Interaction of cysteine and its derivatives with monolayers of dipalmitoylphosphatidylcholine.

Molecular interactions between l-cysteine (Cys) and its ester derivatives (Cysx); l-cysteine ethyl ester (CE), l-cysteine methyl ester (CM) and N-acetyl l-cysteine (NAC) with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) monolayers were investigated using Langmuir film balance technique. The effect of charge on monolayers made of cysteine and three ester derivatives with DPPC was investigated by working with un-buffered and buffered subphases. Also, the effects of cysteine derivatives interaction with DPPC monolayers were studied measuring the change in the surface tension upon aminoacid injection in the subphase whilst keeping lipid molecular density and lateral packing controlled. Cysteine and its ester derivatives showed interfacial activity reducing the air/water surface tension (πi) by 4 mN m-1. However, ester derivatives were able to insert into preformed DPPC monolayers at much higher surface pressures (Δπ), indicating a preferential interaction of Cysx with DPPC. The results indicate that, although the different derivatives of cysteine presented low surface activity, they were able to favourably interact with DPPC monolayers. Also, compression isotherms experiments in binary mixtures indicate that the more surface active compounds stabilized the gel phase of DPPC. The charge on cysteine and its derivatives did not increase the observed effects.

The case for class II bacteriocins: A biophysical approach using "suicide probes" in receptor-free hosts to study their mechanism of action.

Class II bacteriocins are unmodified membrane-active peptides that act over a narrow spectrum of target bacteria. They bind a specific receptor protein on the membrane to form a pore, leading to membrane permeabilization and cell death. However, little is known about the molecular events triggering the pore formation after the bacteriocin recognizes the receptor. It is not clear yet if the pore is the same receptor forced into an open conformation or if the pore results from the bacteriocin insertion and oligomeric assembly in the lipid bilayer. In order to reveal which model is more suitable to explain the toxicity mechanism, in this work we use chimeric peptides, resulting from the fusion of the bitopic membrane protein EtpM with different class II bacteriocins: enterocin CRL35, pediocin PA-1 and microcin V. E. coli strains lacking the specific receptors for these bacteriocins were chosen as expression hosts. As these constructs display a lethal effect when they are heterologously expressed, they are called "suicide probes". The results suggest that, indeed, the specific receptor would act as a docking molecule more than as a structural piece of the pore, as long as the bacteriocin is somehow anchored to the membrane. These set of chimeric peptides also represent an in vivo system that allows to study the interaction of the bacteriocins with real bacterial membranes, instead of model membranes. Hence, the effects of these suicide probes in membrane fluidity and transmembrane potential were also assessed, using fluorescence spectroscopy. The data show that the different suicide probes are able to increase phospholipid order and depolarize the membranes of receptor-free bacterial cells.

Hexagonal phase with ordered acyl chains formed by a short chain asymmetric ceramide.

Ceramides constitute a group of lipids with usually high melting temperature that also favor negative curvature in membranes when mixed with other lipids. The short chain C10:0 ceramide is an asymmetric lipid which consists of an 18 carbon sphingosine base N-acylated with decanoic acid. According to high sensitivity differential scanning calorimetry, it shows a minor exothermic peak at 61°C and a main endothermic transition at 75°C. By small angle X-ray scattering and polarized light microscopy we found that, at temperatures below the main transition, the fully hydrated lipid dispersions are arranged in a tridimensional structure corresponding to an inverted hexagonal phase. Infrared spectroscopy and wide angle X-ray diffraction indicated that the acyl chains of ceramides exhibit a relatively high order in the hexagonal phase. As far as we know, this is the first report of a lipid hexagonal phase having highly ordered acyl chains. Molecular asymmetry due to the different length of the sphingosine and the N-acyl chains of C10:0 ceramide may explain why this novel phase is formed.

The antimicrobial peptide microcin J25 stabilizes the gel phase of bacterial model membranes.

The bacterial membrane interaction of the antimicrobial peptide microcin J25 was studied with the probe-free techniques Langmuir monolayers and infrared spectroscopy. Membrane model systems composed by phosphatidylethanolamine:phosphatidylglycerol 7:3, which mimic the cytoplasmic membrane of Gram negative bacteria, were used in both monolayer and bilayer approaches. The peptide reduced the transition surface pressure of the expanded-to-condensed lipid monolayer states, as well as increased the gel-to-liquid crystalline transition temperature in bilayers, indicating a stabilization of membrane ordered state. In addition, a reduction of the surface pressure at which condensed domains appeared was observed upon mixed monolayers compression after microcin J25 adsorption. The results indicate a favorable interaction of microcin J25 with bacterial membrane model systems. Also, the effects on the ordered phases stabilization are discussed in terms of the biological effects observed in membranes of sensitive cells.

