Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial uncoupling proteins (UCPs) are transporters that are important for thermogenesis. The net result of their activity is the exothermic movement of protons through the inner mitochondrial membrane, uncoupled from ATP synthesis. We have cloned a third member of the UCP family, UCP3. UCP3 is expressed at high levels in muscle and rodent brown adipose tissue. Overexpression in yeast reduced the mitochondrial membrane potential, showing that UCP3 is a functional uncoupling protein. UCP3 RNA levels are regulated by hormonal and dietary manipulations. In contrast, levels of UCP2, a widely expressed UCP family member, showed little hormonal regulation. In particular, muscle UCP3 levels were decreased 3-fold in hypothyroid rats and increased 6-fold in hyperthyroid rats. Thus UCP3 is a strong candidate to explain the effects of thyroid hormone on thermogenesis. White adipose UCP3 levels were greatly increased by treatment with the beta3-adrenergic agonist, CL214613, suggesting another pathway for increasing thermogenesis. UCP3 mRNA levels were also regulated by dexamethasone, leptin, and starvation, albeit differently in muscle and brown adipose tissue. Starvation caused increased muscle and decreased BAT UCP3, suggesting that muscle assumes a larger role in thermoregulation during starvation. The UCP3 gene is located close to that encoding UCP2, in a chromosomal region implicated in previous linkage studies as contributing to obesity.
 ...
PMID:Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, beta3-adrenergic agonists, and leptin. 930 58

Uncoupling proteins 3 and 2 (UCP3 and UCP2) are two newly cloned genes that have been implicated in the regulation of lipids as fuel substrate in skeletal muscle on the basis that their mRNA expressions are upregulated during starvation (when fat stores are being rapidly mobilized) and downregulated during the early phase of refeeding (when fat stores are being rapidly replenished). To test the hypothesis that circulating free fatty acids (FFAs) may have a physiological role as an interorgan signal linking these dynamic changes in the fat stores to skeletal muscle expression of UCP3 and UCP2, the mRNA levels of these UCP homologs were examined in fed and fasted rats treated with the antilipolytic agent nicotinic acid. In 46-h fasted rats, we observed a threefold increase in serum FFA levels and increases in UCP3 and UCP2 mRNA levels that were more marked in the gastrocnemius and tibialis anterior muscles (predominantly fast-twitch fibers) than in the soleus muscle (predominantly slow-twitch fibers). Treatment with nicotinic acid blunted the fasting-induced increase in serum FFA levels and prevented the increase in mRNA levels of UCP3 and UCP2 in the soleus muscle, but had little or no effect on the elevated mRNA levels of these UCP homologs in the gastrocnemius and tibialis anterior muscles. Furthermore, treatment of ad libitum-fed animals with nicotinic acid resulted in a twofold reduction in serum FFA levels (i.e., by a magnitude similar to that observed during early refeeding) and significant reductions in UCP3 and UCP2 mRNA levels in the soleus muscle, but not in the gastrocnemius or tibialis anterior muscles. These results revealed a muscle-type dependency in the way UCP2 and UCP3 gene expression in skeletal muscle is regulated, and suggest that the hypothesis that circulating FFAs function as an interorgan signal between fat stores and skeletal muscle UCP3 and UCP2 gene expression is adequate only for slow-twitch (oxidative) muscles. Consequently, a signal(s) other than circulating FFAs must be implicated in the link between dynamic changes in body fat stores and UCP expression in predominantly fast-twitch (glycolytic/oxidative-glycolytic) muscles, which constitute the major fiber type of the total skeletal muscle mass and which have high susceptibility to developing insulin resistance and impairment in substrate utilization in metabolic diseases.
 ...
PMID:Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs: is there a role for circulating free fatty acids? 979 37

