PubMed Health⌕ Search

Biomedical subjects

A G Dulloo

Publications and source records attributed to A G Dulloo.

At least 37 records · Page 2Linked to original sources
PubMed2001

Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart.

During fasting, when overall metabolism changes, the contribution of glucose and fatty acids (FA) to cardiac energy production alters as well. Here, we examined if the heart is able to adapt to such fasting-induced changes by modulation of its gene expression. Rats were fed ad libitum or fasted for 46 h, resulting in reduced circulating glucose levels and a 3-fold rise in FA. Besides changes in the cardiac activity or content of proteins involved in glucose or FA metabolism, mRNA levels also altered. The cardiac expression of genes coding for glucose-handling proteins (glucose transporter GLUT4, hexokinase I and II) was up to 70% lower in fasted than in fed rats. In contrast, the mRNA levels of various genes involved in FA transport and metabolism (FA translocase/CD36, muscle-type carnitine palmitoyl transferase 1, long-chain acyl-CoA dehydrogenase) and of the uncoupling protein UCP-3 increased over 50% in hearts of fasted rats. Surprisingly, mRNA levels of the fatty acid- activated transcription factors PPARalpha and PPARbeta/delta were reduced in hearts of fasted rats, whereas in livers, fasting led to a marked rise in PPARalpha mRNA. Reducing FA levels by nicotinic acid administration during the final 8 h of fasting did not affect the expression of the majority of metabolic genes, but totally abolished the induction of UCP-3. In conclusion, the adult rat heart responds to changes in nutritional status, as provoked by 46 h fasting, through adjustment of glucose as well as FA metabolism at the level of gene expression.

Acyl-CoA Dehydrogenase↗
PubMed2000

Downregulation of skeletal muscle UCP-3 gene expression during refeeding is prevented by cold exposure.

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.

Animal Feed↗
PubMed2000

Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity.

The thermogenic effect of tea is generally attributed to its caffeine content. We report here that a green tea extract stimulates brown adipose tissue thermogenesis to an extent which is much greater than can be attributed to its caffeine content per se, and that its thermogenic properties could reside primarily in an interaction between its high content in catechin-polyphenols and caffeine with sympathetically released noradrenaline (NA). Since catechin-polyphenols are known to be capable of inhibiting catechol-O-methyl-transferase (the enzyme that degrades NA), and caffeine to inhibit trancellular phosphodiesterases (enzymes that break down NA-induced cAMP), it is proposed that the green tea extract, via its catechin-polyphenols and caffeine, is effective in stimulating thermogenesis by relieving inhibition at different control points along the NA-cAMP axis. Such a synergistic interaction between catechin-polyphenols and caffeine to augment and prolong sympathetic stimulation of thermogenesis could be of value in assisting the management of obesity. International Journal of Obesity (2000) 24, 252-258

Adipose Tissue, Brown↗
PubMed1999

UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged.

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.

Animals↗
PubMed1999

Skeletal muscle UCP3 and UCP2 gene expression in response to inhibition of free fatty acid flux through mitochondrial beta-oxidation.

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.

Animals↗
PubMed1999

The control of partitioning between protein and fat during human starvation: its internal determinants and biological significance.

