Mirror-symmetry violation in bound nuclear ground states.

Conservation laws are deeply related to any symmetry present in a physical system1,2. Analogously to electrons in atoms exhibiting spin symmetries3, it is possible to consider neutrons and protons in the atomic nucleus as projections of a single fermion with an isobaric spin (isospin) of t = 1/2 (ref. 4). Every nuclear state is thus characterized by a total isobaric spin T and a projection Tz-two quantities that are largely conserved in nuclear reactions and decays5,6. A mirror symmetry emerges from this isobaric-spin formalism: nuclei with exchanged numbers of neutrons and protons, known as mirror nuclei, should have an identical set of states7, including their ground state, labelled by their total angular momentum J and parity π. Here we report evidence of mirror-symmetry violation in bound nuclear ground states within the mirror partners strontium-73 and bromine-73. We find that a J π = 5/2- spin assignment is needed to explain the proton-emission pattern observed from the T = 3/2 isobaric-analogue state in rubidium-73, which is identical to the ground state of strontium-73. Therefore the ground state of strontium-73 must differ from its J π = 1/2- mirror bromine-73. This observation offers insights into charge-symmetry-breaking forces acting in atomic nuclei.

Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism.

BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women.

Vasomotor symptoms and cardiometabolic risk factors in menopausal women: a MONET Group study.

INTRODUCTION: Conflicting results have been reported concerning the prevalence of cardiometabolic risk factors in women experiencing vasomotor symptoms (VMS). OBJECTIVES: To compare cardiometabolic risk factors between women with and without VMS during the menopause transition and to determine the influence of physical activity on the prevalence of VMS. METHODS: Yearly assessment of women transitioning through menopause included self-reported VMS (hot flushes and night sweats), body composition and fat distribution, fasting glucose, insulin and lipids, and physical activity levels. RESULTS: Eighty-five of the 102 premenopausal women at baseline were included (age: 49.9 ± 2.0 years; body mass index: 23.2 ± 2.2 kg/m(2)). According to linear mixed model analyses, no statistically significant differences were observed for fat mass, lean body mass, body fat distribution indices and cardiometabolic risk factors, when comparing symptomatic vs. asymptomatic women. Neither physical activity levels nor intensity were associated with the prevalence of VMS. CONCLUSION: Our results suggest that women transitioning through menopause who reported VMS did not show greater deteriorations in body composition, body fat distribution and cardiometabolic risk factors. Furthermore, physical activity levels were not associated with lower prevalence of vasomotor symptoms in the present cohort.

Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons.

3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') is a psychostimulant drug, widely used recreationally among young people in Europe and North America. Although its neurotoxicity has been extensively described, little is known about its ability to strengthen neural circuits when administered in a manner that reproduces human abuse (i.e. repeated exposure to a low dose). C57BL/6J mice were repeatedly injected with MDMA (10 mg kg(-1), intraperitoneally) and studied after a 4-day or a 1-month withdrawal. We show, using in vivo microdialysis and locomotor activity monitoring, that repeated injections of MDMA induce a long-term sensitization of noradrenergic and serotonergic neurons, which correlates with behavioral sensitization. The development of this phenomenon, which lasts for at least 1 month after withdrawal, requires repeated stimulation of α(1B)-adrenergic and 5-hydroxytryptamine (5-HT)(2A) receptors. Moreover, behavioral and neuroendocrine assays indicate that hyper-reactivity of noradrenergic and serotonergic networks is associated with a persistent desensitization of somatodendritic α(2A)-adrenergic and 5-HT1A autoreceptor function. Finally, molecular analysis including radiolabeling, western blot and quantitative reverse transcription-polymerase chain reaction reveals that mice repeatedly treated with MDMA exhibit normal α(2A)-adrenergic and 5-HT(1A) receptor binding, but a long-lasting downregulation of Gαi proteins expression in both locus coeruleus and dorsal raphe nucleus. Altogether, our results show that repeated MDMA exposure causes strong neural and behavioral adaptations and that inhibitory feedback mediated by α(2A)-adrenergic and 5-HT(1A) autoreceptors has an important role in the physiopathology of addictive behaviors.

Satiety quotient linked to food intake and changes in anthropometry during menopause: a MONET Study.