Stable planar mesoscopic photonic crystal cavities.

Mesoscopic self-collimation (MSC) in mesoscopic photonic crystals with high reflectivity is exploited to realize a novel high Q-factor cavity by means of mesoscopic PhC planar mirrors. These mirrors efficiently confine a mode inside a planar Fabry-Perot-like cavity, that results from a beam focusing effect that stabilizes the cavity even for small beam sizes, resembling the focusing behavior of curved mirrors. Moreover, they show an improved reflectivity with respect to their standard distributed Bragg reflector counterparts that allows higher compactness. A Q-factor higher than 104 has been achieved for an optimized 5-period-long mirror cavity. The optimization of the Q-factor and the performances in terms of energy storage, field enhancement, and confinement are detailed.

EEG and electrodermal activity in girls with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This study investigated the Hypoarousal Model of Attention-Deficit/Hyperactivity Disorder (AD/HD) in girls. METHODS: 40 girls with AD/HD and 40 girl controls (aged 7-12 years) had an eyes-closed resting EEG recorded from 19 electrodes and Fourier transformed. Estimates for total power, absolute and relative power in the delta, theta, alpha, beta and gamma frequency bands, and theta/beta ratio were analysed in nine cortical regions. Skin conductance level (SCL) was simultaneously recorded. Regression analyses explored relationships between symptoms and physiology. RESULTS: Compared with controls, girls with AD/HD had globally elevated relative delta, globally reduced absolute beta, and globally reduced absolute and relative gamma activity. Girls with AD/HD also had lower mean SCL. Inattentive symptoms were predicted by elevated frontal relative delta, reduced SCL, and reduced temporal relative gamma activity, while elevated hyperactive-impulsive symptoms correlated with elevated frontal relative delta activity in both the patient and control groups. CONCLUSIONS: These EEG results are comparable with the limited female AD/HD literature. Girls with AD/HD are hypoaroused, indicated by reduced SCL, and appear to have an anomalous arousal mechanism. Absolute and relative gamma results are similar to previous findings in AD/HD children. Symptom correlations with physiology offer intriguing insights for future research. SIGNIFICANCE: This is the first study to examine CNS arousal exclusively in girls with AD/HD.

High angular tolerance and reflectivity with narrow bandwidth cavity-resonator-integrated guided-mode resonance filter.

Guided mode resonance filters (GMRFs) are a promising new generation of reflective narrow band filters, that combine structural simplicity with high efficiency. However their intrinsic poor angular tolerance and huge area limit their use in real life applications. Cavity-resonator-integrated guided-mode resonance filters (CRIGFs) are a new class of reflective narrow band filters. They offer in theory narrow-band high-reflectivity with a much smaller footprint than GMRF. Here we demonstrate that for tightly focused incident beams adapted to the CRIGF size, we can obtain simultaneously high spectral selecitivity, high reflectivity, high angular acceptance with large alignment tolerances. We demonstrate experimentally reflectivity above 74%, angular acceptance greater than ±4.2° for a narrow-band (1.4 nm wide at 847 nm) CRIGF.

Does hyperflex total knee design improve postoperative active flexion?

