Biomedical subjects

D Richard

Publications and source records attributed to D Richard.

At least 55 records · Page 3Linked to original sources

PubMed2000

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.

Adult↗

PubMed2000

Reproducibility of energy and macronutrient intake and related substrate oxidation rates in a buffet-type meal.

The aim of this present study was to determine the reliability of a buffet-type meal as a measure of spontaneous energy and macronutrient intake. In addition, we evaluated the short-term effects of diet on the composition of the substrate mix oxidized postprandially. Fourteen male subjects had ad libitum access to a variety of foods from a buffet-type meal offered in the laboratory during two identical sessions. The foods comprising the test meal had varying amounts of protein, lipid and carbohydrate. The results showed that there were significant intraclass correlations (ri) for energy (ri 0.97, P = 0.0001), lipid (ri 0.97, P = 0.0001), carbohydrate (ri 0.92, P = 0.0003) and protein (ri 0.82, P = 0.0072) intake between the two meal sessions. Hunger and fullness levels measured immediately before and during 4 h after the meal were identical under the two conditions. In addition, there was no significant difference between the two sessions for RQ and resting energy expenditure, which showed significant reproducibility for measurements obtained immediately before, immediately after, as well as 30 min after, the buffet. This present study demonstrates the high reproducibility of energy and macronutrient intake and oxidation rate values obtained with a buffet-type meal in healthy male subjects and suggests that the use of this test is a reliable method for assessment of macronutrient preferences in the laboratory.

Adult↗

PubMed2000

Differential roles of tumor necrosis factor-alpha and interferon-gamma in mouse hypermetabolic and anorectic responses induced by LPS.

Lipopolysaccharide (LPS)-induced effects on energy balance are characterized by alterations in energy expenditure (hypermetabolism) and food intake (anorexia). To study the role of tumour necrosis factor alpha (TNF-alpha) on some of these metabolic responses to endotoxin, we have used transgenic mice expressing soluble tumour necrosis factor receptor-1 IgG fusion protein (TNFR1-IgG) as well as TNF-alpha knockout (KO), lymphotoxin-alpha (LT-alpha) KO, and interferon-gamma receptor (IFN-gamma R) KO mice. The results from TNFR1-IgG transgenic mice suggest that the hypermetabolic and anorectic responses induced by LPS are independently regulated since, in the absence of TNF-alpha or LT-alpha, the LPS-induced hypermetabolism is almost prevented but not the anorexia. The anorectic response shows the strongest association with IFN-gamma since both IFN-gamma R KO mice and mice treated with anti-IFN-gamma antibody showed marked reduction in the LPS-induced anorexia compared to other mice. IFN-gamma R KO mice also have an attenuated thermogenic response to endotoxin. Anti-Asialo GM1 antibody treatment attenuated both the hypermetabolic and anorectic responses to LPS, to an extent comparable to that observed in IFN-gamma R KO mice. This finding suggests that natural killer cells (lymphocytic subsets) may be involved in IFN-gamma production and play an important role in the metabolic alterations induced by LPS. We also showed that the hypermetabolic response of control mice is associated with an upregulation of cytokine expression within the brain and an increase in permeability of the blood brain barrier. LPS-induced anorexia appears to involve peripheral cytokine expression.

Animals↗

PubMed1999

Metabolic fitness in active reduced-obese individuals.

OBJECTIVE: To verify whether a physical activity-low-fat diet follow-up could normalize the metabolic risk profile of reduced-obese men and women having undergone considerable weight loss through energy restriction and drug therapy. RESEARCH METHODS AND PROCEDURES: Twenty obese individuals (12 men, 8 women) participated in a weight-reducing program that included two phases. In the first phase, a non-macronutrient-specific dietary restriction of about 700 kcal/day was prescribed to induce weight loss over 15 weeks, with either fenfluramine or placebo. The second phase consisted of a physical activity-low-fat diet follow-up that was maintained as long as subjects did not experience resistance to further body weight and fat loss. Resistance to lose fat occurred after a mean cumulative fat loss of 14 and 8 kg in men and women, respectively. RESULTS: Despite this substantial decrease in body fat, subjects' adiposity remained much higher at the end of this protocol than values observed in lean control subjects. However, fasting plasma levels of insulin, cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglyceride as well as the response of insulin and glucose to oral glucose were normalized at the end of the physical activity-low-fat diet follow-up. DISCUSSION: These results indicate that further weight and fat losses may not be justified when a moderate body weight loss resulting in a highly favorable improvement of metabolic risk profile is achieved in patients who would have still been diagnosed as overweight or obese on the basis of criteria currently promoted by public health agencies.