Human subjects vary in the extent to which their body's protein and fat compartments are mobilized for fuel during starvation. Although an inverse association between the initial adiposity and the contribution of protein as fuel during starvation has been known for nearly a century, interest in the quantitative importance and functional significance of the initial percentage fat as a determinant of biological variation in energy-partitioning between protein and fat (and hence in determining the partitioning characteristic of the individual) is relatively recent. The present paper addresses these issues by revisiting the classic Minnesota experiment of semi-starvation and refeeding from a standpoint of system physiology. In a quantitative analysis of the relationship between the initial body composition (ration FAT0: fat-free mass (FFM)0) and the composition of weight loss (ratio delta FAT: delta FFM) in the thirty-two men in the Minnesota study, the arguments are put forward that the fraction of FFM lost when the fat stores reach total depletion is independent of the initial percentage fat, and that this fraction represents the 'dispensable' component of the protein compartment that is compatible with life (i.e. the protein energy-reserve, rp). The concepts are developed that (1) the initial percentage body fat (which reflects the initial ratio FAT0:FFM0) provides a 'memory of partitioning' which dictates the control of partitioning between protein and fat in such a way that both the protein energy-reserve (rp) and the fat energy-reserve (rf) each complete depletion simultaneously, a strategy that would ensure maximum length of survival during long-term food scarcity, and that (2) variability in the relative sizes of these two energy reserves (i.e. in rf:rp) could, in addition to the initial percentage fat, also contribute to human variability in energy-partitioning. The basic assumptions underlying this re-analysis of the Minnesota data, and the concepts that are derived from it, have been integrated in the simple mathematical model for predicting the partitioning characteristic of the individual. This model is used to explain how variability in the fraction of the protein compartment that could function as an energy reserve (rp) can be as important as the initial percentage fat in determining inter-individual variability in protein-sparing during the early phase of starvation, in fuel partitioning during prolonged starvation, or in the maximum percentage weight loss during starvation. The elucidation of factors underlying variability in the size of the protein energy-reserve may have important implications for our understanding of the pathophysiology of starvation and age-associated susceptibility to muscle wasting, and in the clinical management of cachexia and obesity.

Body Composition↗
PubMed1999

Low-protein overfeeding: a tool to unmask susceptibility to obesity in humans.

In search for an approach to identify physiological targets for therapeutic intervention in obesity management, we have revisited the classic human overfeeding studies of the 1960s, with new emphasis on a 'subgroup' of volunteers who were shifted between overfeeding on a typical affluent (normal-protein) diet and overfeeding on a low-protein diet. Following a re-analysis of these data, the arguments are put forward that since low-protein overfeeding is not only a potent stimulus of thermogenesis, but also an amplifier (or magnifier) of the small inter-individual variations in thermogenesis on the affluent (normal-protein) diet, it can be used as a tool to unmask some of the genetic and metabolic basis underlying human susceptibility to leanness and fatness.

Body Temperature Regulation↗
PubMed1999

Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans.

BACKGROUND: Current interest in the role of functional foods in weight control has focused on plant ingredients capable of interfering with the sympathoadrenal system. OBJECTIVE: We investigated whether a green tea extract, by virtue of its high content of caffeine and catechin polyphenols, could increase 24-h energy expenditure (EE) and fat oxidation in humans. DESIGN: Twenty-four-hour EE, the respiratory quotient (RQ), and the urinary excretion of nitrogen and catecholamines were measured in a respiratory chamber in 10 healthy men. On 3 separate occasions, subjects were randomly assigned among 3 treatments: green tea extract (50 mg caffeine and 90 mg epigallocatechin gallate), caffeine (50 mg), and placebo, which they ingested at breakfast, lunch, and dinner. RESULTS: Relative to placebo, treatment with the green tea extract resulted in a significant increase in 24-h EE (4%; P < 0.01) and a significant decrease in 24-h RQ (from 0.88 to 0.85; P < 0.001) without any change in urinary nitrogen. Twenty-four-hour urinary norepinephrine excretion was higher during treatment with the green tea extract than with the placebo (40%, P < 0.05). Treatment with caffeine in amounts equivalent to those found in the green tea extract had no effect on EE and RQ nor on urinary nitrogen or catecholamines. CONCLUSIONS: Green tea has thermogenic properties and promotes fat oxidation beyond that explained by its caffeine content per se. The green tea extract may play a role in the control of body composition via sympathetic activation of thermogenesis, fat oxidation, or both.

Adipose Tissue↗
PubMed1999

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.

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.

Animals↗
PubMed1998

Adaptive reduction in basal metabolic rate in response to food deprivation in humans: a role for feedback signals from fat stores.

