Changes in muscle UCP3 expression and serum leptin in food restricted and refed rats.
Explore the source record for details and available documents.
Adipose Tissue↗
Biomedical subjects
D Ricquier
Publications and source records attributed to D Ricquier.
The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research.
Energy expenditure through brown adipose tissue thermogenesis contributes either to maintenance of body temperature in a cold environment or to wasted food energy, i.e. cold-induced or diet-induced thermogenesis. Both mechanisms are due to a specific and unique protein: the uncoupling protein-1. Uncoupling protein-1 is exclusively expressed in mitochondria of brown adipocytes where it uncouples respiration from ATP synthesis, dissipating the proton gradient as heat. In humans, although uncoupling protein-1 can be detected, the inability to quantify brown adipose tissue makes it difficult to argue for a role for uncoupling protein-1 in thermogenesis and energy expenditure. This review summarizes data supporting the existence of brown adipocytes and the role of UCP1 in energy dissipation in adult humans. Understanding the mechanisms which regulate transcription and expression of the human UCP1 gene will facilitate the identification of molecules able to increase the levels of this protein in order to modulate energy expenditure in adult humans.
Adipose Tissue↗
Effect of high-fat diet, surrounding temperature, and enterostatin on uncoupling protein gene expression.
Nonshivering thermogenesis induced in brown adipose tissue (BAT) during high-fat feeding is mediated through uncoupling protein 1 (UCP1). UCP2 is a recently identified homologue found in many tissues. To determine the role of UCP1 and UCP2 in thermoregulation and energy balance, we investigated the long-term effect of high-fat feeding on mRNA levels in mice at two different ambient temperatures. We also treated mice with the anorectic peptide enterostatin and compared mRNA levels in BAT, white adipose tissue (WAT), stomach, and duodenum. Here, we report that high-fat feeding at 23 degrees C increased UCP1 and UCP2 levels in BAT four- and threefold, respectively, and increased UCP2 levels fourfold in WAT. However, at 29 degrees C, UCP1 decreased, whereas UCP2 remained unchanged in BAT and increased twofold in WAT. Enterostatin increased UCP1 and decreased UCP2 mRNA in BAT. In stomach and duodenum, high-fat feeding decreased UCP2 mRNA, whereas enterostatin increased it. Our results suggest that the regulation of uncoupling protein mRNA levels by high-fat feeding is dependent on ambient temperature and that enterostatin is able to modulate it.
Adipose Tissue↗
Correlation between pancreatic islet uncoupling protein-2 (UCP2) mRNA concentration and insulin status in rats.
Hypothesizing that UCP2 may influence insulin secretion by modifying the ATP/ADP ratio within pancreatic islets, we have investigated the expression of intraislet UCP2 gene in rats showing insulin oversecretion (non-diabetic Zucker fa/fa obese rats, glucose-infused Wistar rats) or insulin undersecretion (fasting and mildly diabetic rats). We found that in Zucker fa/fa obese rats, hyperinsulinemia (1222+/-98 pmol/l vs. 128+/-22 pmol/l in lean Zucker rats) was accompanied by a significant increase in UCP2 mRNA levels. In rat submitted to a 5 day infusion with glucose, hyperinsulinemia (1126+/-101 pmol/l vs. 215+/-25 pmol/l in Wistar control rats), coincided with an enhanced intraislet UCP2 gene expression, whereas a 8h or a 2 day-infusion did not induce significant changes in UCP2 mRNA expression. In rats made hypoinsulinemic and mildly diabetic by the injection of a low dose of streptozotocin, and in 4-day-fasting rats (plasma insulin 28+/-5 pmol/l) UCP2 gene expression was sharply decreased. A 3-day-fast was ineffective. The data show the existence of a time-dependent correlation between islet mRNA UCP2 and insulin that may be interpreted as an adaptative response to prolonged insulin excess.
Analysis of Variance↗
[Uncoupling proteins and energy metabolism].