Adult↗

PubMed1999

Involvement of serotonergic pathways in mediating the neuronal activity and genetic transcription of neuroendocrine corticotropin-releasing factor in the brain of systemically endotoxin-challenged rats.

The present study investigated the effect of serotonin depletion on the neuronal activity and transcription of corticotropin-releasing factor in the rat brain during the acute-phase response. Conscious male rats received an intraperitoneal (i.p.) injection with the immune activator lipopolysaccaride (25 microg/100 g body wt) after being treated for three consecutive days with para-chlorophenylalanine (30mg/100 g/day). This irreversible inhibitor of tryptophane-5-hydroxylase decreased hypothalamic serotonin levels by 96%. One, 3 and 6 h after a single i.p. injection of lipopolysaccharide or vehicle solution, rats were killed and their brains cut in 30-microm coronal sections. Messenger RNAs encoding c-fos, nerve-growth factor inducible-B gene, corticotropin-releasing factor and the heteronuclear RNA encoding corticotropin-releasing factor primary transcript were assayed by in situ hybridization using 35S-labeled riboprobes, whereas Fos-immunoreactive nuclei were labeled by immunocytochemistry. Lipopolysaccharide induced a wide neuronal activation indicated by the expression of both immediate-early gene transcripts and Fos protein in numerous structures of the brain. The signal for both immediate-early gene transcripts was low to moderate 1 h after lipopolysaccharide administration, maximal at 3 h and decline at 6 h post-injection, whereas at that time, Fos-immunoreactive nuclei were still detected in most of the c-fos messenger RNA-positive structures. Interestingly, the strong and widespread induction of both immediate-early gene transcripts was almost totally inhibited by para-chlorophenylalanine treatment; in the hypothalamic paraventricular nucleus for example, c-fos messenger RNA signal and the number of Fos-immunoreactive positive cells were reduced by 80 and 48%, respectively, in serotonin-depleted rats treated with the bacterial endotoxin. This blunted neuronal response was also associated with an attenuated stimulation of neuroendocrine corticotropin-releasing factor transcription and plasma corticosterone release. Indeed, lipopolysaccharide caused a selective expression of corticotropin-releasing factor primary transcript in the paraventricular nucleus of the hypothalamus and this effect was significantly reduced by treatment with the serotonin inhibitor. However, basal expression of corticotropin-releasing factor messenger RNA across the brain (bed nucleus of the stria terminalis, medial preoptic area, paraventricular nucleus of the hypothalamus, central nucleus of the amygdala, etc.) was not affected by the para-chlorophenylalanine treatment. These results suggest that the integrity of serotonin pathways plays a role in the neuronal activity triggered by the systemic endotoxin insult. The fact that serotonin depletion largely prevented activation of neurosecretory parvocellular neurons of the paraventricular nucleus of the hypothalamus and neuroendocrine corticotropin-releasing factor gene transcription in response to immunogenic challenge provides the evidence that serotonergic system is part of the brain circuitry involved in the corticotroph axis-immune interface.

Amygdala↗

PubMed1999

Dopamine and serotonin interactions in the modulation of the expression of the immediate-early transcription factor, nerve growth factor-inducible B, in the striatum.

