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Biomedical subjects

D Ricquier

Publications and source records attributed to D Ricquier.

At least 55 records · Page 3Linked to original sources
PubMed1998

Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model.

Rats bearing the Yoshida AH-130 ascites hepatoma showed an increased expression of both uncoupling protein-2 (UCP2) (194%) and UCP3 (189%) mRNA levels in skeletal muscle 7 days after tumour inoculation. Interestingly, an even greater increase was observed in mRNA for both UCP2 (278%) and UCP3 (797%) in the pair-fed animals, suggesting that the increase in gene expression was the result of the anorexia associated with tumour burden. The results constitute the first report of UCP2 and UCP3 gene expression during cancer cachexia and agree to their possible role in the increase of energy expenditure associated with tumour growth.

Adipose Tissue↗
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

A 211-bp enhancer of the rat uncoupling protein-1 (UCP-1) gene controls specific and regulated expression in brown adipose tissue.

The uncoupling protein-1 gene is uniquely expressed in brown adipose tissue (BAT) and is positively regulated by cold exposure of animals and the sympathetic nervous system. To analyse the importance of a previously identified 211-bp enhancer [Cassard-Doulcier, Gelly, Fox, Schrementi, Raimbault, Klaus, Forest, Bouillaud and Ricquier (1993) Mol. Endocrinol. 7, 497-506] in the tissue-specific expression of this gene, transgenic mice were generated using the chloramphenicol acetyltransferase (CAT) gene as a reporter gene. One out of fourteen lines of the control transgenic mice bearing the Herpes simplex thymidine kinase (TK) promoter expressed weakly the CAT reporter gene in several tissues, whereas the other lines did not express CAT. Eight founders bearing the 211-bp enhancer-TK transgene were obtained. In six lines, no expression of CAT was detected. In one line, the expression of CAT was restricted to BAT. In another line, the expression of CAT was found in BAT and, to a lesser extent, in testis. Moreover, in these lines a marked and specific increase in the expression of the reporter gene in BAT was observed either after exposure of mice to the cold or by treating them with a beta-adrenoceptor agonist drug. These results demonstrate that the 211-bp enhancer alone is sufficient to both direct and restrict expression to BAT. This enhancer also mediates the transcriptional response of the gene to beta-adrenergic stimulation, although it does not contain conserved cAMP response element.

Adipose Tissue, Brown↗
PubMed1998

Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice.

Uncoupling protein 2 (UCP2) maps to a region on distal mouse chromosome 7 that has been linked to the phenotypes of obesity and type II diabetes. We recently reported that UCP2 expression is increased by high fat feeding in adipose tissue of the A/J strain of mice, which is resistant to the development of dietary obesity. More recently, a third UCP (UCP3) was identified, which is expressed largely in skeletal muscle and brown adipose tissue. The UCP2 and UCP3 genes are located adjacent to one another on mouse chromosome 7. Thus, the roles of these UCPs in both metabolic efficiency and the linkage to obesity and diabetes syndromes is unclear. For this reason, we examined the expression of UCP2 and UCP3 in white adipose tissue and interscapular brown adipose tissue and in gastrocnemius/soleus muscle preparations from the obesity-resistant A/J and C57BL/KsJ (KsJ) strains and the obesity-prone C57BL/6J (B6) mouse strain. In both KsJ and A/J mice, UCP2 expression in white fat was increased approximately 2-fold in response to 2 weeks of a high fat diet, but there was no effect of diet on UCP2 levels in B6 mice. In skeletal muscle and in brown fat, neither UCP2 nor UCP3 expression was affected by diet in A/J, B6, or KsJ mice. However, in brown fat, we observed a 2-3-fold increase in the expression of UCP1 in response to dietary fat challenge, which may be related to diet-induced elevations in plasma leptin levels. Together, these results indicate that the consumption of a high fat diet selectively regulates UCP2 expression in white fat and UCP1 expression in brown fat and that resistance to obesity is correlated with this early, selective induction of UCP1 and UCP2 and is not associated with changes in expression of UCP3.

Adipose Tissue↗
PubMed1998

Hibernoma development in transgenic mice identifies brown adipose tissue as a novel target of aldosterone action.

Aldosterone is a major regulator of salt balance and blood pressure, exerting its effects via the mineralocorticoid receptor (MR). To analyze the regulatory mechanisms controlling tissue-specific expression of the human MR (hMR) in vivo, we have developed transgenic mouse models expressing the SV40 large T antigen (TAg) under the control of each of the two promoters of the hMR gene (P1 or P2). Unexpectedly, all five P1-TAg founder animals died prematurely from voluminous malignant liposarcomas originating from brown adipose tissue, as evidenced by the expression of the mitochondrial uncoupling protein ucp1, indicating that the proximal P1 promoter was transcriptionally active in brown adipocytes. No such hibernoma occurred in P2-TAg transgenic mice. Appropriate tissue-specific usage of P1 promoter sequences was confirmed by demonstrating the presence of endogenous MR in both neoplastic and normal brown adipose tissue. Several cell lines were derived from hibernomas; among them, the T37i cells can undergo terminal differentiation into brown adipocytes, which remain capable of expressing ucp1 upon adrenergic or retinoic acid stimulation. These cells possess endogenous functional MR, thus providing a new model to explore molecular mechanisms of mineralocorticoid action. Our data broaden the known functions of aldosterone and suggest a potential role for MR in adipocyte differentiation and regulation of thermogenesis.