INTRODUCTION: The rotating platform flexion (RPF) Sigma total knee prosthesis (DePuy; Warsaw, Indiana) was designed for maintaining the contact of the condyles with their corresponding tibial plateau throughout the high-flexion range. However, this requires an additional 3-mm bone cut of the posterior condyles. Compared to the conventional design, this modification is intended to improve the flexion range. This hypothesis was tested by studying the increase in flexion (flexion gain, range of motion [ROM], active flexion) of 59 consecutive patients who had received the hyperflex design implant (RPF), whose preoperative mobility values were retrospectively compared to these same values in another 59 consecutive matched patients who had received an implant with the conventional design of the same implant (rotating platform [RP]) between June 2005 and June 2006. Postoperative mobility was measured visually with a goniometer. PATIENTS AND METHODS: Only osteoarthritic knees were eligible to be included. Knees with more than 20 degrees flexion contracture or less than 90 degrees flexion, and patients with a body mass index (BMI) greater than 30 were excluded. Both groups were comparable with regard to age, preoperative mobility values, and BMI. The sex ratio differed significantly, but preoperative mobility did not differ significantly in male and female patients in the RP and in the RPF groups. The difference in sex ratio did not appear to be a bias influencing preoperative mobility. RESULTS: Overall, the flexion gain was correlated to preoperative flexion (r=-0.75, p<0.001). The flexion gain in the RPF group was significantly greater than in the RP group (13+-20 versus 6+-13; p=0.02) as was the ROM gain (10+/-17 degrees versus 4+/-12 degrees; p=0.02). However, the one-year active mean flexions were not significantly different (118+/-14 degrees versus 116+/-6 degrees; p=0.47). In patients whose preoperative flexion was less than 120 degrees (18 and 27 RPF prostheses), the flexion and ROM gains were significantly greater in the RPF group (23+/-16 degrees versus 14+/-16 degrees; p=0.03 and 26+/-18 degrees versus 17+/-9 degrees; p=0.05), and the mean one-year active flexion was also greater in the RPF group (124+/-13 degrees versus 116+/-8 degrees, p=0.02). In patients with more than 120 degrees of preoperative flexion, the flexion and ROM gains and the final mean flexions in both groups were comparable. In particular, there were nine patients in the RP group and ten patients in the RPF group whose flexion decreased. CONCLUSION: Thus, the Sigma RPF prosthesis provided a significant additional flexion gain in patients with 90-120 degrees preoperative flexion, and less than 20 degrees flexion contracture. Patients with a preoperative flexion greater than 120 degrees were exposed to a decrease in flexion range whichever implant was used, RP or RPF. LEVEL OF EVIDENCE: Level 3, therapeutic study.

Measurement and modeling of 2D hexagonal resonant-grating filter performance.

We report the measurement of a polarization-independent guided-mode resonant filter with a Q factor of approximately 2200 functioning near normal incidence in the near infrared (850 nm). Besides this remarkable performance, we provide a detailed optical and structural characterization of the component, which points out the origins of the limitation of the experimental performance. We conclude that the defaults in question can be corrected by improving the lithography process, and we are confident that even greater performance will be obtained in future realizations.

Molecular evolution of protein O-fucosyltransferase genes and splice variants.

O-Fucose has been described on both epidermal growth factor-like (EGF-like) repeats and Thrombospondin type 1 repeats (TSRs). The enzyme adding fucose to EGF-like repeats, protein O-fucosyltransferase 1 (Pofut1), is a soluble protein located in the lumen of endoplasmic reticulum (ER). A second protein O-fucosyltransferase, Pofut2, quite divergent from its homolog Pofut1, has recently been shown to O-fucosylate TSRs but not EGF-like repeats. To date, Pofut1 genes have only been characterized in human, mouse, and fly, and Pofut2 in mouse, fly, and partially in the nematode Caenorhabditis elegans. Here, we report cDNA sequences and genomic structures of bovine Pofut1 and Pofut2 genes and describe for the first time five alternative spliced transcripts for each gene. Only one transcript for both Pofut1 and Pofut2 encodes an active bovine O-fucosyltransferase. Variant transcript distribution was examined in 13 bovine tissues. Transcripts encoding active forms are ubiquitous, whereas other forms possess a more restricted tissue-expression profile. Sequence comparison and phylogenetic analyses revealed that both Pofut genes are present as a single copy in animal genomes, and their exon-intron organizations are conserved among vertebrates. The last common ancestor of all analyzed bilaterian species would be predicted to possess polyexonic Pofut genes in their genome.

Single-mode in-gap emission of medium-width photonic crystal waveguides on InP substrate.

In this paper, we present a numerical and experimental study of W3-4 photonic crystal (PhC) waveguide lasers fabricated on InP substrate. In such a PhC waveguide, the dispersion curve of the fundamental mode folds in the two-dimensional gap of the triangular lattice. Folding occurs at the Brillouin zone edge as in the case of genuine distributed feedback (DFB) lasers. Single-mode emission is presently observed in both electrical and optical pumping configurations. This behavior is attributed to the different levels of out-of-plane losses experienced by the two DFB mode components. Three-dimensional finite-difference-time-domain calculations are used to finely quantify the quality factors of the waveguide modes. The modal discrimination is shown to be reinforced when lasing occurs far from the conduction band edge. This trend is also predicted for other canonical waveguides in triangular PhCs as for instance W2-3 waveguides.