Nerve growth factor-inducible B is a closely related member of the steroid-thyroid hormone receptor family of ligand-activated transcription factor. Recent evidence suggests a close relationship between nerve growth factor-inducible B and the dopamine system. Basal expression of messenger RNA for nerve growth factor-inducible B is relatively high in the striatum. The aims of the present study were: (i) to study the basal distribution and the modulation of striatal nerve growth factor-inducible B messenger RNA expression by dopamine and serotonin agonists, and (ii) to investigate the effects of combined administration of dopamine (D) and serotonin (5-HT) agonists. First, we investigated the effects of SKF38393 (D1), quinpirole (D2), 8-hydroxy-2-(di-n-propylaminotetralin) (5-HT1A) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (5-HT2A/2C) administered alone on striatal nerve growth factor-inducible B messenger RNA expression. In a second series of experiments, the effects of a combined administration of dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C agonists were studied. The goal of the last series of experiments was to determine the effects of a combined administration of the dopamine D2 agonist and either serotonin 5-HT1A or 5-HT2A/2C agonists. Our results show that: (i) striatal nerve growth factor-inducible B messenger RNA expression exhibited a lateral-medial gradient in drug-naive rats, (ii) quinpirole and 8-hydroxy-2-(di-n-propylaminotetralin) administered alone induced a significant decrease in striatal nerve growth factor-inducible B messenger RNA expression while 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane significantly increased it, (iii) complex interactions were found when dopamine D1 and serotonin 5-HT1A or 5-HT2A/2C agonists were administered in combination, and (iv) combined administration of quinpirole and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane resulted in a significant decrease in nerve growth factor-inducible B expression. Taken together, these results demonstrate that striatal nerve growth factor-inducible B messenger RNA expression can be modulated by both dopamine and serotonin agonists. They also point out the existence of complex interactions between dopamine and serotonin in regard to striatal expression of the immediate-early transcription factor nerve growth factor-inducible B.

Animals↗

PubMed1999

Brain distribution of UCP2 mRNA: in situ hybridization histochemistry studies.

Uncoupling protein-2 (UCP2) is expressed in large amounts in several tissues. In the mouse brain, in situ hybridization studies have revealed an abundant expression of UCP2 mRNA in the ventral septal region, the hypothalamus, the hindbrain (medulla), the ventricular regions and the cerebellum. In the hypothalamus, a very highly intense hybridization signal is apparent in the suprachiasmatic nucleus, in the medial parvicellular and magnocellular lateral parts of the paraventricular hypothalamic nucleus, and in the arcuate nucleus. In the brainstem, UCP2 is found to be strongly expressed in the dorsal motor nucleus of the vagus nerve. The expression of UCP2 mRNA is also clearly noticeable in the choroid plexuses and in the cerebellum. The expression of UCP2 mRNA in specific regions of the brain as well as its presence in neurons with a known chemical identity suggest that UCP2 mRNA is expressed in neurons. It is as yet premature to conclude about a specific function of UCP2 in the brain. The brain distribution pattern of its transcript suggests that this mitochondrial protein could be part of neuronal circuitries involved in the control of neuroendocrine functions and autonomic responses. Assuming that the UCP2 mRNA encodes a functional uncoupling protein, it can be argued that UCP2 contributes to the metabolic rate and thermoregulation of the neuronal structures to which it is associated. In addition, by elevating oxygen consumption in the brain, UCP2 could in specific regions control the production of reactive oxygen species and thereby influence the process of neural degeneration.

Animals↗

PubMed1999

Effect of a moderate weight loss on adipose tissue lipoprotein lipase activity and expression: existence of sexual variation and regional differences.

OBJECTIVE: To evaluate the impact of moderate body weight loss on both adipose tissue lipoprotein lipase (AT-LPL) activity and expression and to verify whether variation in AT-LPL could be related to changes in lipid-lipoprotein metabolism. DESIGN: Intervention study of a 15-week weight reducing program (energy deficit: 500-800 kcal/d below the subjects' estimated sedentary energy expenditure). SUBJECTS: Thirty two obese subjects (14 men and 18 premenopausal women; aged 36-50 y) whose body fatness ranged from 34 to 54% fat. MEASUREMENTS: Adipose tissue biopsies from the abdominal and femoral depots, various fatness and fat distribution parameters (computed tomography and anthropometry), fasting plasma concentrations of high- and low-density lipoprotein cholesterol (HDL-C, LDL-C), and triglycerides at baseline and 4-6 weeks after the 15-week weight reducing program, when subjects were weight stable. RESULTS: In response to weight loss, AT-LPL activity of both regions did not change in men, but decreased in women. Regarding AT-LPL expression, no interaction between time and sex was observed in response to the treatment. In both genders, the higher was the basal AT-LPL activity, the greater was the reduction of this enzyme activity in response to weight loss, in both the abdominal and femoral depots (-0.53<r<-0.84, P values ranging from 0.0001 to 0.05). Body weight loss promoted a significant reduction in plasma triglyceride (TG), insulin and LDL-cholesterol (C) concentrations in men whereas only plasma TG and LDL-C levels were decreased in women (P<0.05). Although the average reduction in HDL-C levels in response to weight loss was not significant, the higher was the decrease in femoral AT-LPL activity, the greater was the reduction in plasma HDL-C levels (r=0.50, P<0.05) in response to weight loss, in women. An inverse relationship was observed between changes in femoral AT-LPL activity and HDL-C levels variation in men (r=-0.64, P<0.05). CONCLUSION: (1) variation in AT-LPL activity differs between men and women in response to moderate body weight loss although the corresponding enzyme mRNA levels remain unchanged; and (2) changes in femoral AT-LPL activity are related to weight loss induced variation in plasma HDL-C concentrations.

