Biomedical subjects

L Pénicaud

Publications and source records attributed to L Pénicaud.

At least 19 recordsLinked to original sources

PubMed2006

Weight-dependent changes of immune system in adipose tissue: importance of leptin.

Ancestral lymphoid cells reside in adipose tissues, and their numbers are highly altered in obesity. Leptin, production of which is correlated to fat mass, is strongly involved in the relationships between adipose tissues and immune system. We investigated in epididymal (EPI) and inguinal (ING) fat pads to determine whether 1) lymphocyte phenotypes were correlated to the tissue weight and 2) leptin was involved in such relationships. Immunohistological analyses revealed a tight relationship between the T and NK lymphocytes of the stromal vascular fraction and adipocytes. We identified a significant negative and positive correlation between EPI weight and the percentage of NK and total T cells respectively by cytofluorometric analyses. The NK and ancestral gammadelta T cell contents were directly dependent of leptin since they increased significantly in high-fat (HF) diet mice but not in leptin-deficient (ob/ob) mice as compared to control. By contrast, the alphabeta T cell content seemed independent of leptin because their percentages increased significantly with the EPI weight whatever the type of mice (control, HF, ob/ob). The present study suggests that adipose tissues present, according to their localization, different immunological mechanisms that might be involved in the regulation of adipose cells functions and proliferations.

Adipose Tissue↗

PubMed2005

Adipose tissues as an ancestral immune organ: site-specific change in obesity.

Close relationships have been demonstrated between adipose tissue and the inflammatory/immune system. Furthermore, obesity is increasingly considered as a state of chronic inflammation. Cytofluorometric analysis reveals the presence of significant levels of lymphocytes in the stroma-vascular fraction of white adipose tissues. In epididymal (EPI) fat, lymphocytes display an "ancestral" immune system phenotype (up to 70% of natural killer (NK), gammadelta+ T and NKT cells among all lymphocytes) whereas the inguinal (ING) immune system presents more adaptive characteristics (high levels of alphabeta+ T and B cells). The percentage of NK cells in EPI fat was decreased in obese mice fed with a high-fat diet, whereas gammadelta positive cells were significantly increased in ING fat. These data support the notion that adipose tissue may elaborate immunological mechanisms to regulate its functions which might be altered in obesity.

Adipose Tissue↗

PubMed2005

Tumor necrosis factor-alpha stimulates HIV-1 production in primary culture of human adipocytes.

Adipose tissue of HIV-1-infected patients shows severe abnormalities such as profound changes in adipose tissue morphology and metabolism. Does HIV-1 infect the adipose cell remains an unsolved question since previous attempts showed that HIV-1 poorly infects human adipocytes in vitro. In the present study, preadipose cells from human subcutaneous fat pads were differentiated in vitro, checked for HIV receptor expression, then infected with R5 and X4 HIV1 strains. Using a sensitive RT-PCR assay, we showed that HIV-1 tat and rev early viral transcripts were expressed in infected adipocytes giving a clear evidence of HIV-1 transcriptional activity in these cells. However, at the same time, no sign of productive infection was demonstrated since infected adipocytes did not efficiently produce Gag p24 antigen. We hypothesized that such a limitation could result from the lack of activation of adipocyte-signaling pathways able to stimulate HIV-1 gene expression in quiescent adipocytes. Indeed, a significant increase in Gag p24 production was observed after stimulation of infected adipocytes with pro-inflammatory cytokines, such as tumor necrosis factor alpha or interleukin-1-beta. Taken together, these results demonstrate that HIV-1 does infect human adipose cells in vitro and suggest that the initial limited infection can be overcome upon pro-inflammatory cytokine treatment.

Adipocytes↗

PubMed2005

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice.