Adipocyte functions are modulated by cell size change: potential involvement of an integrin/ERK signalling pathway.

OBJECTIVES: Adipocyte is the only cell whose size may vary dramatically in physiological conditions. We hypothesized that increase in fat cell size per se could modulate several signalling pathways by changing the relationships between the cell and the extracellular matrix. The aim of the current study was (i). to examine whether within the same fat depot, metabolic functions of adipocyte were modified by cell size and (ii). if such an adaptation exists, to look for an integrin/extracellular-signal-regulated kinases (ERKs) signalling pathway. RESULTS: We isolated two populations of adipocytes with different volumes (67 and 22 x 10(3) microm(3)) within the same adipose location. In large compared to small fat cells, fatty acid synthase and lipoprotein lipase activities were increased two- and seven-fold, respectively; GLUT4 protein concentration and leptin expression were increased three-fold; lipolytic capacity was increased four-fold. The integrin/ERK signalling pathway could be the one responsible for the adaptation of adipose functions to cell size. In large compared with small adipocytes, we showed that beta(1)-integrins are present in adipose membranes and at a higher concentration in large than in small cells. In isolated adipocytes, stimulation of beta(1)-integrins with a specific monoclonal antibody results in ERK(1) and ERK(2) activation. In large compared to small cells, cytoplasmic concentrations of these two mitogen-activated protein kinases were increased two-fold, whereas their activities were increased 10-fold. CONCLUSION: A beta(1)-integrin/ERKs signalling pathway is present in mature adipocyte. Increase in cell size, by modifying the relationships between cell and extracellular matrix, could turn on this pathway. Since ERKs can modulate transcription factors and subsequently modulate gene expression important for adipose function, this pathway could play an important role in the adaptation of adipose functions to cell size.

Impaired beta-adrenergic signaling pathway in white adipocytes of suckling fa/fa Zucker rats: a defect in receptor coupling.

BACKGROUND: In fa/fa Zucker rats, leptin receptor deficiency is responsible for both a deficit of energy expenditure and hyperphagia which lead to massive obesity and insulin resistance in adulthood. This obesity is also characterised by alterations of the beta-adrenergic signaling pathway. OBJECTIVE: To determine whether alterations in beta-adrenergic pathway could occur at the onset of obesity when fa/fa rats are not yet hyperinsulinemic. ANIMALS: Fourteen-day-old suckling fa/fa and Fa/fa littermates (from heterozygous lean (Fa/fa) female and homozygous obese (fa/fa) male mating). MEASUREMENTS: Membranes were prepared from isolated adipocytes after collagenase treatment of inguinal adipose tissue. The response of adenylyl-cyclase activity to stimulation by isoprenaline, GTPgamma-S or forskolin was studied. Bmax and Kd of (beta1+beta2) and of beta3 adrenoceptors were measured using 3H-CGP saturation binding experiments. mRNA concentration of beta1- and beta3-AR was determined by semi-quantitative RT-PCR. G(s)alpha protein was quantified by Western blotting and Gi protein by ADP-ribosylation. RESULTS: Despite an almost normal body weight, inguinal fat pad weight was increased two-fold by the expression of fa mutation. This increase was entirely accounted for by fat cell hypertrophy (x2.5 in volume). In fa/fa compared to Fa/fa pups, response of adenylyl cyclase to isoprenaline was decreased two-fold but responses to GTPgammaS or forskolin were unchanged. Density of (beta1+beta2) and beta3-AR was not affected by the fa/fa genotype, as well as G(s)alpha and Gi concentration. CONCLUSION: Response of inguinal fat cells to catecholamines was decreased without any quantitative modifications of the different elements of the adenylyl cyclase cascade. This suggests an alteration in the coupling between beta-AR and G proteins. Due to the important increase in fat cell volume we hypothesize that changes in the physical properties of plasma membranes and/or changes in cytoskeleton-extracellular-matrix interactions could disturb the beta-adrenergic pathway responsiveness. In addition to the excess of lipid storage, which occurs very early at the onset of obesity, the impairment of the responsiveness to catecholamines reported in this study might worsen the obesity syndrome.

Chemotactic penetration of keratocytes in ePTFE polymer in vitro.