OBJECTIVES: It is unknown whether the satiety quotient (SQ) differs across the menopausal transition, and whether changes in SQ are related to changes in anthropometric/body composition variables. The objective of this study was to evaluate the changes in SQ and its association with energy intake and changes in anthropometric/body composition variables across the menopausal transition. METHODS: At baseline, 102 premenopausal women (aged 49.9 ± 1.9 years, body mass index 23.3 ± 2.2 kg/m(2)) took part in a 5-year observational, longitudinal study. Body composition (DXA), appetite (visual analog scales), energy and macronutrient intakes (ad libitum lunch and 7-day food diary) were assessed annually. The SQ (mm/100 kcal) was calculated at 60 and 180 min post-breakfast consumption. RESULTS: Overall, the SQ increased at years 3 and 4 (p = 0.01-0.0001), despite no significant differences between menopausal status groups. Lower fullness, prospective food consumption and mean SQ values predicted overall increases in lunch energy and macronutrient intakes (p = 0.04-0.01), whereas only prospective food consumption and fullness SQ predicted energy intake and carbohydrate intake, respectively, when assessed with food diaries (p = 0.01). Delta SQs were negatively correlated with changes in waist circumference (p = 0.03-0.02), whereas delta SQs were positively (p = 0.04) and negatively (p = 0.02) associated with delta fat mass between years 1 and 5, and years 4 and 5, respectively. CONCLUSION: These results suggest that variations in SQ across the menopausal transition are related to energy and macronutrient intakes and coincide with changes in body composition and waist circumference.

Light physical activity is a better determinant of lower adiposity during the menopausal transition.

OBJECTIVE: To investigate the relationship between time spent performing physical activity (PA) and adiposity across the menopausal transition. METHODS: Body weight and body composition were analyzed in 65 women (47-54 years old; body mass index 23.2 ± 2.4 kg/m(2)) in a 5-year prospective study. Time spent in PA of varying intensities (sedentary, light, moderate and vigorous) was determined from 7-day accelerometer measurement and energy intake with a 7-day food diary. RESULTS: Significant negative correlations were observed between the time spent in light-intensity PA and fat mass (FM) (r = -0.38, p < 0.005), central FM (r = -0.36, p < 0.005), peripheral FM (r = -0.33, p < 0.01), and percent body fat (r = -0.42, p < 0.001) at year 1, respectively. No significant correlations were noted between measures of adiposity and time spent performing either moderate or vigorous PA. Analyses using tertiles of time spent in light PA at year 1 showed that FM (20.7 ± 4.0 vs. 20.3 ± 6.6 vs. 16.6 ± 4.6 kg, p < 0.05), central FM (10.1 ± 2.6 vs. 10.0 ± 3.8 vs. 7.8 ± 2.4 kg; p < 0.05) and percent body fat (34.5 ± 5.1 vs. 32.2 ± 7.7 vs. 28.1 ± 6.2%, p < 0.01) were all significantly lower in women in the highest tertile. These differences remained significant after covariate analyses using time spent in moderate- and high-intensity PA and total energy intake. Finally, lower levels of FM, percent body fat, central and peripheral FM persisted in women who spent more time in light PA (highest tertiles) over the 5-year follow-up. CONCLUSION: Our results suggest that the time spent performing light PA may have a greater impact on adiposity than moderate and/or vigorous PA, an observation independent of the menopausal status.

Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight.

The decrease in energy expenditure that occurs during weight loss is a process that attenuates over time the impact of a restrictive diet on energy balance up to a point beyond which no further weight loss seems to be possible. For some health professionals, such a diminished energy expenditure is the normal consequence of a progressive decrease in the motivation to exercise over the course of a weight-reducing program. Another explanation of decreased energy needs during weight loss is the decrease in body energy stores (that is, fat mass and muscle mass) and its related obligatory costs of living. Many studies have also documented the existence of adaptive thermogenesis in the context of weight loss, which represents a greater-than-predicted decrease in energy expenditure. In this paper, we pursue the analysis of this phenomenon by demonstrating that an adaptive decrease in thermogenesis can have a major role in the occurrence of resistance to further lose fat in weight-reduced obese individuals. Evidence is also presented to support the idea of greater hunger sensations in individuals displaying more pronounced thermogenic changes. Finally, as the decrease in thermogenesis persists over time, it is also likely associated with a greater predisposition to body-weight regain after weight loss. Globally, these observations suggest that the adaptive reduction in thermogenesis that accompanies a prolonged negative energy balance is a major determinant of the ability to spontaneously lose body fat.