We assessed the importance of lean and fat tissue depletion as determinants of the adaptive reduction in basal metabolic rate (BMR) in response to food deprivation by reanalyzing the data on BMR and body composition for the 32 men participating in the classic Minnesota experiment of semi-starvation and refeeding. We used individual data on BMR, body fat, and fat-free mass (FFM) assessed during the control (prestarvation) period, at weeks 12 and 24 of semistarvation (S12 and S24), and week 12 of restricted refeeding (R 12) to calculate an index of the reduction in thermogenesis at S12, S24, and R12, defined as the change in BMR adjusted for changes in FFM and fat mass, and an index of the state of depletion of the fat mass and FFM compartments at these times, defined as the deviation in fat mass or FFM relative to control values. The results indicated a positive relation between the reduction in thermogenesis and the degree of fat mass depletion (but not FFM depletion) during weight loss as well as during weight recovery (r = 0.5, P < 0.01). Furthermore, the residual variance was predicted by the initial (prestarvation) percentage fat and the cormic index (sitting height/height). Taken together, these results in normal-weight men responding to severe food deprivation reveal anthropometric predictors for human interindividual variability in the capacity for energy conservation and suggest that the adaptive reduction in BMR is partly determined by an autoregulatory feedback control system linking the state of depletion of fat stores to compensatory mechanisms that suppress thermogenesis.

Adipose Tissue↗
PubMed1998

Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate?

The mRNA expressions of UCP2 and UCP3, two newly described genes with high sequence homology to the uncoupling protein UCP1 in brown adipose tissue (BAT), were examined in two skeletal muscles (gastrocnemius and soleus) as well as in interscapular BAT (IBAT) of the rat in response to food deprivation and controlled refeeding. In IBAT (a tissue highly dependent on lipids for thermogenesis), the pattern of mRNA expression of UCP2 and UCP3 closely follows that of UCP1: it was markedly down-regulated during food deprivation (when this tissue's thermogenesis and lipid fuel requirements are decreased) and restored to control levels by day 5 of refeeding. By contrast, in the gastrocnemius muscle (a mixed fiber type muscle with a high capacity to shift between glucose and lipids as fuel substrate), mRNA expression of both UCP2 and UCP3 mRNA was found to be markedly up-regulated during food deprivation (when this tissue's thermogenesis is also decreased but its lipid fuel utilization is increased). The expressions were subsequently found to be markedly down-regulated upon transition to refeeding, with mRNA levels remaining below control levels on days 3, 5, and 10 of refeeding (period of enhanced efficiency of body fat deposition). In the soleus muscle (an oxidative type muscle with higher dependency on lipids than the gastrocnemius, and hence with a lower capacity to shift between lipids and glucose as fuel substrate), UCP homologues were also found to be up-regulated during food deprivation, but changes in their mRNA expression contrast with those in the gastrocnemius muscle both in their much lower magnitude of response to food deprivation and in their more rapid restoration to control levels during refeeding. Up-regulation of UCP2 and UCP3 gene expressions in skeletal muscle during food deprivation was found to persist at thermoneutrality (i.e., under conditions of reduced thermoregulatory thermogenesis). Together, these tissue-dependent differential mRNA expressions of the UCP homologues in IBAT, gastrocnemius, and soleus muscles during food deprivation and refeeding are much more consistent with a role for UCP2 and UCP3 in the regulation of lipids as fuel substrate rather than as mediators of regulatory thermogenesis.

Adipose Tissue, Brown↗
PubMed1998

Metabolic-cytokine responses to a second immunological challenge with LPS in mice with T. gondii infection.