Expanded polytetrafluoroethylene (ePTFE) is used as a support for artificial corneas. Implanted in corneas, most of the time this polymer is colonized by corneal host cells. The absence of colonization often coincides with extrusion of the polymer. Therefore, we decided to introduce keratocytes into ePTFE in vitro before implantation. Because keratocytes do not spontaneously enter ePTFE, we used several chemoattractants, separately and in a mixture, to stimulate the penetration of cultured keratocytes into the polymer. The influence of the passage number on cell penetration was also studied. No significant differences were observed up to the seventh passage, although seventh-passage cells penetrated somewhat more slowly than younger cells. Satisfactory results were obtained with four of the tested chemotactic factors: IL-6, type alpha transforming growth factor (TGF-alpha), platelet derived growth factor isoform BB (PDGF-BB), and fibroblast growth factor-2 (FGF-2). Under our experimental conditions, two to more than six million keratocytes entered the polymer discs with a volume of 706.5 mm(3) in the presence of these four chemoattractants. TGF-alpha was the most efficient and was selected for further in vitro and in vivo studies.

Ancestral exonic organization of FUT8, the gene encoding the alpha6-fucosyltransferase, reveals successive peptide domains which suggest a particular three-dimensional core structure for the alpha6-fucosyltransferase family.

Based on PCR strategies and expression studies, we define the genomic organization of the FUT8b gene. This gene encodes the only known mammalian enzyme transferring fucose in an alpha1-->6 linkage on the asparagine-branched GlcNAc residue of the chitobiose unit of complex N:-glycans. The intron/exon organization of the bovine coding sequence determines five successive functional domains. The first exon encodes a domain homologous to cytoskeleton proteins, the second presents a proline-rich region including a motif XPXPPYXP similar to the peptide ligand of the SH3-domain proteins, the third encodes a gyrase-like domain (an enzyme which can bind nucleotides), and the fourth encodes a peptide sequence homologous to the catalytic domain of proteins transferring sugars. Finally, the last exon encodes a domain homologous to the SH3 conserved motif of the SH2-SH3 protein family. This organization suggests that intramolecular interactions might give a tulip-shaped scaffolding, including the catalytic pocket of the enzyme in the Golgi lumen. Deduced from the published sequence of chromosome 14 (AL109847), the human gene organization of FUT8 seems to be similar to that of bovine FUT8b, although the exon partition is more pronounced (bovine exons 1 and 2 correspond to human exons 1-6). The mosaicism and phylogenetic positions of the alpha6-fucosyltransferase genes are compared with those of other fucosyltransferase genes.

Evidence for the presence of several phosphodiesterase isoforms in brown adipose tissue of Zucker rats: modulation of PDE2 by the fa gene expression.

The present study was undertaken to characterise the phosphodiesterases (PDEs) present in brown adipose tissue (BAT) of Zucker rat pups and to determine whether the capacity for degradation of cyclic nucleotides was affected by the fatty genotype. Regardless of the genotype, PDE2-4 contributed to total PDE activity, the PDE3 activity equalling the sum of PDE2 and 4 activities. In fa/fa compared to Fa/fa rats, (a) PDE2 activity was significantly increased, (b) Western blot analysis of PDE2 revealed two signals at 71 and 105 kDa, with changes in protein being in good parallelism with changes in activity, (c) the PDE2 mRNA concentration was also significantly increased. In good agreement, the cGMP concentration was decreased in BAT from fa/fa pups.

A single amino acid in the hypervariable stem domain of vertebrate alpha1,3/1,4-fucosyltransferases determines the type 1/type 2 transfer. Characterization of acceptor substrate specificity of the lewis enzyme by site-directed mutagenesis.

Alignment of 15 vertebrate alpha1,3-fucosyltransferases revealed one arginine conserved in all the enzymes employing exclusively type 2 acceptor substrates. At the equivalent position, a tryptophan was found in FUT3-encoded Lewis alpha1,3/1,4-fucosyltransferase (Fuc-TIII) and FUT5-encoded alpha1,3/1,4-fucosyltransferase, the only fucosyltransferases that can also transfer fucose in alpha1, 4-linkage. The single amino acid substitution Trp111 --> Arg in Fuc-TIII was sufficient to change the specificity of fucose transfer from H-type 1 to H-type 2 acceptors. The additional mutation of Asp112 --> Glu increased the type 2 activity of the double mutant Fuc-TIII enzyme, but the single substitution of the acidic residue Asp112 in Fuc-TIII by Glu decreased the activity of the enzyme and did not interfere with H-type 1/H-type 2 specificity. In contrast, substitution of Arg115 in bovine futb-encoded alpha1, 3-fucosyltransferase (Fuc-Tb) by Trp generated a protein unable to transfer fucose either on H-type 1 or H-type 2 acceptors. However, the double mutation Arg115 --> Trp/Glu116 --> Asp of Fuc-Tb slightly increased H-type 1 activity. The acidic residue adjacent to the candidate amino acid Trp/Arg seems to modulate the relative type 1/type 2 acceptor specificity, and its presence is necessary for enzyme activity since its substitution by the corresponding amide inactivated both Fuc-TIII and Fuc-Tb enzymes.