Trade off-free entanglement stabilization in a superconducting qutrit-qubit system.

Quantum reservoir engineering is a powerful framework for autonomous quantum state preparation and error correction. However, traditional approaches to reservoir engineering are hindered by unavoidable coherent leakage out of the target state, which imposes an inherent trade off between achievable steady-state state fidelity and stabilization rate. In this work we demonstrate a protocol that achieves trade off-free Bell state stabilization in a qutrit-qubit system realized on a circuit-QED platform. We accomplish this by creating a purely dissipative channel for population transfer into the target state, mediated by strong parametric interactions coupling the second-excited state of a superconducting transmon and the engineered bath resonator. Our scheme achieves a state preparation fidelity of 84% with a stabilization time constant of 339 ns, leading to a 54 ns error-time product in a solid-state quantum information platform.

Association between physical activity energy expenditure and inflammatory markers in sedentary overweight and obese women.

OBJECTIVE: Chronic subclinical inflammation and regular physical activity have opposing relationships to obesity-related metabolic diseases. Yet, the association between chronic inflammation and physical activity has rarely been examined in obese subjects. We examined the association between physical activity energy expenditure (PAEE), total (TEE) and resting energy expenditure (REE) and cardiorespiratory fitness (VO(2)peak) with inflammatory markers in overweight/obese women. DESIGN: Cross-sectional study. METHODS: The study included 152 overweight/obese postmenopausal women who were sedentary and free of chronic/inflammatory diseases (mean age: 57.5 (95% confidence interval (CI) 56.7-58.3) years, body mass index (BMI): 32.5 (95% CI 31.8-33.2) kg m(-2)). The following parameters were measured: TEE (doubly labeled water), REE (indirect calorimetry), PAEE (as (TEE x 0.90)-REE), VO(2)peak (ergocycle) and serum high-sensitive C-reactive protein (hsCRP), haptoglobin, soluble tumor necrosis factor-α receptor 1 (sTNFR1), interleukin-6, orosomucoid and white blood cells. RESULTS: Sedentary women with the highest tertile of PAEE (1276 (1233-1319) kcal day(-1)) had lower concentrations of hsCRP and haptoglobin than those in the lowest tertile (587 (553-621) kcal day(-1)) after adjustment for fat mass (P<0.05). Soluble TNFR1 was positively correlated with VO(2)peak, TEE and REE (P<0.05), and hsCRP and orosomucoid were positively associated with REE (P<0.01), whereas haptoglobin was negatively associated with PAEE (P<0.05). In stepwise regression analyses that examined the concomitant associations of components of energy expenditure with inflammatory markers, PAEE remained the only predictor of hsCRP and haptoglobin (P<0.05), explaining 14 and 5%, respectively, of their variation,whereas REE was the only predictor of orosomucoid (r (2) = 0.05, P = 0.02) after adjustment for fat mass. Adding leptin to the regression models results in similar relationships between inflammatory markers and components of energy expenditure. CONCLUSION: PAEE is an independent predictor of hsCRP and haptoglobin in sedentary overweight/obese postmenopausal women free of chronic disease. Our data support the role of physical activity in reducing subclinical inflammation and risk of metabolic and cardiovascular diseases.

Normal weight men and women overestimate exercise energy expenditure.