Adipose Tissue↗

PubMed1999

The role of corticotropin-releasing factor and urocortin in the modulation of ingestive behavior.

Participation of the hypothalamo-pituitary-adrenocortical axis, and its primary brain trigger, corticotropin-releasing factor (CRF) in the control of ingestive behavior can be inferred from data suggesting that CRF and its homologue urocortin act in brain to limit appetite following administration in rodents. Moreover, levels of endogenous CRF, CRF(1)and CRF(2)receptors and CRF-binding protein, which sequesters CRF and urocortin, are altered by changes in nutritional status brought about by food restriction/repletion. Mediation of the anorexic effects of CRF and urocortin appear not to privilege CRF(1)receptors, unlike the anxiogenic effects of CRF which are primarily a consequence of CRF(1)receptor activation. Such fear-like consequences of CRF system activation constitute a non-specific mechanism whereby the emergence of behaviors incompatible with food intake may appear to suppress appetite without affecting hunger per se. However, enhanced appetite following administration of CRF receptor antagonists and the involvement of CRF systems in sexual appetite and drug-seeking behavior all suggest a role for CRF in ingestive behavior. In particular, available evidence suggests that physiologically relevant suppression of appetite may accompany CRF system activation occurring as a consequence of stressor exposure induced by nutrient imbalance, for example, or under conditions of excessive intake or consumption of unfamiliar foodstuffs.

Animals↗

PubMed1999

Corticotropin-releasing hormone-binding protein in brain and pituitary of food-deprived obese (fa/fa) Zucker rats.

The present study was conducted to verify whether experimental conditions such as obesity and food deprivation, which promote food intake and reduce thermogenesis, could modify the expression of the corticotropin-releasing hormone (CRH)-binding protein (BP) in the rat brain. In situ hybridization, histochemistry, and immunohistochemistry were used to assess the expression of CRH-BP in lean (Fa/?) and obese (fa/fa) Zucker rats that were fed ad libitum, food deprived for 24 h, or food deprived for 24 h and refed for 6 h. In both lean and obese rats, food deprivation led to a reduction in body weight that was accompanied by a reversible increase in plasma corticosterone levels. Food deprivation and, to a lesser degree, obesity induced the expression of CRH-BP mRNA in the dorsal part of the medial preoptic area (MPOA). This induction of the CRH-BP gene led to by food deprivation was confirmed by the appearance in the dorsal part of the MPOA of neurons immunoreactive to CRH-BP. Food deprivation (in particular) and obesity also increased the levels of CRH-BP mRNA in the basolateral amygdala (BLA). The enhanced CRH-BP expression in the MPOA and BLA in response to food deprivation was reversed by refeeding. In lean Fa/? rats, the CRH-BP mRNA level in the pituitary cells was significantly decreased after food deprivation and restored after refeeding. When food was provided ad libitum, the number of cells expressing CRH-BP in the anterior pituitary was significantly higher in lean rats than in obese animals. Food deprivation for 24 h decreased dramatically the number of pituitary cells expressing CRH-BP in lean rats. Altogether, the present results demonstrate that food deprivation and, to a lesser extent, obesity can selectively affect the expression of CRH-BP. Given both the inactivating effect of CRH-BP on the CRH system and the potential roles played by the MPOA and BLA in the thermogenic and anorectic effects of CRH, it can be argued that the induction of the CRH-BP gene in obesity and after food deprivation occurs as a mechanism to reduce energy expenditure and to stimulate food intake.

Amygdala↗

PubMed1999

Effects of leptin on melanin-concentrating hormone expression in the brain of lean and obese Lep(ob)/Lep(ob) mice.