Adipose Tissue, Brown↗
PubMed1998

TH-, NPY-, SP-, and CGRP-immunoreactive nerves in interscapular brown adipose tissue of adult rats acclimated at different temperatures: an immunohistochemical study.

Interscapular brown adipose tissue (IBAT), a site of nonshivering thermogenesis in mammals, is neurally controlled. The co-existence of sympathetic and peptidergic innervation has been demonstrated in different brown adipose depots. We studied the morphological profile of IBAT innervation and tested by immunohistochemical methods whether cold and warm stimulation are accompanied by modifications in the density of parenchymal noradrenergic nerve fibers. We also studied the immunoreactivity of afferent fibers--which contain calcitonin gene-related peptide (CGRP) and substance P (SP)--in different functional conditions. IBAT was obtained from adult rats (6 weeks old) acclimated at different temperatures (4 degrees, 20 degrees, and 28 degrees C). Tissue activity was evaluated by studying the immunolocalization of uncoupling protein (UCP-1), a specific marker of brown adipose tissue. Noradrenergic and peptidergic innervation were seen to arise from morphologically different nerves. Fibers staining for tyrosine hydroxylase (TH) were thin, unmyelinated hilar nerves, and CGRP- and SP-positive fibers were in thick nerves containing both myelinated and unmyelinated fibers. Under cold stimulation, noradrenergic neurons produce greater amounts of TH, and their axons branch, resulting in increased parenchymal nerve fibers density. Neuropeptide Y (NPY) probably co-localizes with TH in noradrenergic neurons, but only in the perivascular nerve fiber network. The parenchymal distribution of NPY to interlobular arterioles and capillaries suggests that this peptide must have other functions besides that of innervating arteriovenous anastomoses, as hypothesized by other researchers. The different distribution of CGRP and SP suggests the existence of different sensory neuronal populations. The detection of CGRP at the parenchymal level is in line with the hypothesis of a trophic action of this peptide.

Acclimatization↗
PubMed1998

Analysis of the uncoupling protein-1 (UCP1) gene in obese and lean subjects: identification of four amino acid variants.

Uncoupling protein-1 (UCP1) is uniquely expressed in brown adipose tissue (BAT) and of major importance for the tissues thermogenic capacity. This study was undertaken to detect variants in the UCP1 gene by single strand conformational polymorphism (SSCP) analysis and subsequent sequencing, and determine their potential association with obesity. Four variants predicting for amino acid substitutions were detected, of which Arg40Trp (exon 1) and Lys257Arg (exon 5) were rare mutations. In contrast, the allele frequency of a polymorphism in exon 2 predicting for an Ala64Thr substitution was 8.2% in a cohort of 293 obese children and adolescents compared to 4.1% in 134 lean individuals, while the allele frequency of a Met229Leu variant (exon 5) was not markedly different between the obese (10.4%) and lean (12.0%) study groups. Although one of the identified polymorphisms tends to have a higher frequency in obese than in lean subjects, variants of the UCP1 gene do not seem to contribute significantly to the development of early-onset obesity in the German population.

Adolescent↗
PubMed1998

Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians.

The UCP2-UCP3 gene cluster maps to chromosome 11q13 in humans, and polymorphisms in these genes may contribute to obesity through effects on energy metabolism. DNA sequencing of UCP2 and UCP3 revealed three polymorphisms informative for association studies: an Ala-->Val substitution in exon 4 of UCP2, a 45 bp insertion/deletion in the 3'-untranslated region of exon 8 of UCP2 and a C-->T silent polymorphism in exon 3 of UCP3. Initially, 82 young (mean age = 30 +/- 7 years), unrelated, full-blooded, non-diabetic Pima Indians were typed for these polymorphisms by direct sequencing. The three sites were in linkage disequilibrium ( P < 0.00001). The UCP2 variants were associated with metabolic rate during sleep (exon 4, P = 0.007; exon 8, P = 0.016) and over 24 h (exon 8, P = 0.038). Heterozygotes for UCP2 variants had higher metabolic rates than homozygotes. The UCP3 variant was not significantly associated with metabolic rate or obesity. In a further 790 full-blooded Pima Indians, there was no significant association between the insertion/deletion polymorphism and body mass index (BMI). However, when only individuals >45 years of age were considered, heterozygotes (subjects with the highest sleeping metabolic rate) had the lowest BMI (P = 0.04). The location of the insertion/deletion polymorphism suggested a role in mRNA stability; however, it appeared to have no effect on skeletal muscle UCP2 mRNA levels in a subset of 23 randomly chosen Pima Indians. In conclusion, these results suggest a contribution from UCP2 (or UCP3) to variation in metabolic rate in young Pima Indians which may contribute to overall body fat content later in life.