AIMS/HYPOTHESIS: Fibrates and thiazolidinediones are commonly used for the treatment of dyslipidemia and type 2 diabetes, respectively. The aim of this study was to investigate the effects on body weight as well as on glucose and lipid homeostasis of ligands for PPARalpha and PPARgamma, Fenofibrate and Rosiglitazone, alone or in association. METHODS: Ob/ob mice were divided into four groups: control, and mice daily injected (intraperitoneally), either with 10 mg/kg Rosiglitazone, 100 mg/kg Fenofibrate or both molecules. Body weight and food intake were monitored daily. After 13 days of treatment, mice were killed, and blood samples were collected for posterior metabolite quantification. The liver and adipose tissues were dissected and weighed. RESULTS: Body weight was significantly reduced or increased by Fenofibrate and Rosiglitazone, respectively. The effect of Rosiglitazone was prevented by coadministration of Fenofibrate. This was accompanied by a normalization of the daily food efficiency. Compared to those treated with Rosiglitazone, animals treated with Fenofibrate alone or in combination presented a decreased white adipose tissue mass. Fenofibrate or Rosiglitazone alone significantly reduced the levels of plasma lipid parameters. Surprisingly, Fenofibrate also decreased blood glucose levels in ob/ob mice, despite having no effect on insulin levels. By contrast, both glucose and insulin levels were decreased by Rosiglitazone treatment. Coadministration of both drugs improved all parameters as with Rosiglitazone. Fenofibrate restored almost normal hepatocyte morphology and significantly reduced the triglyceride content of the liver. This was accompanied by an increase in fatty acid oxidation in the liver in all groups receiving Fenofibrate. CONCLUSION/INTERPRETATION: These biological effects suggest that combined therapy with a PPARalpha and a PPARgamma ligand is more effective in ameliorating, specifically, lipid homeostasis than in activating any of this receptor separately. Furthermore, Fenofibrate prevents one of the most undesirable effects of Rosiglitazone, namely increased adiposity and body weight gain.

Animals↗

PubMed2005

Plasticity of adipose tissue: a promising therapeutic avenue in the treatment of cardiovascular and blood diseases?

The adipose tissue represents a large amount of adult tissues. For long time, it was considered as a poorly active overgrown and undesirable tissue even if its usefulness was demonstrated in reconstructive surgery. It was studied for its main involvement in energy metabolism and disorders as diabetes and obesity. More recently, its endocrine functions emerged and appeared to play a key role in many physiological situations such as inflammation and immunity. The presence of preadipocytes throughout life was demonstrated using primary culture technology from cells derived from adipose tissue. These cells can display a macrophagic or endothelial potential according to their environment and could be now considered as vascular progenitors. Differentiation of various adipose derived cell subsets towards functional cardiomyocytes, osteoblasts, haematopoietic and neural cells was also obtained in vitro. Altogether, these data emphasise the need to consider with a new look preadipocyte status and adipose tissue biology. These spectacular data, together with the fact that adipose tissue is easy to obtain lead to numerous and promising perspectives in regenerative medicine. They highlight the concept that progenitor cells from adipose tissue constitute an alternative for cells-based strategies designed for the treatment of cardiovascular diseases.

Adipose Tissue↗

PubMed2004

Acute intracarotid glucose injection towards the brain induces specific c-fos activation in hypothalamic nuclei: involvement of astrocytes in cerebral glucose-sensing in rats.

The detection of changes in glucose level constitutes the first step of the control of glucose homeostasis. Glucose sensors are therefore expected to be present in different parts of the body and particularly in the central nervous system. Some studies have already attempted to determine glucose-sensitive cerebral structures either after a glucoprivic stimulus or after prolonged hyperglycaemia. By analogy to beta cells, it was postulated that the glucose sensors in the brain could involve GLUT2, glucokinase and/or ATP-sensitive K(+) channels. Surprisingly, GLUT2 was mainly found in astrocytes. Thus, the aims of the present investigation were to determine, in awake rats: (i) the hypothalamic areas that respond to acute hyperglycaemic condition induced by an intracarotid injection of glucose and (ii) the involvement of astrocytes in glucose-sensing by the use of a glial drug, methionine sulfoximine. Rats were given intracarotid injections of glucose solution to trigger a transient insulin secretion without change in peripheral glycaemia, thus involving only central nervous regulation. Hypothalamic activation was determined by immunodetection of the immediate early gene c-fos protein. Acute glucose injection induces significant activation of arcuate and paraventricular nuclei. This stimulation mainly affects neurones in both nuclei, but also astrocytes in the former as illustrated by double immunohistochemistry (Fos and neuronal nuclei or glial fibrillary acidic protein). After specific impairment of astrocyte metabolism by methionine sulfoximine, cerebral activation disappears in the arcuate nucleus, correlated with the lack of cerebral glucose-induced insulin secretion. Therefore, arcuate and paraventricular hypothalamic nuclei are able to detect acute cerebral hyperglycaemia, leading to a peripheral stimulation of insulin secretion. Arcuate nucleus and more especially astrocytes in this nucleus play a pivotal role in glucose-sensing.

Animals↗

PubMed2003

Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells.