The effect of leptin on the expression of melanin-concentrating hormone (MCH) was investigated in lean and genetically obese Lepob/Lepob mice. Murine leptin was subcutaneously infused using osmotic minipumps. The treatment period extended to 7 days and the daily dose of leptin delivered was 100 microgram/kg of body weight. In situ hybridization was used to assess the effects of leptin infusion on the expression of MCH mRNA. MCH levels in the brain (hypothalamus/thalamus and the remaining part), spleen and testis were measured by radioimmunoassay coupled to HPLC of selected tissue extracts. Leptin significantly reduced final body weight, weight of brown adipose tissue, daily food intake in obese mice but not in lean animals. In obese mice, leptin led to a rapid reduction in food intake which reached statistical significance after only 24 h and which led to a significant reduction in the body weight after 3 days of treatment. Leptin restored the normal circulating levels of glucose and insulin in obese mice. The present results mainly provide evidence for a stimulating effect of leptin infusion on the MCH neuronal system. The hypothalamic/thalamic levels of MCH mRNA and peptide were higher in mice treated with leptin than in mice infused with phosphate-buffered saline. The stimulation of MCH neurons appeared particularly intense in obese mice, in which the effects of leptin infusion led to the reduction in MCH content of neuron fibers and terminals. Leptin did not affect spleen and testis MCH contents. In the light of the acknowledged orexigenic effects of MCH, the results of this study questioned the direct role of MCH in the action of leptin on energy balance. The increase in MCH expression following leptin could occur as a mechanism to compensate the decrease in energy deposition led to by leptin. It may also indicate that MCH mediates the metabolic actions of leptin indirectly or else that leptin influences actions of MCH other than those related to the regulation of energy balance.

Adipose Tissue, Brown↗

PubMed1999

Response of adipose tissue lipoprotein lipase to the cephalic phase of insulin secretion.

Modulation of lipoprotein lipase (LPL) allows a tissue-specific partitioning of triglyceride-derived fatty acids, and insulin is a major modulator of its activity. The present studies were aimed to assess in rats the contribution of insulin to the response of adipose tissue and muscle LPL to food intake. Epididymal and retroperitoneal adipose LPL rose 65% above fasting values as early as 1 h after the onset of a 30-min high-carbohydrate meal, with a second activity peak 1 h later that was maintained for an additional 2 h. Soleus muscle LPL was decreased by 25% between 0.5 and 4 h after meal intake. The essential contribution of insulin to the LPL response to food intake was determined by preventing the full insulin response to meal intake by administration of diazoxide (150 mg/kg body wt, in the meal). The usual postprandial changes in adipose and muscle LPL did not occur in the absence of an increase in insulinemia. However, the early (60 min) increase in adipose tissue LPL was not prevented by the drug, likely because of the maintenance of the early centrally mediated phase of insulin secretion. In a subsequent study, rats chronically implanted with a gastric cannula were used to demonstrate that the postprandial rise in adipose LPL is independent of nutrient absorption and can be elicited by the cephalic (preabsorptive) phase of insulin secretion. Obese Zucker rats were used because of their strong cephalic insulin response. After an 8-h fast, rats were fed a liquid diet ad libitum (orally, cannula closed), sham fed (orally, cannula opened), or fed directly into the stomach via the cannula during 4 h. Insulinemia increased 10-fold over fasting levels in ad libitum- and intragastric-fed rats and threefold in sham-fed rats. Changes in adipose tissue LPL were proportional to the elevation in plasma insulin levels, demonstrating that the cephalic-mediated rise in insulinemia, in the absence of nutrient absorption, stimulates adipose LPL. These results demonstrate the central role of insulin in the postprandial response of tissue LPL, and they show that cephalically mediated insulin secretion is able to stimulate adipose LPL.

Adipose Tissue↗

PubMed1999

Effect of drastic undernutrition on digestion in Zebu cattle receiving a diet based on rice straw.

