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Biomedical subjects

Denis Richard

Publications and source records attributed to Denis Richard.

At least 37 records · Page 2Linked to original sources
PubMed2004

Corticosterone-dependent metabolic and neuroendocrine abnormalities in obese Zucker rats in relation to feeding.

The obese Zucker (fa/fa) rat is characterized by hyperphagia, hyperinsulinemia, an increase in fat deposition, and a hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis in fa/fa rats is hypersensitive to stressful experimental conditions. Food deprivation even leads to a stress reaction in obese fa/fa rats. The present study was conducted to investigate the role of corticosterone in obese rats on the basal, fasting, and postprandial metabolic rate as well as on the central expression of the thyrotropin-releasing hormone (TRH) in these conditions. In addition, the study was aimed at clarifying whether the high levels of corticosterone in obese rats are responsible for the induction of the stress reaction to food deprivation in these animals. The present results demonstrate that whole body fat oxidation and postprandial metabolic responses in obese Zucker rats were improved by adrenalectomy (ADX). At the level of the central nervous system, ADX reversed a decrease in TRH mRNA expression in the paraventricular hypothalamus (PVH) detected in fasting animals. Considering all feeding conditions, the obese rats demonstrated lower TRH mRNA levels compared with lean animals. ADX resulted in an enhanced postprandial activation of the parvocellular PVH. In contrast, the magnocellular part of the PVH was less responsive to refeeding in ADX animals. Finally, ADX failed to prevent the stress response of obese rats to food deprivation. The present results provide evidence that the removal of adrenals resolve some of the metabolic defects encountered in obese Zucker rats. They also demonstrate that not all the abnormalities of the obese Zucker rats are attributable to the hyperactivity of the HPA axis.

Animals↗
PubMed2004

Actions of PPARgamma agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists improve insulin sensitivity and lipemia partly through enhancing adipose tissue proliferation and capacity for lipid retention. The agonists also reduce local adipose glucocorticoid production, which may in turn contribute to their metabolic actions. This study assessed the effects of a PPARgamma agonist in the absence of glucocorticoids (adrenalectomy, ADX). Intact, ADX, and intact pair-fed (PF) rats were treated with the PPARgamma agonist rosiglitazone (RSG) for 2 wk. RSG increased inguinal (subcutaneous) white (50%) and brown adipose tissue (6-fold) weight but not that of retroperitoneal (visceral) white adipose tissue. ADX but not PF reduced fat accretion in both inguinal and retroperitoneal adipose depots but did not affect brown adipose mass. RSG no longer increased inguinal weight in ADX and PF rats but increased brown adipose mass, albeit less so than in intact rats. RSG increased cell proliferation in white (3-fold) and brown adipose tissue (6-fold), as assessed microscopically and by total DNA, an effect that was attenuated but not abrogated by ADX. RSG reduced the expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) in all adipose depots. RSG improved insulin sensitivity (reduction in fasting insulin and homeostasis model assessment of insulin resistance, both -50%) and triacylglycerolemia (-75%) regardless of the glucocorticoid status, these effects being fully additive to those of ADX and PF. In conclusion, RSG partially retained its ability to induce white and brown adipose cell proliferation and brown adipose fat accretion and further improved insulin sensitivity and lipemia in ADX rats, such effects being therefore independent from the PPARgamma-mediated modulation of glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2004

Peroxisome proliferator-activated receptor gamma agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.

Adipose Tissue↗
PubMed2004

The brown adipocyte: update on its metabolic role.

Brown adipocytes are multilocular lipid storage cells that play a crucial role in non-shivering thermogenesis. These cells are located in brown adipose tissue (BAT) depots which are found in abundance in small mammals as well as in newborns of larger mammals, including humans. Brown adipocytes comprise a very large number of mitochondria packed with cristae and are densely innervated by the sympathetic nervous system (SNS). Sympathetic nerve endings release noradrenaline (NA) in the proximity of brown fat cells, where noradrenaline activates G-protein-coupled beta-adrenergic receptors (AR) and by doing so initiates a cascade of metabolic events culminating in the activation of uncoupling protein 1 (UCP1). Uncoupling protein 1 is a unique feature of brown adipocytes that allows for the generation of heat upon sympathetic nervous system stimulation. It is found in the inner membrane of the mitochondrion, where uncoupling protein 1 uncouples the oxidation of fuel from adenosine triphosphate (ATP) production. The expression of uncoupling protein 1 is strongly induced by cold exposure, revealing the importance of this uncoupling protein in thermoregulation. The thermoregulatory role of uncoupling protein 1 has been emphasized in uncoupling protein 1-deficient mice, whose resistance to cold is impaired. Uncoupling protein 1 expression is modulated by diet and metabolic hormones such as leptin and glucocorticoids, which suggests that the protein is a player in energy balance regulation.

