A role for interferon-gamma in the hypermetabolic response to murine toxoplasmosis.

Toxoplasma gondii (Me49 strain) infection into Swiss Webster mice is followed by hypermetabolism and weight loss in the acute phase lasting 14 days. In the subsequent chronic phase of infection, mice showed either a resolution of hypermetabolism and partial weight recovery (Gainers) or persistent hypermetabolism, with stable weight loss (Non-Gainers). The hypermetabolic response was not associated with an augmentation in the thermogenic uncoupling protein 1 (UCP1) mRNA expression in interscapular brown adipose tissue (BAT), but rather UCP1 expression was reduced. Hypermetabolism is associated with high lipid oxidation as attested by a low respiratory quotient (RQ). Neither BAT nor sympathetic nervous system appear to be involved in the increased lipid utilization, since propranolol did not increase the lower RQ in infected mice. The mitochondrial lipid oxidation blocker mercaptoacetate did not reestablish the respiratory quotient RQ in acute infection (on day 4) and in chronically infected Non-Gainer mice. This suggests an important extra-mitochondrial mechanism of lipid oxidation. Increased lipid peroxidation was detected especially in serum, lung, spleen and liver, which are rich in macrophage-type cells. Following infection peritoneal macrophages exhibited an enhanced capacity to produce reactive oxygen species (ROS). Using IFN-gamma knockout mice we observed that not only the hypermetabolic response was ablated in these mice but there was not a marked increase in ROS production or preferential oxidation/peroxidation of lipids in the acute phase of infection prior to the cachectic phase. The present study described a novel hypermetabolic mechanism involving enhanced lipid peroxidation dependent on IFN-gamma, especially associated with tissues rich in macrophages.

Differential roles of tumor necrosis factor-alpha and interferon-gamma in mouse hypermetabolic and anorectic responses induced by LPS.

Lipopolysaccharide (LPS)-induced effects on energy balance are characterized by alterations in energy expenditure (hypermetabolism) and food intake (anorexia). To study the role of tumour necrosis factor alpha (TNF-alpha) on some of these metabolic responses to endotoxin, we have used transgenic mice expressing soluble tumour necrosis factor receptor-1 IgG fusion protein (TNFR1-IgG) as well as TNF-alpha knockout (KO), lymphotoxin-alpha (LT-alpha) KO, and interferon-gamma receptor (IFN-gamma R) KO mice. The results from TNFR1-IgG transgenic mice suggest that the hypermetabolic and anorectic responses induced by LPS are independently regulated since, in the absence of TNF-alpha or LT-alpha, the LPS-induced hypermetabolism is almost prevented but not the anorexia. The anorectic response shows the strongest association with IFN-gamma since both IFN-gamma R KO mice and mice treated with anti-IFN-gamma antibody showed marked reduction in the LPS-induced anorexia compared to other mice. IFN-gamma R KO mice also have an attenuated thermogenic response to endotoxin. Anti-Asialo GM1 antibody treatment attenuated both the hypermetabolic and anorectic responses to LPS, to an extent comparable to that observed in IFN-gamma R KO mice. This finding suggests that natural killer cells (lymphocytic subsets) may be involved in IFN-gamma production and play an important role in the metabolic alterations induced by LPS. We also showed that the hypermetabolic response of control mice is associated with an upregulation of cytokine expression within the brain and an increase in permeability of the blood brain barrier. LPS-induced anorexia appears to involve peripheral cytokine expression.

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

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.

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.

Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii.

The temporal pattern of changes in energy balance and cytokine mRNA expression in spleen and brain were examined in a mouse model of infection with Toxoplasma gondii. During days 1-7 postinfection, food intake was unaltered, but energy expenditure was significantly increased, and this was associated with elevated tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1, IL-5, and interferon (IFN)-gamma. The hypermetabolic state persisted during subsequent anorexia, whose onset coincided with elevated IL-2, and at the end of the acute phase of cachexia, the dual anorexic and hypermetabolic states were associated with the cytokines examined: TNF-alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, and IFN-gamma. In the chronic phase of the infection, the mice showed either partial weight recovery (gainers) or no weight regain (nongainers). The infected gainers, though still hypophagic, were no longer hypermetabolic, and their cytokine mRNA was no longer elevated, except for TNF-alpha and IL-10. In contrast, the infected nongainers continued to show both anoroxia and hypermetabolism, which were associated with elevations in all cytokines examined and particularly those of the TH2 profile (IL-4 and IL-5) and IL-6. Taken together, these studies reveal a distinct pattern of cytokine mRNA expression underlying 1) hypermetabolism vs. anorexia, 2) acute vs. chronic cachexia, and 3) stable weight loss vs. partial weight recovery.