Explore the source record for details and available documents.
Adipocytes↗
Retinoids activate proton transport by the uncoupling proteins UCP1 and UCP2.
In mammalian brown adipose tissue, thermogenesis is explained by uncoupling mitochondrial respiration from ATP synthesis. Uncoupling protein-1 (UCP1) is responsible for this uncoupled state, because it allows proton re-entry into the matrix and thus dissipates the proton gradient generated by the respiratory chain. Proton transport by UCP1 is regulated negatively by nucleotides and positively by fatty acids. Adrenergic stimulation of brown adipocytes stimulates lipolysis and therefore enhances uncoupling and thermogenesis. Adrenergic stimulation also boosts ucp1 gene transcription. Since retinoic acid also promotes ucp1 gene transcription and its structure makes it a possible activator of UCP1, we hypothesized that retinoic acid, like noradrenaline, could have a dual action and trigger the activity of the protein UCP1 itself. Here we show that retinoic acid strongly increases proton transport by UCP1 in brown adipose tissue mitochondria and that it is much more potent than fatty acids. These data are corroborated with yeast mitochondria where UCP1 was introduced by genetic manipulation. The yeast expression system allows the comparison of the UCP1 with the newly described homologues UCP2 and UCP3. The search for regulators of UCP2 has demonstrated that it is positively regulated by retinoids in a pH-dependent manner.
Adipose Tissue, Brown↗
Acute effects of exercise on circulating leptin in lean and genetically obese fa/fa rats.
Mechanisms of regulation of plasma leptin in lean and genetically obese animals are not completely understood. In particular a relation has been proposed between energy metabolism and leptin. However, it is not clear how energy expenditure and leptin are related under exercise in lean and obese animals. To clarify these aspects we investigated lean and genetically obese (fa/fa) Zucker rats undergoing a single bout (30 min) of swimming and measured several biochemical and hormonal parameters of energy metabolism and leptin changes throughout the study. Moreover ob-gene expression in adipose tissue was also measured. Our results showed that plasma leptin is decreased by 30% at the end of exercise in lean animals while resulting unaffected in obese animals. Leptin changes in lean rats are concomitant with the peak of NEFA and glycerol release from adipose tissue rather than with the reduction of plasma insulin. Ob-gene expression in adipose tissue was markedly increased in fa/fa compared to lean rats, but was not modified by exercise both in lean and obese animals. In conclusion our data show that leptin changes during exercise are related to lipolytic events in adipose tissue and support a link between leptin and energy expenditure.
Adipose Tissue↗
Functional organization of the human uncoupling protein-2 gene, and juxtaposition to the uncoupling protein-3 gene.
Human and mouse UCP2 genes were cloned and sequenced. Transcriptional start sites were identified using primer extension analysis. The transcription unit of UCP2 gene is made of 2 untranslated exons followed by 6 exons encoding UCP2. In vitro translation analysis demonstrated that an open-reading-frame for a putative peptide of 36 residues present in exon 2 did not prevent UCP2 translation and confirmed that the initiation site of translation was in exon 3 as predicted from sequencing data. Short (bp -125 to +93) and long (bp -1383 and +93) CAT-constructs containing DNA upstream of the transcriptional start site of the human gene were made and transfected in adipocytes or HeLa cells allowing characterization of a potent promoter. Analysis of several genomic clones encompassing UCP2 and/or UCP3 genes demonstrated that the 2 genes are adjacent, the human UCP2 gene being located 7 kb downstream of the UCP3 gene.
Animals↗
An uncoupling protein 2 gene variant is associated with a raised body mass index but not Type II diabetes.