The effect of drastic undernutrition was studied in Bos indicus cows. Four nonlactating cows (body weight = 208 kg) fitted with ruminal cannulas were used in a crossover design. They received, in two 1-mo periods, a diet of 80% rice straw and 20% cotton-seed meal fed either at energy maintenance [3.91 kg of dry matter (DM)/d] or at one-third of this intake (1.30 kg of DM/d). The variation in digestibility was studied in relation to particle retention time and microbial events. Organic matter digestibility decreased with underfeeding (64.5 and 53.7%, respectively, at high and low intakes) without modification of mean ruminal or total tract retention times. This lower digestibility can be related to a decrease in protozoal population in the rumen; however, other characteristics of microbial activity did not vary, such as in situ DM degradability (41.9 and 43.3%, respectively, at high and low intakes) and ruminal soluble Ca concentration, a factor involved in the attachment of microorganisms to feed particles. Mean size of ruminal particles was not modified, although more time spent chewing was observed at the low intake (165 and 221 min/kg of DM intake, respectively, at high and low intakes). This experiment confirms that, at intakes below maintenance, digestibility can decrease when feed intake is restricted, contrary to the general view described in the literature.

Ammonia↗

PubMed1998

BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast.

We report here the cloning and functional analysis of a novel homologue of the mitochondrial carriers predominantly expressed in the central nervous system and referred to as BMCP1 (brain mitochondrial carrier protein-1). The predicted amino acid sequence of this novel mitochondrial carrier indicates a level of identity of 39, 31, or 30%, toward the mitochondrial oxoglutarate carrier, phosphate carrier, or adenine nucleotide translocator, respectively, and a level of identity of 34, 38, or 39% with the mitochondrial uncoupling proteins UCP1, UCP2, or UCP3, respectively. Northern analysis of mouse, rat, or human tissues demonstrated that mRNA of this novel gene is mainly expressed in brain, although it is 10-30-fold less expressed in other tissues. In situ hybridization analysis of brain showed it is particularly abundant in cortex, hippocampus, thalamus, amygdala, and hypothalamus. Chromosomal mapping indicates that BMCP1 is located on chromosome X of mice and at Xq24 in man. Expression of the protein in yeast strongly impaired growth rate. Analysis of respiration of total recombinant yeast or yeast spheroplasts and in particular of the relationship between respiratory rate and membrane potential of yeast spheroplasts revealed a marked uncoupling activity of respiration, suggesting that although BMCP1 sequence is more distant from the uncoupling proteins (UCPs), this protein could be a fourth member of the UCP family.

Amino Acid Sequence↗

PubMed1998

Distribution of the uncoupling protein 2 mRNA in the mouse brain.

The present study was conducted to investigate the brain distribution of the recently cloned uncoupling protein 2 (UCP2). Northern blot analyses were first carried out to confirm the presence of UCP2 in the brain. These analyses revealed the brain presence of UCP2 mRNA and the absence of the mRNAs encoding uncoupling protein 1 and uncoupling protein 3. They also demonstrate that UCP2 mRNA expression was abundant in the hypothalamus and not affected by cold acclimation. In situ hybridization histochemistry was used to determine the brain distribution of the mRNA encoding UCP2. A markedly intense hybridization signal was found in the hypothalamus, the ventral septal region, the caudal hindbrain (medulla), the ventricular region, and the cerebellum. A very highly intense hybridization signal was apparent in the suprachiasmatic nucleus, the medial parvicellular part of the paraventricular hypothalamic nucleus, the arcuate nucleus, the dorsal motor nucleus of the vagus nerve, and the choroid plexus. The specifically localized expression of UCP2 mRNA suggests that this mRNA has a neuronal localization. Neuronal expression was particularly manifest in the nucleus of the horizontal limb of the diagonal band, the submedius thalamic nucleus and the dorsal motor nucleus of the vagus nerve, where agglomerations of the silver grains delineated individual cells. The role played by UCP2 in the brain has yet to be fully described, but the pattern of distribution of the transcript suggests that this mitochondrial protein is part of neuronal circuitries controlling neuroendocrine functions, autonomic responses, and the general arousal of the brain. Given the involvement of the proteins from the uncoupling protein's family in the uncoupling of cellular respiration, it can be argued that UCP2 contributes to the metabolic rate and thermoregulation of these circuitries. In addition, by promoting oxygen consumption in the brain, UCP2 could control the production of reactive oxygen species and thereby influence the process of neural degeneration.

Animals↗

PubMed1998

Multicenter, open-label study of recombinant human DNase in cystic fibrosis patients with moderate lung disease. DNase International Study Group.