UCP2 and UCP3 are two recently cloned genes with high sequence homology to the gene for uncoupling protein (UCP)-1, which regulates thermogenesis in brown adipose tissue. In the context of the current debate about whether UCP2 and UCP3 in the skeletal muscle may also function as mediators of thermogenesis or as regulators of lipids as fuel substrate, we have examined their mRNA expressions in rat gastrocnemius muscle in response to dietary manipulations known to differentially affect thermogenesis during the phase of weight recovery after starvation. Compared with ad libitum-fed control rats, the refeeding of isocaloric amounts of a low-fat (high-carbohydrate) diet resulted in lower energy expenditure and lower mRNA levels of muscle UCP2 and UCP3. This downregulation of UCP homologs was abolished by the refeeding of a high-fat diet, even though energy expenditure was significantly lower during refeeding on the high-fat than on the low-fat diet. Furthermore, major alterations in the fatty acid composition of the refeeding diet in favor of n-6 polyunsaturated or medium-chain fatty acids resulted in significant increases in energy expenditure, but with no significant changes in the expression of skeletal muscle UCP homologs. Regression analysis of gastrocnemius UCP mRNA levels against parameters that included body composition, energy expenditure, and plasma levels of free fatty acids (FFAs), insulin, and glucose as well as the increase in plasma glucose after a glucose load, revealed that only the latter (an index of insulin resistance) could explain the variability in muscle UCP2 and UCP3 mRNA expressions (r = 0.41, P < 0.02; r = 0.45, P < 0.01, respectively). Taken together, these data are at variance with a role for skeletal muscle UCP2 and UCP3 in dietary regulation (or modulation) of thermogenesis. However, they are consistent with the notion that these UCP homologs may function as regulators of lipids as fuel substrate and raise the possibility that high-fat induced upregulation of muscle UCP2 and UCP3 may be more closely linked to insulin resistance than to changes in circulating FFAs.
 ...
PMID:Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition: a link with insulin resistance. 1033 28

Uncoupling protein-3 gene expression in skeletal muscle is up-regulated during postnatal development of mice. A high-carbohydrate diet at weaning induces a decrease in uncoupling protein-3 mRNA levels that does not occur when mice were weaned onto a high-fat diet. Uncoupling protein-3 mRNA levels do not increase in response to fasting in young pups. Only after day 15 of life, when fasting increases serum non-esterified fatty acids, uncoupling protein-3 mRNA is up-regulated by starvation. Over-nutrition or under-nutrition during lactation increases or decreases, respectively, uncoupling protein-3 mRNA expression in skeletal muscle. Regulation of uncoupling protein-3 gene expression in skeletal muscle during development is mediated by ontogenic and nutritional factors determining changes in circulating non-esterified fatty acids.
 ...
PMID:Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids. 1040 4

Studies of starvation and refeeding have implicated the genes coding for uncoupling protein-3 and -2 (UCP3, UCP2) as candidate genes in the regulation of lipids as metabolic fuels in skeletal muscle. To gain insight into the role of free fatty acid (FFA) flux in regulating the expression of these muscle UCP homologues, we recently reported that, in response to the anti-lipolytic agent nicotinic acid, utilized to reduce FFA flux at the input supply (i.e. circulating) level in fed and fasted rats, expression of the UCP3 and UCP2 genes was reduced in the soleus (predominantly slow-oxidative fibres), but not in the gastrocnemius (predominantly fast-glycolytic fibres) or tibials anterior (predominantly fast-oxidative-glycolytic fibres) muscles. In the present study, we examined UCP2 and UCP3 gene expression in these muscles from fed or fasted rats treated with etomoxir, an inhibitor of FFA flux at the output (i.e. mitochondrial oxidation) level. Fasting per se resulted in a threefold increase in serum FFA (P < 0.001) and in marked increases in the messenger ribonucleic acid (mRNA) expression of both UCP2 and UCP3 in all three muscles (P < 0.001). Treatment with etomoxir had no significant effect on serum FFA in the fed rats, but further elevated serum FFA in the fasted rats (P < 0.001). The mRNA levels of both UCP3 and UCP2 in response to etomoxir were significantly reduced in the tibialis anterior muscle in both fed and fasted states (P < 0.01), unaltered in the gastrocnemius muscle in both fed and fasted states and unaltered in the soleus muscle in the fed state, but increased in the fasted state, in parallel with the etomoxir-induced changes in serum FFA levels. Taken together, these results suggest the existence of positive feedback loops between FFA flux and muscle UCPs only in oxidative muscles--with that loop operating at the input FFA supply level for muscles with predominantly slow-oxidative fibres, and at the output FFA oxidation level for muscles with predominantly fast-oxidative-glycolytic fibres.
 ...
PMID:Skeletal muscle UCP3 and UCP2 gene expression in response to inhibition of free fatty acid flux through mitochondrial beta-oxidation. 1051 37