Adolescent↗
PubMed1998

Leptin and UCP1 genes are reciprocally regulated in brown adipose tissue.

In a previous work we showed that only unilocular brown adipocytes express leptin. In order to investigate the relationship between leptin gene expression, brown adipocyte activity (UCP1) and morphology, we studied brown adipose tissues of mice (C57BL, female, 7 weeks old) acclimated at different temperatures (19 degrees C and 28 degrees C). Northern blot analysis revealed higher leptin and lower UCP1 mRNA levels in mice exposed to 28 degrees C than in the group acclimated at 19 degrees C. Also protein expression (immunohistochemistry) differed in the two groups: at 28 degrees C brown adipocytes were positive for leptin and only weakly positive for UCP1, while at 19 degrees C they were leptin-negative and UCP1-positive. In the former group the morphology was mainly unilocular. Our data suggest that in brown adipocytes of warm-acclimated mice leptin expression is closely related to their hypoactive functional stage, as evidenced by their low level of UCP1 synthesis and the morphological rearrangement of the lipid content (unilocularity).

Adipose Tissue, Brown↗
PubMed1998

Leptin and corticosterone have opposite effects on food intake and the expression of UCP1 mRNA in brown adipose tissue of lep(ob)/lep(ob) mice.

The present study was conducted to assess the interaction effect of leptin and corticosterone on food intake and the expression of uncoupling protein 1 (UCP1) mRNA in interscapular brown adipose tissue (IBAT). To this end, a 3 x 3 factorial experiment was designed in which adrenalectomized (ADX) lep(ob)/lep(ob) mice were subjected to three doses of corticosterone and three doses of leptin. The results confirm the anorectic and orexigenic effects of leptin and corticosterone, respectively. The results also emphasize the abilities of leptin and corticosterone to respectively increase and reduce the expression of UCP1 mRNA in IBAT. The effects of leptin and corticosterone on food intake and the expression of UCP1 mRNA translated into effects on body weight and body composition; leptin reduced body weight and corticosterone increased the weight of IBAT. The present results do not provide evidence for leptin-corticosterone interactions in the control of food intake and thermogenesis. Corticosterone increased food intake and reduced the expression of IBAT UCP1 regardless of the leptin status, and leptin reduced food intake and induced the expression of IBAT UCP1 independently of the corticosterone levels.

Adipose Tissue, Brown↗
PubMed1998

Chronic central leptin infusion enhances insulin-stimulated glucose metabolism and favors the expression of uncoupling proteins.

Continuous (4 days) intracerebroventricular leptin infusion (12 microg/day) was performed in lean rats, and its hormonometabolic effects were determined. Intracerebroventricular leptin administration did not result in leakage of the hormone into the peripheral circulation. Thus, its effects were elicited by its presence within the central nervous system. Intracerebroventricular leptin infusion produced marked decreases in food intake and body weight gain relative to vehicle-infused fed ad libitum rats. Because decreases in food intake alter hormonometabolic homeostasis, additional control rats pair-fed to the amount of food consumed by leptin-infused ones were included in the study. Intracerebroventricular leptin-infused and vehicle-infused pair-fed rats were characterized, relative to vehicle-infused ad libitum-fed animals, by decreases in body weight and insulinemia and by increases in insulin-stimulated overall glucose utilization and muscle and brown adipose tissue glucose utilization index. Brown adipose tissue uncoupling protein (UCP)1, UCP2, and UCP3 mRNA levels were markedly decreased in pair-fed animals relative to those of fed ad libitum control animals, as were liver and white adipose tissue UCP2 and muscle UCP3 mRNA levels. In marked contrast, intracerebroventricular leptin administration was accompanied by the maintenance of high UCP1, UCP2, and UCP3 expression in all these tissues. Thus, despite analogies between leptin's effects and those of pair-feeding with regard to glucose handling, their respective underlying mechanisms differ. While leptin maintains or favors energy-dissipating mechanisms (UCP1, UCP2, and UCP3), the latter are markedly depressed in pair-fed rats. This effect of leptin may prevent subsequent excessive storage processes, thereby maintaining normal body homeostasis.

Adipose Tissue, Brown↗
PubMed1997

Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans.