Adipocytes↗
PubMed2004

A role for lipoprotein lipase during synaptic remodeling in the adult mouse brain.

Lipoprotein lipase (LPL) is a member of a lipase family known to hydrolyze triglyceride molecules found in lipoprotein particles. This particular lipase also has a role in the binding of lipoprotein particles to different cell-surface receptors. LPL has been identified in the brain but has no specific function yet. This study aimed at elucidating the role of LPL in the brain in response to injury. Mice were subjected to hippocampal deafferentation using the entorhinal cortex lesion and mRNA and protein expression were assessed over a time-course of degeneration/reinnervation. Hippocampal LPL levels peaked at 2 days post-lesion (DPL) both at the mRNA and protein levels. No change was observed for receptors of the LDL-receptor family or RAP at DPL 2 in the hippocampus but the glia-specific syndecan-4 was found to be significantly upregulated at DPL 2. These results suggest that LPL is involved in the recycling of cholesterol and lipids released from degenerating terminals after a lesion through a syndecan-4-dependent pathway.

Animals↗
PubMed2004

Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice.

The objective of the present study was to investigate the effects of the antiepileptic drug topiramate (TPM) on components of energy balance in lean and obese (ob/ob) mice in the presence or absence of leptin. Lean and ob/ob mice infused with either leptin or phosphate-buffered saline were treated with TPM for 7 days. TPM was mixed into the diet and administered at a dose of 60 mg/kg/day, whereas leptin was infused at the rate of 100 microg/kg/day using osmotic minipumps, which were subcutaneously implanted in the interscapular region. Food intake and body weight were monitored throughout the study. Body composition was measured prior to and following treatment with TPM and leptin, using dual-energy X-ray absorptiometry (DEXA). Glucose (glucose oxidase method) and insulin (radioimmunoassay) were also determined. TPM and leptin significantly reduced body weight gain, food intake and body fat gain in obese mice. The effects of TPM and leptin on fat gain were also statistically significant in lean animals. There was no interaction of TPM and leptin on the energy balance variables, the effects of the two substances being additive instead. Leptin abrogated hyperinsulinemia in obese mutants whereas TPM did not alter insulin levels in either lean or obese mice. The combination of leptin and TPM led to the normalization of glucose levels in obese mice. Our study demonstrates an effect of TPM in leptin-deficient animals, which suggests that TPM does not require the presence of leptin to exert its effect. They also show that the effects of leptin and TPM can be additive. The treatment with leptin in ob/ob mice neither accentuated nor blunted the effect of TPM on energy balance.

Adipose Tissue↗
PubMed2004

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection.

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

Adipocytes↗
PubMed2004

A survey of genes differentially expressed in subcutaneous and visceral adipose tissue in men.

Adipose tissue located within the abdominal cavity has been suggested to be functionally and metabolically distinct from that of the subcutaneous compartment. These differences could play a role in obesity-related complications. The aim of this study was to compare gene expression profiles of subcutaneous and visceral adipose tissues of 10 nondiabetic, normolipidemic obese men. Affymetrix human U133A arrays (10 arrays for subcutaneous fat samples and 10 arrays for visceral fat samples) were used. Differential gene expression was confirmed by real-time polymerase chain reaction in a subset of genes. A total of 5894 transcripts were detected in both depots in all 10 subjects, and 409 transcripts representing 347 encoded genes were differentially expressed. Of these, 131 genes were expressed at higher levels in subcutaneous adipose tissue, and 216 were expressed more abundantly in visceral fat. Differentially expressed profiles included genes of the Wnt signaling pathway, as well as CEPBA and HOX genes. In addition, genes involved in lipolytic stimuli and cytokine secretion were differentially expressed. The identification of a consistent and rather uniform pattern of differentially expressed genes between the two fat depots using multiple array replicates (10 arrays per fat compartment) generated new perspectives for future research on regional differences in adipose tissue biology.