The relationship between UCP2 and UCP3 expression and mitochondrial proton conductance of rat skeletal muscle was examined. Rats were starved for 24 h and the levels of UCP2 and UCP3 mRNA and UCP3 protein were determined by Northern and Western blots. Proton conductance was measured by titrating mitochondrial respiration rate and membrane potential with malonate. Starvation increased UCP2 and UCP3 mRNA levels more than 5-fold and 4-fold, respectively, and UCP3 protein levels by 2-fold. However, proton conductance remained unchanged. These results suggest either that Northern and Western blots do not reflect the levels of active protein or that these UCPs do not catalyse the basal proton conductance in skeletal muscle mitochondria.
 ...
PMID:UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. 1062 7

We wished to gain insights into the role of skeletal muscle uncoupling protein-3 (UCP-3) in the elevated efficiency of fat recovery during refeeding after starvation. Previous observations have revealed that muscle UCP-3 expression is downregulated in rats during refeeding at 22 degrees C. Therefore, we investigated whether this also occurs during refeeding at thermoneutrality (29 C) or in the cold (6 C), since at these environmental temperatures the refed animals also show diminished thermogenesis and a higher rate of fat deposition than controls. The UCP-3 mRNA level in the skeletal muscles studied (soleus, gastrocnemius and tibialis anterior) was significantly lower in the refed group than in controls at thermoneutrality, but there were no such differences between these two groups in the cold. This effect of cold, namely abolishing refeeding-induced downregulation of skeletal muscle UCP, is specific to UCP-3 since the gene expression of skeletal muscle UCP-2 remained significantly lower in the refed than in the controls both at thermoneutrality and in the cold. These findings during refeeding in the cold therefore dissociate UCP-3 gene regulation from the adaptive reduction in thermogenesis that accelerates fat deposition during weight recovery. They also reveal differential responses of UCP-3 and UCP-2, whose significance is discussed in the light of our previously proposed hypothesis, which centers upon a role for these UCP homologues in the regulation of lipids as a fuel substrate.
 ...
PMID:Downregulation of skeletal muscle UCP-3 gene expression during refeeding is prevented by cold exposure. 1078 46

Fasting elicits a progressive increase in lipid metabolism within skeletal muscle. To determine the effects of fasting on the transcriptional regulation of genes important for metabolic control in skeletal muscle composed of different fiber types, nuclei from control and fasted (24 and 72 h) rats were subjected to nuclear run-on analysis using an RT-PCR-based technique. Fasting increased (P < 0.05) transcription rate of the muscle-specific uncoupling protein-3 gene (UCP3) 14.3- to 21.1-fold in white gastrocnemius (WG; fast-twitch glycolytic) and 5.5- to 7.5-fold in red gastrocnemius (RG; fast-twitch oxidative) and plantaris (PL; mixed) muscles. No change occurred in soleus (slow-twitch oxidative) muscle. Fasting also increased transcription rate of the lipoprotein lipase (LPL), muscle carnitine palmitoyltransferase I (CPT I), and long-chain acyl-CoA dehydrogenase (LCAD) genes 1.7- to 3.7-fold in WG, RG, and PL muscles. Transcription rate responses were similar after 24 and 72 h of fasting. Surprisingly, increasing metabolic demand during the initial 8 h of starvation (two 2-h bouts of treadmill running) attenuated the 24-h fasting-induced transcriptional activation of UCP3, LPL, CPT I, and LCAD in RG and PL muscles, suggesting the presence of opposing regulatory mechanisms. These data demonstrate that fasting elicits a fiber type-specific coordinate increase in the transcription rate of several genes involved in and/or required for lipid metabolism and indicate that exercise may attenuate the fasting-induced transcriptional activation of specific metabolic genes.
 ...
PMID:Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle. 1082 11