AIMS/HYPOTHESIS: Linkage between markers close to the uncoupling protein 2 and 3 genes (11q13) and resting metabolic rate and a pre-diabetic phenotype have been found. The syntenic region in mouse has been found to be linked to quantitative traits associated with obesity and diabetes. UCP2 and UCP3 could therefore have an important role in body weight regulation and susceptibility to diabetes. We investigated a recently identified variant of the UCP2 gene in exon 8 as a marker for glucose and weight homeostasis. METHODS: Length variation of the UCP2 exon 8 variant was studied by the polymerase chain reaction and agarose gel electrophoresis. Sequence variants of the UCP3 gene were sought by semi-automated DNA sequencing. RESULTS: In 453 South Indian subjects, we found an association in women between the UCP2 exon variant and body mass index (p = 0.018). These findings were replicated in a separate group of South Indian subjects (n = 143, p < 0.001) irrespective of sex. Although no association was found between the UCP2 exon 8 variant and overt obesity in British subjects, the UCP2 genotype of obese women (n = 83) correlated with fasting serum leptin concentration (p = 0.006) in the presence of extreme obesity. These observations could not be explained by tight linkage disequilibrium with a coding region variant in the region of the UCP3 gene of biological significance. Lastly, no association was found between UCP2 and Type II (non-insulin-dependent) diabetes using either a family based design (85 families) or case control study (normal glucose tolerance n = 335, impaired glucose tolerance n = 42, Type II diabetes n = 76). CONCLUSION/INTERPRETATION: We have described a UCP2 gene exon 8 variant that may affect susceptibility to weight gain by influencing regulation of leptin.
Adult↗
Contribution to the identification and analysis of the mitochondrial uncoupling proteins.
This review is primarily focused on the contribution of our laboratory to study of the mitochondrial uncoupling UCPs. The initial stage was the description of a 32-kDa membranous protein specifically induced in brown adipose tissue mitochondria of cold-adapted rats. This protein was then shown by others to be responsible for brown fat thermogenesis and was referred to as the uncoupling protein-UCP (recently renamed UCP1). cDNA and genomic clones of UCP1 were isolated and used to investigate the topology and functional organization of the protein in the membrane and the mechanisms of control of UCP1 gene transcription. Orientation of the transmembrane fragments was proposed and specific amino acid residues involved in the inhibition of UCP1 by purine nucleotides were identified in recombinant yeast. A potent enhancer mediating the response of the UCP1 gene to retinoids and controlling the specific transcription in brown adipocytes was identified using transgenic mice. More recently, we identified UCP2, an UCP homolog widely expressed in human and rodent tissues we also collaborated to characterize the plant UCP. Although the biochemical activities and physiological roles of the novel UCPs are not well understood, these recent data stimulate research on mitochondrial carriers, mitochondrial bioenergetics, and energy expenditure.
Adipose Tissue, Brown↗
Uncoupling protein-2 (UCP2): molecular and genetic studies.
Thermogenesis is associated to oxygen consumption and cellular respiration. This process is coupled to adenosine-diphosphate (ADP) phosphorylation through the existence of a proton gradient across the inner mitochondrial membrane. It was postulated that proton leaks through this membrane would uncouple respiration from adenosine-triphosphate (ATP) synthesis and induce energy dissipation as heat. Such a mechanism was identified in thermogenic brown adipose tissue mitochondria which contain a unique proton carrier referred to as uncoupling protein (UCP). This UCP is activated by fatty acids and its synthesis is positively controlled by retinoids, thyroid hormones, catecholamines and rexinoids. In fact, in most types of cells, respiring mitochondria release heat and the coupling of substrate oxidation to ADP phosphorylation is under 100%. It suggested that the partial coupling of respiration to ADP phosphorylation was due to proton leaks possibly related to the brown fat UCP. This approach led to the identification of UCP2 and UCP3, two homologues of the brown fat UCP (renamed UCP1). UCP2 gene is widely expressed in tissues and cell types, whereas the UCP3 gene is dominantly expressed in skeletal muscles (and brown fat in mice). Recent genetic, biochemical and physiological studies suggest that these novel UCP2 contribute to resting metabolic rate, fat oxidation and may represent new targets for anti-obesity compounds.