Abdomen↗
PubMed2004

Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels.

Uncoupling protein 2 (UCP2) is suggested to be a regulator of reactive oxygen species production in mitochondria. We performed a detailed study of brain injury, including regional and cellular distribution of UCP2 mRNA, as well as measures of oxidative stress markers following permanent middle cerebral artery occlusion in UCP2 knockout (KO) and wild-type (WT) mice. Three days post ischemia, there was a massive induction of UCP2 mRNA confined to microglia in the peri-infarct area of WT mice. KO mice were less sensitive to ischemia as assessed by reduced brain infarct size, decreased densities of deoxyuridine triphosphate nick end-labelling (TUNEL)-labelled cells in the peri-infact area and lower levels of lipid peroxidation compared with WT mice. This resistance may be related to the substantial increase of basal manganese superoxide dismutase levels in neurons of KO mice. Importantly, we found a specific decrease of mitochondrial glutathione (GSH) levels in UCP2 expressing microglia of WT, but not in KO mice after ischemia. This specific association between UCP2 and mitochondrial GSH levels regulation was further confirmed using lipopolysaccharide models of peripheral inflammation, and in purified peritoneal macrophages. Moreover, our data imply that UCP2 is not directly involved in the regulation of ROS production but acts by regulating mitochondrial GSH levels in microglia.

Animals↗
PubMed2004

Hormone-sensitive lipase-independent adipocyte lipolysis during beta-adrenergic stimulation, fasting, and dietary fat loading.

In white adipose tissue, lipolysis can occur by hormone-sensitive lipase (HSL)-dependent or HSL-independent pathways. To study HSL-independent lipolysis, we placed HSL-deficient mice in conditions of increased fatty acid flux: beta-adrenergic stimulation, fasting, and dietary fat loading. Intraperitoneal administration of the beta(3)-adrenergic agonist CL-316243 caused a greater increase in nonesterified fatty acid level in controls (0.33 +/- 0.05 mmol/l) than in HSL(-/-) mice (0.12 +/- 0.01 mmol/l, P < 0.01). Similarly, in isolated adipocytes, lipolytic response to CL-316243 was greatly reduced in HSL(-/-) mice compared with controls. Fasting for <or=48 h produced normal mobilization and oxidation of fatty acids in HSL(-/-) mice, as judged by similar values of respiratory quotient and oxygen consumption as in HSL(+/+) controls. In isolated adipocytes, lipolysis in the absence of beta-adrenergic stimulation was 1.9-fold greater in HSL(-/-) than in HSL(+/+) cells (P < 0.05), increasing to 6.5-fold after fasting (P < 0.01). After 6 wk of a fat-rich diet containing 31.5% of energy as lipid, weight gain of HSL(-/-) mice was 4.4-fold less than in HSL(+/+) mice (P < 0.01), and total abdominal fat mass was 5.2-fold lower in HSL(-/-) than in HSL(+/+) mice (P < 0.01). In white adipose tissue, HSL is essential for normal acute beta-adrenergic-stimulated lipolysis and permits normal triglyceride storage capacity in response to dietary fat loading. However, HSL-independent lipolysis can markedly increase during fasting, both in isolated adipocytes and in intact mice, and can mediate a normal flux of fatty acids during fasting.

Adipocytes↗
PubMed2004

The corticotropin-releasing factor system as a potential target for antiobesity drugs.

Corticotropin-releasing factor (CRF)-related peptides are involved in numerous physiological and behavioral actions, including activation of the pituitary-adrenal axis, stimulation of anxiety-related behaviors and modulation of cardiovascular and gastrointestinal functions. They are also capable of strong anorectic and thermogenic effects. In fact, the CRF system, which promotes a negative energy profile upon activation, could represent a potential target for the pharmacological treatment of obesity. The recent identification of two endogenous ligands for the CRF(2) receptor, urocortins 2 and 3, and the development of selective CRF receptor antagonists, has paved the way for improving our understanding of the specific physiological roles played by each CRF receptor. Based on recent progress, we conclude that the CRF(2) receptor could be a potential target for the development of an antiobesity drug.