AIM: The limited potential of exercise to induce weight loss could be partly due to the overestimation of the energy cost of exercise. The objectives of this study were twofold: 1) to investigate whether men and women are able to accurately estimate exercise energy expenditure (EE); and 2) to determine whether they have the ability to accurately compensate for the EE of exercise during a buffet-type meal. METHODS: Sixteen (8 men, 8 women) moderately active (VO2 peak=45.4±7.7 mL.kg-1.min-1), normal weight (BMI=22.8±3.3 kg/m2) individuals, aged 20-35 years, were studied. They were blinded to two randomly assigned experimental conditions: a 200 and a 300 kcal (measured by indirect calorimetry) exercise sessions that were performed on a treadmill at the same intensity (50% of VO2 peak). At the end of each exercise session individuals were asked to estimate EE of the exercise sessions and to then eat the caloric equivalent of their estimated exercise EE from a buffet-type meal. RESULTS: Estimated EE was higher than measured EE for both the 200 kcal (825.0±1061.8 vs. 200.1±0.7 kcal, P<0.05) and 300 kcal (896.9±952.4 vs. 300.2±0.7 kcal, P<0.05) sessions. Further, post-exercise energy intake was higher than measured EE for the 200 kcal (556.8±204.4 vs. 200.1±0.7 kcal, P<0.001) and the 300 kcal (607.2±166.5 vs. 300.2±0.7 kcal, P<0.001) sessions. Although post-exercise energy intake was lower than estimated EE, no significant differences were noted. CONCLUSION: These results suggest that normal weight individuals overestimate EE during exercise by 3-4 folds. Further, when asked to precisely compensate for exercise EE with food intake, the resulting energy intake is still 2 to 3 folds greater than the measured EE of exercise.

Substituting food restriction by resistance training prevents liver and body fat regain in ovariectomized rats.

OBJECTIVE: Fat mass gain and regain following weight loss are major concerns and may be even more critical after menopause. The present study was undertaken to evaluate the effect of a resistance training protocol on body weight and fat mass in ovariectomized Sprague-Dawley rats following diet-induced weight loss. DESIGN: Rats were randomly divided into ovariectomized (Ovx) and sham-operated (Sham) groups. Five weeks after ovariectomy, Ovx rats were subjected to a 26% food restriction (OvxFR) for 8 weeks. Following this period, OvxFR rats went back to a normal ad libitum feeding and were divided into two groups: either sedentary or undergoing a resistance training program for an additional 5 weeks, which consisted of climbing a 6-m vertical grill, 20-40 times, with progressively increasing load four times/week. RESULTS: The food restriction program decreased (p < 0.01) body mass, fat pad weight (intra-abdominal and subcutaneous), and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Stopping the food restriction program over a 5-week period resulted in a partial regain in body weight and intra-abdominal fat pad weight (p < 0.05), and in an almost complete regain in liver TAG compared to normally fed Ovx rats. On the other hand, no significant increases in these variables were noted when the food restriction was replaced by resistance training over the same 5-week period. CONCLUSION: These results indicate that a resistance training program could be useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. It is suggested that changing from a food restriction regimen to a resistance training program can be an interesting strategy to promote successful long-term weight reduction in postmenopausal women.

Compensation in response to energy deficits induced by exercise or diet.

Obesity is an extremely resilient condition. Weight loss is most challenging, and weight recidivism is rampant. There is accumulating evidence highlighting that energy deficits meant to produce increased mobilization of energy stores trigger a number of somewhat persistent adaptations that together increase the drive to eat and decrease energy output. These adaptations ostensibly enable a context where the likelihood of energy compensation is heightened. In fact, energy compensation is present for both diet and exercise induced energy deficits although at different magnitudes. For the most part, the energy compensation in response to exercise induced energy deficits seems to be larger. Interestingly, energy compensation appears to be greater for longer interventions, an effect independent of whether the energy deficit is induced through diet or exercise. The latter suggests that the increased drive to eat and the reduced energy expenditure that accompany weight loss might be successfully fought off initially. However, with time there seems to be increasing erosion of the behaviours that initially opposed adaptations to weight loss and increased energy compensation progressively sets in. Under such conditions, it would seem prudent to propose weight loss targets that align with a level of behaviour modifications that can be sustained indefinitely.

Immunohistochemical studies of cyclic guanosine monophosphate and nuclear function.