Cardiomyocyte regeneration is limited in adult life. Thus, the identification of a putative source of cardiomyocyte progenitors is of great interest to provide a usable model in vitro and new perspective in regenerative therapy. As adipose tissues were recently demonstrated to contain pluripotent stem cells, the emergence of cardiomyocyte phenotype from adipose-derived cells was investigated. We demonstrated that rare beating cells with cardiomyocyte features could be identified after culture of adipose stroma cells without addition of 5-azacytidine. The cardiomyocyte phenotype was first identified by morphological observation, confirmed with expression of specific cardiac markers, immunocytochemistry staining, and ultrastructural analysis, revealing the presence of ventricle- and atrial-like cells. Electrophysiological studies performed on early culture revealed a pacemaker activity of the cells. Finally, functional studies showed that adrenergic agonist stimulated the beating rate whereas cholinergic agonist decreased it. Taken together, this study demonstrated that functional cardiomyocyte-like cells could be directly obtained from adipose tissue. According to the large amount of this tissue in adult mammal, it could represent a useful source of cardiomyocyte progenitors.

Adipose Tissue↗

PubMed2003

Human adipose cells as candidates in defense and tissue remodeling phenomena.

Macrophages are part of the immunity defense mechanism via oxidative burst and phagocytosis. They are also involved in tissue remodeling via cytokine secretion and apoptotic body clearance. Previously, we demonstrated that adipose cells and macrophages share some of their features and functions. Our aim was to further test this hypothesis in humans. We first demonstrated that human preadipocytes exhibit phagocytosis of yeast, this effect being specific compared to another fibroblastic cell type, the skin fibroblast. Furthermore, as in rodents, human preadipocytes exhibit anti-microbial activity. Finally, for the first time, it was shown that these cells were able to phagocyte apoptotic lymphocytes. Altogether, these data suggest an active involvement of fat cells in host defense and tissue remodeling, which might play an important role at the level of the whole organism due to the large amount of adipose tissue. This gives support for some observations linking obesity or cachexia to immunological disorders.

Adipocytes↗

PubMed2003

Cerebral insulin increases brain response to glucose.

The hypothalamus participates in the regulation of carbohydrate metabolism involving a feedback loop between the brain and the periphery in which glucose-sensitive hypothalamic areas appear to be involved. We have previously shown that a glucose injection (9 mg/kg) in the carotid artery toward the brain, in an amount that did not modify glycaemia, caused a rapid and transient increase in plasma insulin concentrations. To determine whether central insulin could influence this response, we investigated the change in central glucose-induced insulin secretion in intracerebroventricular (i.c.v) insulin-injected rats and in hyperinsulinaemic obese Zucker rats. Central glucose-induced insulin secretion was increased by 50% in i.c.v. insulin-injected rats compared to control rats. When a similar test was performed at a lower dose of glucose (3 mg/kg), a significant insulin secretion was observed only in rats submitted to a prior central insulin injection. These data indicate an increase in the brain response to glucose after insulin treatment. Using an identical lower glucose dose, we also demonstrated an enhanced brain glucose sensitivity in hyperinsulinaemic and insulin-resistant obese Zucker rats. Together, these results indicate that acute i.c.v. insulin or pathological hyperinsulinaemic state (i.e. obese Zucker rat) modulates the nervous control of insulin secretion by increasing the brain response to glucose.

Animals↗

PubMed2003

Therapeutic perspectives for melatonin agonists and antagonists.

Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases.

Animals↗

PubMed2002

Pancreatic beta-cell alpha2A adrenoceptor and phospholipid changes in hyperlipidemic rats.

We previously showed that a 48-h intravenous lipid infusion in rats induces pancreatic beta-cell hypersensitivity to catecholamines. Our aim was to study the lipid-related changes that may account for such hypersensitivity in pancreatic islets. We show here that a 48-h increase in plasma FFA alters the binding characteristics of beta-cell alpha2 adrenoceptors in rats. Lipid infusion decreases pancreatic norepinephrine (NE) turnover rate by 28%, reflecting a reduction of pancreatic NE stores. Following lipid infusion, the density of alpha2 adrenoceptor binding sites is significantly lower and receptor affinity higher, both in islet homogenates (by three- and fivefold, respectively) and isolated whole beta-cells (by two- and sixfold, respectively). These changes correlate with the elevated insulin response to glucose found in lipid-infused rats. We also found a modification of islet phospholipid content, particularly in phosphoethanolamine species containing infused FA such as palmitate, oleate, stearate, and linoleate. This may account for the modifications in receptor affinity. These results suggest that hyperlipidemia-associated pathologies such as diabetes and obesity not only may result from alterations of metabolic pathways but also may be a consequence of early modifications in nervous firing rates and signal transduction pathways.

Animals↗

PubMed2001

Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells.