Animals↗
PubMed2004

Circuitries involved in the control of energy homeostasis and the hypothalamic-pituitary-adrenal axis activity.

The regulation of bodyweight is a complex process involving the interplay of neuronal circuitries controlling food intake and energy expenditure (thermogenesis) with endocrine secretions modulating the activity of the neurons making up those circuitries. The neurons controlling food intake and thermogenesis also modulate the hypothalamic-pituitary-adrenal axis, the role of which in the regulation of energy balance has been acknowledged for some time. These neurons secrete various neuromolecules or neuropeptides including endocannabinoids, neuropeptide Y, agouti-related protein, melanin-concentrating hormone, orexins (hypocretins), melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, corticotropin-releasing hormone, and urocortins. Among those peptides, neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, orexins, and endocannabinoids have been classified as being anabolic molecules whereas melanocortins, cocaine- and amphetamine-regulated transcript, thyrotropin-releasing hormone, and corticotropin-releasing hormone are referred to as catabolic peptides. The expression and secretion of these neuromolecules are known to be affected by the anabolic (corticosteroids and ghrelin) and catabolic (leptin, insulin, and glucagon-like peptide 1) peripheral hormones. A link is made between the pathways regulating energy balance and those modulating the activity of the hypothalamic-pituitary-adrenal axis.

Animals↗
PubMed2004

Mother to infant or infant to mother? Reciprocal regulation of responsiveness to stress in rodents and the implications for humans.

Optimal early development in most species is dependent upon a stable relationship between the mother and her infant. The research described here focuses on the reciprocal nature of this dyad in rodents and humans, with respect to the regulation of responsiveness to stress in both mother and offspring. Dietary influences are critical not only to regulate infant growth but also to modulate the response of the neuroendocrine system to stress and, possibly, to influence some aspects of brain development. In particular, we discuss the role of leptin, a protein produced in the adipose tissue and present in maternal milk, that reduces responses to stress in the infant. We suggest that leptin acts on both central (hypothalamus and hippocampus) and peripheral (pituitary, adrenal gland) targets in the infant to reduce exposure to glucocorticoids and enhance hippocampal development during a sensitive period of brain development. There is also evidence to support the reverse regulatory influence, in which maternal state is profoundly affected by stimulation from the young. During the period of lactation, mothers exhibit lower neuroendocrine and behavioural responses to several types of stressors, except possibly those representing a threat to the infant. This ability to "filter" relevant from irrelevant stimuli while caring for their young might be viewed as adaptive for the mother-infant dyad, and the inability to filter adequately stressful stimuli could at least in part be associated with the development of postpartum depression.

Animals↗
PubMed2003

Kainic acid upregulates uncoupling protein-2 mRNA expression in the mouse brain.

Intraperitoneal injection of kainic acid (KA) in C57BL/6J and 129T2SvEmsJ mice led to a transient induction of uncoupling protein-2 (Ucp2) mRNA expression in several brain regions, which included the CA1 subfield of the hippocampus, the dorsal endopiriform nucleus and the piriform cortex in both strains. In all those regions, levels of Ucp2 mRNA expression, as determined by in situ hybridization, peaked at 24 h and returned to basal levels within 72 h post-injection. The increase in mRNA expression was mainly observed in neurons, with microglial cells displaying only scattered expression of the gene. The neuronal induction of Ucp2 in response to KA was stronger in 129T2SvEmsJ mice than in C57BL/6J, which suggests a role for Ucp2 in excitotoxic challenges and neuroprotection.

Animals↗
PubMed2003

Uncoupling protein 2, but not uncoupling protein 1, is expressed in the female mouse reproductive tract.