Mitochondrial proton leak in rat muscle is responsible for approx. 15% of the standard metabolic rate, so its modulation could be important in regulating metabolic efficiency. We report in the present paper that physiological concentrations of AMP (K(0.5)=80 microM) increase the resting respiration rate and double the proton conductance of rat skeletal-muscle mitochondria. This effect is specific for AMP. AMP also doubles proton conductance in skeletal-muscle mitochondria from an ectotherm (the frog Rana temporaria), suggesting that AMP activation is not primarily for thermogenesis. AMP activation in rat muscle mitochondria is unchanged when uncoupling protein-3 is doubled by starvation, indicating that this protein is not involved in the AMP effect. AMP activation is, however, abolished by inhibitors and substrates of the adenine nucleotide translocase (ANT), suggesting that this carrier (possibly the ANT1 isoform) mediates AMP activation. AMP activation of ANT could be important for physiological regulation of metabolic rate.
 ...
PMID:AMP decreases the efficiency of skeletal-muscle mitochondria. 1102 14

The hormone-sensitive and lipoprotein lipases are critical determinants of the metabolic adaptation to starvation. Additionally, the uncoupling proteins have emerged with potential roles in the metabolic adaptations required by energy deficiency. The objective of this study was to evaluate the expression (mRNA abundance) of uncoupling proteins 2 and 3 and that of hormone-sensitive and lipoprotein lipase in the adipose tissue and skeletal muscle of the pig in relationship to feed deprivation. Thirty-two male castrates (87 kg +/- 5%) were assigned at random to fed and feed-deprived treatment groups. After 96 hr, the pigs were euthanized and adipose and skeletal muscle tissue obtained for total RNA extraction and nuclease protection assays. Feed deprivation increased uncoupling protein 3 mRNA abundance 103-237% (P < 0.01) in longissimus and red and white semitendinosus muscle. In contrast, the increase in uncoupling protein 3 mRNA in adipose tissue was only 23% (P < 0.06), and adipose uncoupling protein 2 mRNA was not influenced (P > 0.66) by feed deprivation. The increased abundance of uncoupling protein 2 mRNA in the longissimus muscle of feed-deprived pigs was small (22%), but significant (P < 0.04). The expression of hormone-sensitive lipase was increased 46% and 64% (P < 0.04) in adipose tissue and longissimus muscle, respectively, by feed deprivation, whereas adipose lipoprotein lipase expression was reduced (P < 0.01) to 20% of that of the fed group. Longissimus lipoprotein lipase expression in the feed-deprived group was 37% of that of the fed group (P < 0.01), and similar reductions were detected in red and white semitendinosus muscle. Overall, these findings indicate that uncoupling protein 3 expression in skeletal muscle is quite sensitive to starvation in the pig, whereas uncoupling protein 2 changes are minimal. Furthermore, we conclude that hormone-sensitive lipase is upregulated at the mRNA level with prolonged feed deprivation, whereas lipoprotein lipase is downregulated.
 ...
PMID:Changes in the expression of uncoupling proteins and lipases in porcine adipose tissue and skeletal muscle during feed deprivation*(1). 1118 50


1 2 Next >>