In previous immunohistochemical studies, it has been found that all nuclei contain cyclic (c)GMP, which occurs in discrete aggregates and in the nucleolus. We have studied the nature of the cGMP aggregates in isolated mouse fetal nuclei using a specific immunofluorescent technique. These aggregates correspond to the areas of condensation of DNA, demonstrable by either Felugen's or acridine orange stain. Treatment with DNAase eliminated DNA and cGMP staining. Staining for RNA, with a human anti-RNA antibody, demonstrated RNA to be distributed diffusely throughout the nucleus and not preferentially in the areas of discrete cGMP aggregates. The diffuse stain for nuclear RNA was eliminated by pretreatment with RNAase but not DNAase, but aggregates of cGMP were not affected by pretreatment with RNAase. Sites of active RNA synthesis were determined by autoradiography using [3H]uridine, and did not correspond to the aggregates of cGMP. The relationship of cGMP to nucleolar function was examined in the endothelial cells of the isthmus and ampulla of the rat fallopian tube. Previous studies have shown that in proestrous, a period of increased RNA synthesis, nucleoli detectable by staining for RNA appear in the endothelial cells lining the fallopian tube. After immunofluorescent staining, we found prominent accumulation of cGMP in the nucleoli. During other phases of the cycle, there is an absence of nucleoli detectable by staining for RNA, and an absence of nucleolar cGMP. After we treated hypophysectomized or oophorectomized rats with estrogen, which is known to increase nucleolar RMA synthesis in the fallopian tube and endometrium, nucleoli in the endothelial cells of the rat fallopian tube and uterus stained strongly for cGMP. In conclusion, our studies suggest that the discrete aggregates of nuclear cGMP are associated with a fraction of DNA uninvolved in RNA synthesis. In contrast, cGMP appears in the nucleolus during a period of increased RNA synthesis, suggesting a role for cGMP in regulating nucleolar synthesis and processing of RNA.

The effects of partial sleep restriction and altered sleep timing on olfactory performance.

Olfaction can increase the drive to eat and may partially explain the consistent increases in energy intake (EI) following sleep restriction. We investigated the effects of 50% sleep restriction with altered sleep timing on olfactory performance. We also evaluated whether changes (Δ) in olfactory performance were associated with Δ24 h EI. Twelve men and six women (age: 23±4 years; BMI: 23±3 kg/m2) completed three randomized cross-over conditions: habitual sleep duration, 50% sleep restriction with advanced wake-time, and 50% sleep restriction with delayed bedtime. Sleep was measured in-laboratory (polysomnography). Olfactory performance ('sniffin sticks') and 24 h EI (food menu) were evaluated the next day. A trend for a significant condition*sex interaction was noted for threshold-discrimination-identification (TDI) scores (P=0.09); TDI scores were lowest in women and highest in men, following sleep restriction with advanced wake-time. Δolfactory performance were not associated with Δ24 h EI. The impact of sleep restriction on olfactory performance may differ between sexes. Changes in olfactory performance were not associated with changes in 24 h EI. Studies investigating prolonged effects of sleep loss on the relationship between olfactory performance with EI are needed.

Greater than predicted decrease in resting energy expenditure with age: cross-sectional and longitudinal evidence.

OBJECTIVE: To determine whether the age-related decrease in resting energy expenditure (REE) is explained by variations in body composition. DESIGN: In Study 1, adult subjects (20-70 years) from the Quebec Family Study were classified into five different age groups. Body composition was measured by hydrodensitometry to determine fat mass and fat-free mass as predictors of REE. In the youngest group of individuals these predictors were used to plot a reference regression that was then used to predict REE in the other age groups. In Study 2, this issue was investigated in a longitudinal design (6-year follow-up). Subjects were subdivided into three groups and a reference regression was plotted at the beginning of the follow-up and was then used to predict REE 6 years later in the three age groups. SUBJECTS: In Study 1, 627 adults (288 men and 339 women), aged between 20 and 70 years. In Study 2, 191 adults (93 men and 98 women). RESULTS: In Study 1, measured REE was 329, 302, 528 and 636 kJ/day (P < 0.0001) below predicted REE at 34, 44, 54 and 64 years, respectively. In Study 2 the most marked deviation from predicted REE in response to the 6-year follow-up in men was observed in young adults (-548 kJ/day, P < 0.001) while in women, the largest deviation occurred later in life (-720 kj/day, P < 0.001). CONCLUSION: Aging is accompanied by a decrease in REE that is significantly greater than what is predicted by variations in body composition. This decrease may reach a mean level of about 500-800 kj/day.