Uncoupling proteins (UCPs) are transporters of the inner mitochondrial membrane. Whereas UCP1 is uniquely present in brown adipose tissue where it uncouples respiration from ATP synthesis and activates respiration and heat production, UCP2 is present in numerous tissues, and its exact function remains to be clarified. Two sets of data provided the rationale for this study: (i) the intriguing report that UCP1 is present in uterus of mice (Nibbelink, M., Moulin, K., Arnaud, E., Duval, C., Penicaud, L., and Casteilla, L. (2001) J. Biol. Chem. 276, 47291-47295); and (ii) an observation that Ucp2(-/-) female mice (homozygous matings) have smaller litters compared with Ucp2(+/+) animals (S. Rousset and A.-M. Cassard-Doulcier, unpublished observations). These data prompted us to examine the expression of UCP1 and UCP2 in the reproductive tract of female mice. Using wild type, Ucp1(-/-) mice, and Ucp2(-/-) mice, we were unable to detect UCP1 in uterus of mice with appropriate antibodies, and we conclude that the signal assigned to UCP1 by others was neither UCP1 nor UCP2. Using a polyclonal antibody against UCP2 and tissues from Ucp2(-/-) mice as controls, UCP2 was detected in ovary, oviduct, and uterus. Expression of Ucp2 mRNA was also observed in ovary and uterus using in situ hybridization analysis. Bone marrow transplantation experiments revealed that the UCP2 signal of the ovary was restricted to ovarian cells. UCP2 level in ovary decreased during follicular growth and increased during the pre-ovulatory period, during which aspects of an inflammatory process are known to exist. Because UCP2 down-regulates reactive oxygen species, a role in the regulation of inflammatory events linked to the preparation of ovulation is suggested.

Adenosine Triphosphate↗
PubMed2003

The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet- and ovariectomy-induced obesity.

OBJECTIVE: EM-652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat. This study aimed to assess the ability of EM-652, alone or with dehydroepiandrosterone (DHEA), to prevent obesity and related metabolic abnormalities induced by an obesity-promoting diet and ovariectomy. RESEARCH METHODS AND PROCEDURES: Female rats were fed a high-sucrose, high-fat (HSHF) diet, were left intact or ovariectomized (OVX), and were treated with EM-652, DHEA, or both for 20 days. Variables of energy balance and determinants of lipid metabolism and insulin sensitivity were assessed. RESULTS: The HSHF diet (vs. chow) and OVX both increased energy intake and gain, as well as energetic efficiency. Both EM-652 and DHEA prevented diet- and OVX-induced energy gain mainly by decreasing fat deposition, without being additive. The modest EM-652-induced increase in liver triglycerides of intact rats was prevented by its combination with DHEA. EM-652, but not DHEA, decreased cholesterolemia. The HSHF diet and OVX reduced insulin sensitivity, an effect that was attenuated by EM-652 and abrogated by DHEA and EM-652+DHEA. Treatment with EM-652, DHEA, or their combination abolished the diet- and OVX-induced increase in adipose lipoprotein lipase activity that accompanied fat gain. DISCUSSION: EM-652 is an effective agent to prevent diet- and OVX-induced obesity and its associated cardiovascular risk factors such as insulin resistance. The addition of DHEA prevents hepatic lipid accumulation and further ameliorates insulin sensitivity. The beneficial metabolic effects of such combined steroid therapy may, therefore, eventually prove to be clinically relevant.

Adipose Tissue↗
PubMed2003

Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear hormone receptors expressed in tissues that preferentially metabolize fatty acids. Despite the molecular characterization of ERRalpha and identification of target genes, determination of its physiological function has been hampered by the lack of a natural ligand. To further understand the in vivo function of ERRalpha, we generated and analyzed Estrra-null (ERRalpha-/-) mutant mice. Here we show that ERRalpha-/- mice are viable, fertile and display no gross anatomical alterations, with the exception of reduced body weight and peripheral fat deposits. No significant changes in food consumption and energy expenditure or serum biochemistry parameters were observed in the mutant animals. However, the mutant animals are resistant to a high-fat diet-induced obesity. Importantly, DNA microarray analysis of gene expression in adipose tissue demonstrates altered regulation of several enzymes involved in lipid, eicosanoid, and steroid synthesis, suggesting that the loss of ERRalpha might interfere with other nuclear receptor signaling pathways. In addition, the microarray study shows alteration in the expression of genes regulating adipogenesis as well as energy metabolism. In agreement with these findings, metabolic studies showed reduced lipogenesis in adipose tissues. This study suggests that ERRalpha functions as a metabolic regulator and that the ERRalpha-/- mice provide a novel model for the investigation of metabolic regulation by nuclear receptors.

Adipose Tissue↗