Uncoupling protein-2 and -3 (UCP2 and UCP3) are mitochondrial proteins that show high sequence homology with the brown adipocyte-specific UCP1. UCP1 induces heat production by uncoupling respiration from ATP synthesis. UCP2 is widely expressed in human tissues, whereas UCP3 expression seems restricted to skeletal muscle, an important site of thermogenesis in humans. We have investigated the regulation of UCP2 and UCP3 gene expression in skeletal muscle and adipose tissue from lean and obese humans. UCP2 and -3 mRNA levels were not correlated with body mass index (BMI) in skeletal muscle, but a positive correlation (r = 0.55, P < 0.01, n = 22) was found between UCP2 mRNA level in adipose tissue and BMI. The effect of fasting was investigated in eight lean and six obese subjects maintained on a hypocaloric diet (1,045 kJ/d) for 5 d. Calorie restriction induced a similar 2-2.5-fold increase in UCP2 and -3 mRNA levels in lean and obese subjects. To study the effect of insulin on UCP gene expression, six lean and five obese subjects underwent a 3-h euglycemic hyperinsulinemic clamp. Insulin infusion did not modify UCP2 and -3 mRNA levels. In conclusion, the similar induction of gene expression observed during fasting in lean and obese subjects shows that there is no major alteration of UCP2 and -3 gene regulation in adipose tissue and skeletal muscle of obese subjects. The increase in UCP2 and -3 mRNA levels suggests a role for these proteins in the metabolic adaptation to fasting.

Adipose Tissue↗
PubMed1997

Characterization of a melatonin binding site in Siberian hamster brown adipose tissue.

Melatonin has been shown, in various rodent species, to mediate photoperiodic effects on body weight and, consequently, fat mass. Pharmacological investigations indicated that the brown adipose tissue of Siberian hamsters possesses a melatonin binding site with a dissociation constant of 570+/-300 pM and a density of 3.2+/-1.8 fmol/mg protein. This binding site can also be detected on mature brown adipocyte membranes. The rank order of potency of a variety of drugs to displace 2-[125I]iodomelatonin from binding sites on Siberian hamster brown adipose tissue was as follows: 2-iodomelatonin > melatonin = prazosin > GR135531 (5-methoxycarbonylamino-N-acetyltryptamine) > N-acetylserotonin > 6-chloromelatonin > S20304 (N-(2-(1-naphthyl)ethyl)cyclobutanecarboxamide) >> methoxamine, phenylephrine, serotonin. Mel(1a) mRNA was not detected by RT-PCR (reverse transcription-polymerase chain reaction) in brown adipose tissue. Melatonin had no effect on either basal or stimulated lipolysis. Moreover, melatonin did not modify intracellular cAMP accumulation or inositol phosphate content. Together, these results suggest that the melatonin binding site characterized in brown adipose tissue is clearly different from the Mel(1) cloned subtype and has some features different from those of the Mel2 subtype.

Adipose Tissue, Brown↗
PubMed1997

Induction of UCP2 mRNA by thyroid hormones in rat heart.

The possible regulation of the expression of uncoupling protein-2 (UCP2) mRNA by thyroid hormones in different tissues was examined in rats. Triiodothyronine (T3) was found to produce an organ-specific enhancement of UCP2 expression in rat tissues. The effect of T3 was markedly observed in heart, whereas a moderate effect was seen in skeletal muscle and no effect in kidney or liver. These results suggest that UCP2 is a protein that may be involved in the nuclear-mediated effect of T3 on resting metabolic rate in the rat.

Animals↗
PubMed1997

Up-regulation of UCP-2 gene expression by PPAR agonists in preadipose and adipose cells.

UCP-2 is a member of the emerging family of UCP homologues. Upon high-fat feeding, UCP-2 mRNA levels are increased in epididymal fat pads of A/J mice, suggesting that the flux of fatty acids entering adipose tissue may regulate UCP-2 gene expression. Since fatty acids act as positive transcriptional regulators of lipid-related genes by means of peroxisome proliferator-activated receptors (PPARs), the regulation of UCP-2 gene expression by PPAR agonists (carbacyclin, alpha-bromopalmitate, BRL49653) has been examined in mouse preadipose and adipose cells in primary cultures or from clonal lines (Ob1771, 3T3-F442A, 1B8). In preadipose cells, carbacyclin and alpha-bromopalmitate are active and BRL49653 shows no effect, whereas all these ligands are active in adipose cells. The stimulatory effect of PPAR agonists is potentiated by RXR agonists in adipose cells. In contrast to the UCP-1 gene, norepinephrine as a cAMP-elevating agent does not enhance the expression of UCP-2 gene. Altogether, the data favor a predominant role of PPARdelta in preadipose cells and the involvement of PPARgamma2 in adipose cells in up-regulating UCP-2 gene expression. Thus, a potential link between fatty acid metabolism and thermogenesis may exist in PPAR-expressing tissues.

Adipocytes↗