the extracellular medium. We assessed the implication of these PLA(2) isoforms in transcription of the interleukin-2 (IL-2) gene, involved in T-cell proliferation. Hence, aristolochic acid and BEL, but not AACOCF(3), significantly inhibited the PMA and ionomycin-induced induction of mRNA of IL-2. Similarly, aristolochic acid and BEL, but not AACOCF(3), significantly inhibited the PMA and ionomycin-induced secretion of IL-2 in the culture supernatants. Together these results suggest that human Jurkat T-cells possess two secretory and two cytosolic PLA(2) isoforms and only three of them (type IB, type V and type VI) are implicated in T-cell proliferation.

Synthesis and characterization of 5-octylthieno[3,4-c]pyrrole-4,6-dione derivatives as new monomers for conjugated copolymers.

An efficient route for the synthesis of 1-iodo-5-octyl-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione as a key intermediate to build new electron-deficient monomers and related conjugated polymers is reported. Along these lines, two new low bandgap copolymers were synthesized from Stille or Suzuki coupling. These polymers were characterized and their properties compared to those of analogous conjugated polymers.

High pancreatic n-3 fatty acids prevent STZ-induced diabetes in fat-1 mice: inflammatory pathway inhibition.

OBJECTIVE: Because of confounding factors, the effects of dietary n-3 polyunsaturated fatty acids (PUFA) on type 1 diabetes remain to be clarified. We therefore evaluated whether fat-1 transgenic mice, a well-controlled experimental model endogenously synthesizing n-3 PUFA, were protected against streptozotocin (STZ)-induced diabetes. We then aimed to elucidate the in vivo response at the pancreatic level. RESEARCH DESIGN AND METHODS: ß-Cell destruction was produced by multiple low-doses STZ (MLD-STZ). Blood glucose level, plasma insulin level, and plasma lipid analysis were then performed. Pancreatic mRNA expression of cytokines, the monocyte chemoattractant protein, and GLUT2 were evaluated as well as pancreas nuclear factor (NF)-κB p65 and inhibitor of κB (IκB) protein expression. Insulin and cleaved caspase-3 immunostaining and lipidomic analysis were performed in the pancreas. RESULTS: STZ-induced fat-1 mice did not develop hyperglycemia compared with wild-type mice, and ß-cell destruction was prevented as evidenced by lack of histological pancreatic damage or reduced insulin level. The prevention of ß-cell destruction was associated with no proinflammatory cytokine induction (tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase) in the pancreas, a decreased NF-κB, and increased IκB pancreatic protein expression. In the fat-1-treated mice, proinflammatory arachidonic-derived mediators as prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were decreased and the anti-inflammatory lipoxin A4 was detected. Moreover, the 18-hydroxyeicosapentaenoic acid, precursor of the anti-inflammatory resolvin E1, was highly increased. CONCLUSIONS: Collectively, these findings indicate that fat-1 mice were protected against MLD-STZ-induced diabetes and pointed out for the first time in vivo the beneficial effects of n-3 PUFA at the pancreatic level, on each step of the development of the pathology-inflammation, ß-cell damage-through cytokine response and lipid mediator production.

Inhibition of stearoyl-CoA desaturase 1 expression induces CHOP-dependent cell death in human cancer cells.

BACKGROUND: Cancer cells present a sustained de novo fatty acid synthesis with an increase of saturated and monounsaturated fatty acid (MUFA) production. This change in fatty acid metabolism is associated with overexpression of stearoyl-CoA desaturase 1 (Scd1), which catalyses the transformation of saturated fatty acids into monounsaturated fatty acids (e.g., oleic acid). Several reports demonstrated that inhibition of Scd1 led to the blocking of proliferation and induction of apoptosis in cancer cells. Nevertheless, mechanisms of cell death activation remain to be better understood. PRINCIPAL FINDINGS: In this study, we demonstrated that Scd1 extinction by siRNA triggered abolition of de novo MUFA synthesis in cancer and non-cancer cells. Scd1 inhibition-activated cell death was only observed in cancer cells with induction of caspase 3 activity and PARP-cleavage. Exogenous supplementation with oleic acid did not reverse the Scd1 ablation-mediated cell death. In addition, Scd1 depletion induced unfolded protein response (UPR) hallmarks such as Xbp1 mRNA splicing, phosphorylation of eIF2α and increase of CHOP expression. However, the chaperone GRP78 expression, another UPR hallmark, was not affected by Scd1 knockdown in these cancer cells indicating a peculiar UPR activation. Finally, we showed that CHOP induction participated to cell death activation by Scd1 extinction. Indeed, overexpression of dominant negative CHOP construct and extinction of CHOP partially restored viability in Scd1-depleted cancer cells. CONCLUSION: These results suggest that inhibition of de novo MUFA synthesis by Scd1 extinction could be a promising anti-cancer target by inducing cell death through UPR and CHOP activation.

Hepatic and very low-density lipoprotein fatty acids in obese offspring of overfed dams.

The combined effects of developmental programming and high-fat feeding at weaning on fatty acid metabolism of the offspring are not well known. In the present study, we aim at characterizing the influence of maternal and offspring's own diets on liver and very low-density lipoprotein (VLDL) lipids; fatty acid profiles of VLDL and liver phospholipids, triglycerides, and cholesteryl esters; and hepatic enzyme activities. Twenty obese male rats born to cafeteria diet-fed dams and 20 control rats born to control diet-fed dams were selected. At weaning, 10 rats of each group were fed control or cafeteria diet. Obese rats had a significant increase in serum glucose, insulin, leptin, VLDL apolipoprotein B100 and lipid levels, and hepatic fatty acid synthase and a reduction in acyl-coenzyme A oxidase and dehydrogenase activities compared with control pups at day 21 and day 90. Hepatic steatosis was apparent only at day 90. The proportions of saturated fatty acids and monounsaturated fatty acids and the oleic to stearic acid ratio were significantly increased, whereas polyunsaturated fatty acids and the arachidonic to linoleic acid ratio were decreased, in liver and VLDL lipids of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal cafeteria diet induced a permanent reduction in hepatic ß-oxidation and an increase in hepatic lipogenesis that caused liver steatosis and VLDL and fatty acid alterations in adult offspring. These preexisting alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Nutritional recommendations in obesity must then target maternal and postnatal nutrition, especially fatty acid composition.