Adipose Tissue, Brown↗
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↗
Contributions of studies on uncoupling proteins to research on metabolic diseases.
The coupling of O2 consumption to ADP phosphorylation in mitochondria is partial. This is particularly obvious in brown adipocyte mitochondria which use a regulated uncoupling mechanism generating heat production from substrate oxidation, and catalysing thermogenesis in rodents or infants in response to cold, and arousing hibernators. In the case of brown adipose tissue, the uncoupling mechanism is related to a specific protein in the inner mitochondrial membrane referred to as UCP1. Although the biological importance of UCP1 in human adults is not demonstrated, genetic analysis of various human cohorts suggested a participation of UCP1 to control of fat content and body weight. Very recently, the cloning of UCP2 and UCP3, two homologues of UCP1, has renewed the field of research on the importance of respiration control in metabolic processes and metabolic diseases. UCP2 is widely expressed in organs, whereas UCP3 is mainly present in muscles. These proteins may explain why the coupling of respiration to ADP phosphorylation is less than perfect. Their biological importance should be studied. They also represent new putative targets for drugs against metabolic diseases such as obesity.
Adipocytes↗
Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.
It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.
Animals↗
[Genetic and molecular aspects of obesity: recent data].
Obesity is a disease responsible for many serious complications. The sharp rise in the prevalence of obesity in many countries is supplying a powerful drive to basic and clinical research. Several genes responsible for monogenic murine obesity have recently been identified. One of these genes encodes the OB protein, or leptine, which is secreted by fat tissue and inhibits appetite by means of an effect on the hypothalamus. In humans, obese subjects carrying a mutation of this gene or of the leptine receptor have been identified. Several other genes implicated in human obesity have been mapped to chromosomes 1, 11, 18, and 20. Several transcription factors that control fat cell differentiation have been identified, such as C/ERB alpha, beta, and delta; ADD1/SREBP1, and PPAR gamma 2. It has been established that fat tissue can secrete many factors, including TNF alpha, CETP, IGF beta, TGF beta, PGE2, and LPA. Mitochondrial uncoupling proteins (UCPs) are recently characterized proteins capable of uncoupling respiration and contributing to energy expenditures. The hypothalamic neuropeptides and their receptors are a focus of active research. About ten of these neuropeptides have been identified.
Animals↗
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↗
In the rat, tumor necrosis factor alpha administration results in an increase in both UCP2 and UCP3 mRNAs in skeletal muscle: a possible mechanism for cytokine-induced thermogenesis?
Since the discovery of the new members of the UCP (uncoupling protein) family, UCP2 and UCP3, very few studies have dealt with the regulation of their expression. Bearing this in mind, administration of a single intravenous injection of TNF-alpha (100 microg/kg body weight) to rats resulted in a significant increase in UCP2 (242%) and UCP3 (113%) gene expression in skeletal muscle. The results suggest a possible role for UCP2 and UCP3 in the increase of energy expenditure associated with cytokine treatment.
Animals↗
Increased uncoupling protein-2 and -3 gene expressions in skeletal muscle of STZ-induced diabetic rats.
Streptozotocin (STZ)-induced diabetic animals are vulnerable to cold stress. Uncoupling proteins (UCPs) play an important role in regulating thermogenesis. We investigated the gene expressions of UCPs in brown adipose tissue (BAT), white adipose tissue (WAT), liver and gastrocnemius muscle of STZ-diabetic rats using Northern blot. UCP-1, -2 and -3 mRNA expressions in BAT were all remarkably lower in STZ-diabetic rats than those in control rats. Both UCP-2 and -3 gene expressions in gastrocnemius muscle were substantially elevated in STZ-diabetic rats and insulin treatment restored UCP gene expressions to normal levels. These results suggest that in STZ-diabetic rats, the overexpression of UCP-2 and UCP-3 in skeletal muscle provides a defense against hypothermogenesis caused by decreased UCPs in BAT.
Adipose Tissue, Brown↗