Injection of 10 cysts of Toxoplasma gondii (Me49 strain) into Swiss Webster mice results in 1) an acute phase of infection lasting for 2-3 wk, characterized by weight loss, and 2) a chronic phase in which surviving mice show either partial weight recovery (Gainers) or persistent, although stable, cachexia (Nongainers). In response to a second immunological stimulation with lipopolysaccharide (LPS) in the chronic phase of the infection, it is shown that 1) the increase in energy expenditure was more prolonged in both groups of infected mice than in controls, 2) the intensity and duration of hypophagia were also differently affected with Nongainers > Gainers > controls, and 3) the infected mice had higher serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-10 and a lower ratio of IL-10 to TNF-alpha than controls. In contrast, serum IL-4 increased to the same level in all three groups. Evaluation of the permeability of the blood-brain barrier by intravenous injection of Evans blue revealed a marked staining in the brain of only the infected Nongainers. Taken together, these results indicate that, in mice with chronic toxoplasmosis, a second nonspecific challenge (with LPS) exacerbates the hypophagic and hypermetabolic states, the latter being associated with hyperresponsiveness in TNF-alpha and IL-10 production. Furthermore, the greater exacerbation of the hypophagic state in mice showing persistent cachexia may be due to a preexisting higher permeability of the blood-brain barrier, which would allow a greater access of plasma-borne cytokines and/or other neuroimmunologically active substances to the central nervous system.

Animals↗
PubMed1998

Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs: is there a role for circulating free fatty acids?

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.

Adipose Tissue↗
PubMed1997

Regulation of body composition during weight recovery: integrating the control of energy partitioning and thermogenesis.

Studies of experimental starvation that were carried out in healthy volunteers during the first half of this century often provide an invaluable source of 'untapped' data. The motivation and desire to gain a better insight into the regulation of body composition by re-analysing these data in the light of more 'modern' concepts of energy partitioning and thermogenesis become irresistible when similar studies can no longer be performed in humans, if only for ethical reasons. This paper brings together new findings, largely centered upon recent re-analysis of data from the classical studies of experimental starvation, semi-starvation and refeeding, and proposes a theory of regulation of body composition during weight recovery in which the cardinal features rest upon three auto-regulatory control systems. These control systems--operating via energy partitioning and two distinct forms of adaptive thermogenesis--have been integrated into a compartmental model for the autoregulation of body composition during cycles of underfeeding/refeeding. This model can be used to explain the individual pattern of lean and fat tissue deposition during weight recovery in situations ranging from rehabilitation after malnutrition/cachexia to the relapse of obesity. It also provides a framework of 'system physiology' for integrating the advances in molecular biology into this area of nutritional energetics.

Journal Article↗
PubMed1997

Poststarvation hyperphagia and body fat overshooting in humans: a role for feedback signals from lean and fat tissues.

An increase in the sensation of hunger and overeating after a period of chronic energy deprivation can be part of an autoregulatory phenomenon attempting to restore body weight. To gain insights into the role of fat and lean tissue depletion as determinants of such a hyperphagic response in humans, we reanalyzed the individual data on food intake and body composition available for the 12 starved and refed men in the classical Minnesota Experiment after a shift from a 12-wk period of restricted refeeding to an ad libitum refeeding period of 8 wk. For each individual, the following were determined: 1) the total hyperphagic response during the ad libitum refeeding period, calculated as the energy intake in excess of that during the prestarvation (control) period; 2) the degree of fat recovery and that of fat-free-mass (FFM) recovery before ad libitum refeeding, calculated as the deviation in fat and FFM from their respective prestarvation values (ie, the amount of fat or FFM before ad libitum refeeding as a percentage of fat or FFM during the control period); and 3) the deficit in energy intake before ad libitum refeeding, calculated as the difference between the energy intake during the period of restricted refeeding and that during the control period. The results indicate that 1) the total hyperphagic response is inversely correlated with the degree of fat recovery (r = -0.6) as well as with that of FFM recovery (r = -0.5), 2) the correlation between hyperphagia and FFM recovery persists after adjustment for fat recovery, and 3) the correlations between hyperphagia and fat recovery or FFM recovery persist after adjustment for the variance in the energy deficit during the preceding period of restricted refeeding. Taken together, these results in humans suggest that poststarvation hyperphagia is determined to a large extent by autoregulatory feedback mechanisms from both fat and lean tissues. These findings, which have implications for both the treatment of obesity and for nutritional rehabilitation after malnutrition and cachexia, have been integrated into a compartmental model of autoregulation of body composition, and can be used to explain the phenomenon of poststarvation overshoot in body fat.

Adipose Tissue↗