Early alterations in the brown adipose tissue adenylate cyclase system of pre-obese Zucker rat fa/fa pups: decreased G-proteins and beta 3-adrenoceptor activities.

This study was undertaken to determine whether receptor and non-receptor components of the adenylate cyclase (AC) cascade were altered in brown adipose tissue (BAT) of 14-day-old pre-obese (fa/fa) rats, before endocrine status is strongly modified by fa gene expression. Activity of the AC catalytic subunit did not differ between the two genotypes. In fa/fa rats compared with control Fa/fa rats, there was a 50% decrease in the activity of alpha Gs (stimulated by NaF or guanosine 5'-[gamma-thio]triphosphate) but no change in protein content (Western blotting). alpha Gi function, assessed by the inhibitory action of low concentrations of guanosine 5'-[beta gamma-imido]triphosphate upon 10(-4) M forskolin-stimulated AC activity, was equally low in both genotypes. Analysis of dose-response curves for different beta-agonists revealed that (i) both the basal and the maximally stimulated activity of AC were 2-fold lower in fa/fa rats than in Fa/fa rats; (ii) BRL37344 and CGP12177 (beta 3 agonists) were less potent in fa/fa than in Fa/fa rats (Kact. multiplied by 2); (iii) noradrenaline and isoprenaline (Iso), at the low-affinity site (beta 3-AR), were less potent in fa/fa than in Fa/fa pups (Kact. increased by 30 and 20% respectively). At the high-affinity site (mainly beta 1) these two agonists were more potent in fa/fa than in Fa/fa rats (Kact. decreased by 40 and 80% respectively). In good agreement with the latter result, the beta 1-adrenergic receptor (beta 1-AR)-selective antagonist CGP20712A had more effect on the Iso-stimulated AC activity in pre-obese than in lean pups (2-fold decreased in IC50). Binding experiments with [3H]CGP12177 show that in BAT of suckling rats, beta 3-ARs represent 80% of the total beta-ARs. Bmax values for the two sites were not affected by the genotype, although the beta 3-AR mRNA concentration in BAT (quantitative reverse-transcriptase PCR) was 3-fold lower in fa/fa rats than in Fa/fa pups. In conclusion, these results provide evidence for alterations in beta 1- and beta 3-AR signalling in BAT of 14-day-old suckling pre-obese Zucker rats with a decreased activity of alpha Gs. The impaired AC responsiveness to catecholamines might be a primary contributor to the development of this genetic obesity.

Effect of the beta-adrenoceptor agonist BRL-35135 on development of obesity in suckling Zucker (fa/fa) rats.

This study was undertaken to determine whether administration of a thermogenic beta-agonist drug to Zucker fatty rats could correct some of the earliest metabolic defects detectable in brown adipose tissue (BAT). Fa/fa and fa/fa littermates were given oral administration of BRL-35135 from 8 to 16 days of age. In fa/fa rats, the lipid content of white and brown adipose tissues was significantly reduced. In the BAT of fa/fa rats, thermogenic capacity was restored to the level observed in Fa/fa rats, whereas hyperactivity of fatty acid synthetase was abolished, and a deficit in lipoprotein lipase (activity and mRNA) was partly corrected. Hyperinsulinemia in fa/fa pups was significantly reduced. The decreased content of GLUT-4 mRNA that characterized BAT of fa/fa pups was also restored to normal. At variance with observations in preobese rats, BRL had very little or no effect on lean Fa/fa rats. The present study reveals that chronic administration of a beta-agonist drug early in life prevents emergence of most of the metabolic abnormalities that characterize fa/fa rats at the onset of obesity. This suggests that impaired sympathetic activity may play a role in the development of this genetic obesity.