Validity of foot-to-foot bioelectrical impedance analysis in overweight and obese children and parents.

AIM: The aim of this study was to evaluate the validity of foot-to-foot bioelectrical impedance analysis (FF-BIA) in the measurement of body composition in overweight and obese children and their parents by comparison to dual-energy X-ray absorptiometry (DXA). METHODS: Seventeen, 7-12 year old overweight and obese children (6 boys, 11 girls) and 17 parents (5 fathers, 12 mothers) were evaluated for body composition with FF-BIA and DXA. Measures of percent body fat (PBF), fat mass (FM) and fat free mass (FFM) derived from FF-BIA and DXA were compared. Measures of validity were determined by Pearson correlations between FF-BIA and DXA, paired t-tests to assess mean differences, as well as biases and limits of agreement using the Bland Altman tests. RESULTS: FF-BIA produced estimates of body composition that were highly correlated with DXA in overweight and obese children and parents. For children, the correlations for PBF, FM, and FFM were 0.85, 0.97, and 0.94, respectively. For parents, the correlations for PBF, FM, and FFM were 0.92, 0.97, and 0.91, respectively. However, mean differences between FF-BIA and DXA were significant in children but not in parents. Bland-Altman tests of agreement showed moderate to large within-subject differences in body composition variables between FF-BIA and DXA. CONCLUSIONS: FF-BIA is strongly related to DXA in the measurement of body composition in both overweight and obese preadolescent children and parents, but the two measures may not be used interchangeably. Although FF-BIA may lack the precision to assess small changes in body composition in overweight and obese individuals, it is appropriate for epidemiological use.

Agonist-induced internalization of serotonin-1a receptors in the dorsal raphe nucleus (autoreceptors) but not hippocampus (heteroreceptors).

Serotonin-1A (5-HT(1A)) receptors in the CNS are a major target for psychotropic drugs. In nucleus raphe dorsalis (NRD) and hippocampus (CA3), the selective 5-HT(1A) agonist (+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT) reduces the firing activity of serotoninergic (5-HT) and pyramidal neurons, respectively. When located on 5-HT (autoreceptors), but not on non-5-HT (heteroreceptors) neurons, 5-HT(1A) receptors are known to be subject to desensitization. Using quantitative electron microscopy after pre-embedding immunogold labeling with specific antibodies, we examined the subcellular distribution of these receptors after acute administration of 8-OH-DPAT (0.5 mg/kg, i.v.). Silver-intensified immunogold particles associated with the plasma membrane or the cytoplasm were counted in somata and dendrites within the NRD, 15 min, 1 hr and 24 hr after 8-OH-DPAT injection, and in hippocampal dendrites 1 hr after the same treatment. Significant decrease in the density of membrane labeling and concomitant increase of cytoplasmic labeling were demonstrated in the NRD, 15 min and 1 hr after 8-OH-DPAT administration, with a return to baseline level at 24 hr. Internalization was blocked by previous administration of the 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635), which, by itself, was without apparent effect. In hippocampus (CA3), there were no apparent changes in the distribution of the receptor after 8-OH-DPAT administration. These findings are in line with earlier results showing a desensitization of 5-HT(1A) autoreceptors but not heteroreceptors after treatment with 5-HT(1A) receptor agonist. They suggest that this desensitization is the result of autoreceptor internalization.

Role of alpha-glucosidase in fetal lung maturation.

The role of lysosomal enzyme acid alpha-glucosidase in fetal lung development was investigated with the aid of a specific inhibitor, the pseudosaccharide acarbose. The drug was added to a Waymouth culture medium of fetal rat lung explants cultivated for 48 h from gestational stage 19.5 days, an in vitro system previously shown to allow morphological and biochemical maturation of alveolar epithelium. Glycogenolysis was reduced by 40% as compared with tissue cultivated on control medium, which means that alpha-glucosidase could account for as much as 40% of fetal lung glycogenolysis, the remaining 60% being presumably achieved by cytosolic phosphorylase and by a microsomal neutral alpha-glucosidase. By the same time, the increase of phospholipids of surfactant fraction extracted from cultivated explants was partially inhibited: total and saturated phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol were about 30-40% lower than in lungs cultivated on control medium. It should be emphasized that DNA concentration and increases in non-surfactant phospholipids were unchanged by the drug. alpha-Glucosidase activity was evidenced in the lysosomal fraction, in the microsomal fraction and, although in lower amounts, in the surfactant fraction extracted from term fetal lung. The results suggest that lysosomal alpha-glucosidase plays a major role in lung maturation and could facilitate glycogenolysis for the specific use of glycogen stores in providing substrates for surfactant phospholipid biosynthesis.