Until now, uncoupling protein 1 (UCP1) was considered as unique to brown adipocytes. It supports a highly regulated uncoupling of oxidative phosphorylation that is associated with diet as well as with non-shivering thermogenesis. Here we report that UCP1 is not specific to brown adipocytes and can be expressed in longitudinal smooth muscle layers. In the uterus, this conclusion was drawn from different convergent data. A specific antibody against mouse UCP1 revealed, in mitochondrial fractions, a protein with the same molecular weight as brown fat UCP1. Sensitive and specific reverse transcriptase-polymerase chain reaction detected a mRNA whose sequence was totally homologous to that of brown fat UCP1 mRNA. Antibody against UCP1 as well as a UCP1 antisense probe specifically stained uterine longitudinal smooth muscles. UCP1 was also expressed in longitudinal smooth muscle of digestive and male reproductive tracts but was never expressed in other types of smooth muscle, including those of arterial vessels. In uterine tract, UCP1 content was increased after cold exposure or beta-adrenergic agonist treatment. It was also up-regulated during the postovulatory period after sexual cycle synchronization. Its content transiently increased during gestation and decreased markedly after birth. These regulations strongly argue about a role for UCP1 in thermogenesis as well as in relaxation of longitudinal smooth muscle layers.

Adipose Tissue, Brown↗

PubMed2001

Altered Glut4 mRNA levels in specific brain areas of hyperglycemic-hyperinsulinemic rats.

The insulin sensitive glucose transporter Glut4 is expressed in neurons of the brain among which those of hypothalamic nuclei. It has been proposed that this transporter might be involved in the hypothalamic glucose-insulin sensing mechanism and thus in the nervous regulation of metabolism. In order to get further insights into its putative role, Glut4 expression was analyzed by quantitative competitive reverse transcription-polymerase chain reaction, in hypothalamic nuclei of hyperglycemic-hyperinsulinemic (HG-HI) rats, a model characterized by alteration of the autonomic nervous system activity. Glut4 mRNA content was decreased in the lateral hypothalamic area (33%) and arcuate nucleus (27%) but significantly only in the former. It was unchanged in other structures. These results are in favor of an alteration of Glut4 expression by short-term hyperglycemia and hyperinsulinemia that, in turn, could affect autonomic nervous system activity.

Animals↗

PubMed2001

Emergence during development of the white-adipocyte cell phenotype is independent of the brown-adipocyte cell phenotype.

In mammals, two types of adipose tissue are present, brown and white. They develop sequentially, as brown fat occurs during late gestation whereas white fat grows mainly after birth. However, both tissues have been shown to have great plasticity. Thus an apparent transformation of brown fat into white fat takes place during post-natal development. This observation raises questions about a possible conversion of brown into white adipocytes during development, although indirect data argue against this hypothesis. To investigate such questions in vivo, we generated two types of transgenic line. The first carried a transgene expressing Cre recombinase specifically in brown adipocytes under the control of the rat UCP1 promoter. The second corresponded to an inactive lacZ gene under the control of the human cytomegalovirus promoter. This dormant gene is inducible by Cre because it contains a Stop sequence between two loxP sequences, separating the promoter from the coding sequence. Adipose tissues of progeny derived by crossing independent lines established from both constructs were investigated. LacZ mRNA corresponding to the activated reporter gene was easily detected in brown fat and not typically in white fat, even by reverse transcriptase PCR experiments. These data represent the first direct experimental proof that, during normal development, most white adipocytes do not derive from brown adipocytes.

Adipocytes↗

PubMed2001

Altered macrophage-like functions of preadipocytes in inflammation and genetic obesity.

We recently demonstrated that preadipocytes exhibit functional features of macrophages, such as phagocytosis and anti-microbial activity, suggesting that preadipose cells could play a role in the inflammatory process or immune response. The aim of this study was to compare these functions of both macrophages and cells from stroma-vascular fraction (SVF) of the adipose tissue in two different situations, obesity and inflammation, characterized by alterations in immune responsiveness. We demonstrated that ob/ob mice exhibited strong decrease in antimicrobial activity of both macrophages and SVF. This defect is compensated in SVF, at least in part, by an enhancement of phagocytosis that does not seem to be due to an increased macrophage number. In vitro leptin treatment of SVF and macrophages from obese mice did not restore their immune defects. Thioglycollate treatment of lean and obese mice induced an inflammatory process that led to an increase in macrophage activity in both strains. This stimulation also observed in SVF from lean mice is not present in obese ones. This work demonstrated that SVF immune functions could be modified in different pathological situations such as inflammation and obesity and sustained the new physiological role of preadipocytes in these processes.