Cystic fibrosis is characterized by the accumulation of thick viscous purulent secretions. Recombinant human deoxyribonuclease I (rhDNase) breaks down extracellular DNA, which contributes to the increased viscosity of sputum. A multinational, open-label study was conducted in 974 cystic fibrosis patients with moderate lung disease [forced vital capacity (FVC) 40-70% of predicted values] to examine the safety and efficacy of aerosolized rhDNase, 2.5 mg, once daily over a period of at least 12 weeks. Patients were assessed under conditions reflecting routine clinical practice. During rhDNase therapy, at least one respiratory tract infection (RTI) requiring intravenous antibiotics was experienced by 29.5% of patients. Forced expiratory volume in 1 second (FEV1) and FVC were significantly improved from baseline by a mean of 10.5% and 7.2%, respectively. Voice alteration and pharyngitis were the most frequent rhDNase-related adverse events, but only 2% of all patients discontinued treatment due to adverse events. The results obtained were similar to a subanalysis of data from the first 3 months of a placebo-controlled U.S. study. The patients in the present study had a similar frequency of RTIs and improvement in pulmonary function, and reported fewer rhDNase-related and cystic fibrosis-related adverse events than patients in the U.S. study. We conclude that administration of rhDNase is safe, well tolerated, and effective under conditions reflecting routine clinical practice in patients with cystic fibrosis and moderate lung disease.

Administration, Inhalation↗

PubMed1998

Effects of leptin adipose tissue lipoprotein lipase in the obese ob/ob mouse.

OBJECTIVE: To characterize the adaptations of lipid metabolism, with special emphasis on tissue lipoprotein lipase, to negative energy balance brought by chronic treatment of obese ob/ob mice with leptin. DESIGN: According to a 2 x 2 factorial analysis, lean and obese C57BL/6J mice were subcutaneously infused with leptin (100 micrograms.kg-1.day-1) or vehicle (phosphate-buffered saline) during seven days. RESULTS: Cumulative food intake and final body weight of vehicle-infused obese mice were twofold higher than in lean controls. Leptin decreased cumulative food intake and body weight of obese, but not lean mice. Lipoprotein lipase (LPL) activity in white inguinal and epididymal and brown interscapular adipose tissues of control obese mice was at least twofold higher than in lean mice, but comparable in the vastus lateralis muscle. Leptin treatment of obese mice significantly lowered LPL activity to that of lean mice in all tissues examined. Vehicle-infused obese mice had higher liver triglyceride content and were hypertriglyceridemic compared to lean mice, and triglyceride concentrations in plasma and liver were decreased proportionally after leptin treatment. Leptin lowered glycemia and insulinemia of obese mice to lean levels and decreased plasma corticosterone. Leptin infusion had no notable effect on tissue lipoprotein lipase nor plasma variables of lean mice. CONCLUSIONS: Leptin infusion abolished hyperinsulinemia in the ob/ob mouse, an effect that was probably responsible for the concomitant normalization of adipose LPL activity. This study shows that decreased LPL activity, plasma triglyceride concentrations and hepatic triglyceride production constitute some of the adaptive peripheral adaptations of lipid metabolism, which accompany the reduction in fat mass accretion brought by leptin treatment of the obese ob/ob mouse.

Adipose Tissue↗

PubMed1998

Effect of dehydroepiandrosterone on brown adipose tissue and energy balance in mice.

In order to investigate the reported antiobesity action of dehydroepiandrosterone (DHEA), a complete energy balance was made on four groups of mice. Group A was fed the standard Purina diet, group B the same diet to which DHEA was added (0.3%), group C the Purina diet supplemented with palatable high fat food (meat spread), and group D the same diet as group C, to which DHEA was added. Food intake which was larger in groups C and D, was not altered by DHEA treatment. Body weight gain which was comparable for groups A and C, was significantly reduced in the two groups receiving DHEA. The resulting reduced food efficiency caused by DHEA was completely explained by body fat utilization. It was also found that the weight and the protein content of the interscapular brown adipose tissue (BAT) were increased by DHEA treatment suggesting, because of the great thermogenic capacity of this tissue in mice, that it may have been involved in causing the observed reduction in food efficiency. It is also proposed that the action of DHEA may be related to the activation of other tissues such as the liver and muscles. Further investigations are needed to verify this possibility.

Adipose Tissue, Brown↗