Changes in energy expenditure and substrate oxidation resulting from weight loss in obese men and women: is there an important contribution of leptin?

The aim of the present study was to determine the impact of weight loss and its related metabolic and hormonal changes on resting energy expenditure (REE) and substrate oxidation. Forty subjects (16 men and 24 women) took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy restriction (-700 Cal/day). Subjects were asked to come to the laboratory after an overnight fast for an indirect calorimetry measurement before and after weight loss. Fasting blood samples were also drawn and were analyzed for plasma glucose, insulin, leptin, and free fatty acid determinations. This program reduced body weight by 11% and 9% (P < 0.01) in men and women, respectively. Fat mass (FM) and fat-free mass (FFM) were also significantly reduced in both sexes. A significant decrease in REE (13%; P < 0.01) and fat oxidation (11%; P = 0.08) was observed in men in response to this program, whereas no significant differences were noted for these variables in women. In men, positive correlations were found between changes in FFM and energy-related variables, whereas the best predictor of changes in REE and substrate oxidation was the change in FM in women. The most important finding of this study is that in men, the association between changes in fasting plasma leptin and changes in REE (r = 0.50; P < 0.01) and fat oxidation (r = 0.63; P < 0.01) persist after correction for changes in body composition. These results suggest that a comparable weight loss is accompanied by a greater decrease in REE and substrate oxidation in men than in women, and that these changes are better explained by changes in leptinemia in men and by changes in FM in women.

Fasting insulin levels influence plasma leptin levels independently from the contribution of adiposity: evidence from both a cross-sectional and an intervention study.

The aim of the present investigation was to determine whether leptinemia is only a reflection of the status of fat stores or if insulinemia has a significant influence over leptin levels. Study 1 focused on the association between fasting plasma insulin and leptin in subjects of the Quebec Family Study who were first classified as either high- or low-insulin individuals and were then individually matched on the basis of fat mass (FM). In Study 2, 19 men and 23 women took part in a 15-week weight loss program that consisted of drug therapy (fenfluramine, 60 mg/day) or placebo coupled to an energy-restricted diet (-2930 kJ/day). Body weight, FM, and fat-free mass (assessed by underwater weighing) as well as visceral and sc abdominal and mid-thigh adipose tissue measured by computed tomography were assessed before and after weight loss. Blood samples were drawn and analyzed for fasting plasma insulin and leptin before and after weight loss. In Study 1, significant positive associations were noted between log10 transformed fasting insulin and leptin in both men (r = 0.55, P < 0.0001) and women (r = 0.48, P < 0.0001). Moreover, after having carefully matched high-insulin to low-insulin individuals on the basis of FM, significantly lower leptin levels were observed in the low-insulin groups, in men (5.5 vs. 8.1 ng/mL, P < 0.05) as well as in women (18.7 vs. 24 ng/mL, P < 0.05). Results from Study 2 showed significant reductions of body weight, FM, fat-free mass, visceral abdominal tissue, sc abdominal tissue, and mid-thigh adipose tissue levels in men and women in response to the weight loss protocol. Moreover, the decrease in fasting plasma insulin was the only significant correlate of changes in fasting plasma leptin levels during weight loss, even after corrections for changes in FM in both men (r = 0.50, P < 0.05) and women (r = 0.46, P < 0.05). These results suggest that in a population characterized by a wide range of adiposity hyperinsulinemia has the potential to modulate leptin levels beyond what can be explained by total adiposity. Moreover, this relation also seems to exist in a dynamic setting (i.e. during weight loss) because changes in insulin were independent predictors of the changes in leptinemia in both men and women after correction for changes in FM.