Adipocytes↗

PubMed2001

Evidence for a direct effect of melatonin on mitochondrial genome expression of Siberian hamster brown adipocytes.

Photoperiod variations are known to participate in the regulation of energy balance in different rodent species via melatonin, a neurosecretory product synthesized by the pineal gland during the night. A direct effect of melatonin on adipose tissue has been suggested since binding sites for the indole have been described on brown adipocytes. The aim of this study was to investigate a genetic effect of melatonin on isolated Siberian hamster brown adipocytes using differential display RT-PCR (DDRT-PCR). Brown adipose cells were isolated from brown adipose tissue and treated for 3 hr with 0.1 and 10 microM melatonin. Total RNA was extracted and DDRT-PCR experiments were performed. A differential band, which disappeared after melatonin treatment, was detected. After confirmation and cloning, the corresponding cDNA fragment B18 was sequenced. B18 had 85 and 81% similarity with a portion of rat and mouse cytochrome b mRNA, respectively, suggesting that B18 corresponds to hamster cytochrome b. This hypothesis was confirmed by the close parallel between the changes in mRNA content, detected by B18, and by cytochrome b mRNA content, detected by a rat probe. Cytochrome b mRNA is encoded by the mitochondrial genome, suggesting a similar effect of melatonin on the whole mitochondrial transcripts. Indeed, 3 hr of treatment with melatonin (10 nM and 0.1 microM) decreased by 44% mitochondrial transcript contents. This work constitutes the first evidence of a direct biological effect of melatonin on Siberian hamster brown adipocytes.

Adipocytes↗

PubMed2001

Adipose tissues display differential phagocytic and microbicidal activities depending on their localization.

OBJECTIVE AND DESIGN: We recently reported that white preadipocytes phagocyte and kill micro-organisms, suggesting an active involvement of fat cells in host defence. Since characteristics of adipose tissues vary according to their localization, we measured the phagocytic capacity of stromal-vascular fraction (SVF) cells from different pads of white and brown adipose tissue in primary culture. RESULTS: The microbicidal activities of SVF cells in inguinal and epididymal white depots were similar, but much higher than in brown fat pad. Considering the whole pad, the highest cytotoxic potential was found in inguinal white adipose tissue (WAT) depot, whereas interscapular brown adipose tissue (BAT) showed an extremely low ability to kill micro-organisms. These differences might be mainly attributed to preadipocyte activities, with regard to the low content in resident macrophages identified by their expression of F4/80 antigen. CONCLUSIONS: Taken together these results suggest that the role as macrophage-like cells for cells of the fat stroma-vascular fraction, among which preadipocytes, is not negligible. This emphasizes the relationship existing between inflammatory and adipose cells. A differential responsiveness of adipose pads to infections and inflammatory situations due to the specific phagocytic ability of their SVF cells was thus proposed.

Adipocytes↗

PubMed2001

Cloning of BUG demonstrates the existence of a brown preadipocyte distinct from a white one.

BACKGROUND: Several indirect arguments agree with the existence of a brown preadipocyte distinct from a white one. Nevertheless, to date, no molecular marker has been available to directly in vivo demonstrate this hypothesis. OBJECTIVE: The aim of this study was to find a gene expressed in brown preadipocyte but not in white and to use it as a molecular marker to analyse brown preadipocyte recruitment in different physiological and physiopathological situations. METHOD: Differential display was performed on stromal-vascular and adipocyte fractions of white and brown adipose tissues in rat. RESULTS: We identified a new gene, BUG, preferentially expressed in the stromal-vascular fraction of brown fat vs other adipose tissues fractions in adult rat. This RNA is also highly expressed in heart and, to a lesser extent, in other tissues such as kidney and brain. The BUG transcript is detected by in situ hybridization in putative preadipocytes within brown adipose tissue. Its level is transiently and specifically up-regulated during early stages of brown preadipocyte differentiation in a primary culture system, before the acquisition of late brown adipocyte phenotype. During development, BUG can be detected before the emergence of UCP-1 expression. In adult rats, BUG expression is inversely associated to brown adipose tissue (BAT) activation during cold exposure as well as in obese animals. CONCLUSIONS: The pattern of BUG expression agrees with an early divergence between brown and white adipocyte lineages. It also reveals the existence of a pool of committed brown preadipocytes within BAT that are recruited during cold exposure. BUG expression is increased in obese animals, suggesting that an early defect in brown preadipocyte differentiation could account for impaired BAT function in genetically obese rats.

Adipocytes↗