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.

Dissociation of systemic GH-IGF-I axis from a genetic basis for short stature in African Pygmies.

OBJECTIVES: To test the hypothesis that the primary cause of short stature in African Pygmies resides in low levels of insulin-like growth factor I (IGF-I), and to evaluate whether any observed alterations in their systemic IGF-I status can be dissociated from the effects of malnutrition and/or altered immune status. SETTING: Expedition to camps of partially sedentarized African Pygmies and neighbouring Bantu farmers living in the equatorial rain forest of Eastern Cameroon. DESIGN: Serum assays for hormonal and immune status were conducted for individuals (children, adolescents, young and old adults) showing no overt clinical nor biochemical signs of malnutrition, as judged from anthropometry, clinical examinations and serum assays of albumin, pre-albumin, retinol-binding protein, transferrin, iron, zinc, magnesium and calcium. RESULTS: African Pygmies did not differ from Europeans or Bantus in mean serum IGF-I concentrations, nor in the relationship between serum IGF-I and its major binding protein (IGFBP-3). However, although in both African groups the immunoglobulins IgG, IgM and IgE as well as the C-reactive protein and ceruloplasmin were above the normal range of European references, the Pygmies differed from their Bantu neighbours in their much higher IgG and IgM serum levels. A plot of serum IGF-I against these immunoglobulins in Pygmies revealed a reverse sigmoidal relationship, with the low IGF-I values associated with serum levels of IgG and IgM which clearly exceeded those found in the Bantus. CONCLUSIONS: This study indicates that in growing and adult African Pygmies showing no clinical nor biochemical signs of nutritional deficiency, serum IGF-I and IGFBP-3 (hence IGF-I bioavailability to its receptors) are essentially normal, and that low circulating levels of IGF-I in Pygmies reside in differential exposure and/or responsiveness to environmental challenge (e.g. infections) rather than in an inherited defect in the systemic growth-hormone (GH)-IGF-I axis.

Autoregulation of body composition during weight recovery in human: the Minnesota Experiment revisited.

OBJECTIVES: To gain insights into the control systems underlying human variability in the regulation of body composition during weight recovery, as well as the disproportionate recovery of fat relative to lean tissue, the classical Minnesota Experiment conducted on 32 men subjected to long-term semi-starvation and refeeding was revisited with the following objectives: (1) to determine whether the control of energy-partitioning between lean and fat tissues during weight loss and weight recovery is an individual characteristic, and if a predictor can be statistically identified, (2) to determine whether the reduction in thermogenesis during weight loss persists during weight recovery, and underlies the disproportionate recovery of fat tissue and (3) to integrate the control of energy-partitioning and that of thermogenesis in order to explain the pattern of lean and fat tissue mobilisation and deposition during weight loss and weight recovery. METHODS: Individual data on body weight, body fat, fat-free-mass (FFM), and basal metabolic rate (BMR), assessed during the control baseline period (i.e. prior to weight loss), at the end of 24 weeks of semi-starvation, and at the end of a 12 week period of restricted refeeding, were used to calculate the following parameters: (i) a quantitative index of energy-partitioning, the P-ratio, defined as the proportion of body energy mobilised as protein during weight loss, or as the proportion of body energy deposited as protein during weight recovery, (ii) a quantitative index of changes in thermogenesis, defined as the change in BMR adjusted for FFM (or for both FFM and fat mass) and (iii) the degree of replenishment of fat and FFM compartments, defined as the recovery of body fat and FFM (during refeeding) as a percentage of that lost during semi-starvation. RESULTS: This re-analysis indicates the following: (i) a large inter-individual variability in P-ratio during both weight loss and weight recovery, but for a given individual, the P-ratio during refeeding is strongly correlated with the P-ratio during semi-starvation, (ii) body composition during the control period is the most important predictor of variability in P-ratio, such that the higher the initial % body fat, the lower the proportion of energy mobilised as protein, and hence the greater the propensity to mobilise fat during semi-starvation and to subsequently deposit fat during refeeding and (iii) at week 12 of refeeding, the change in adjusted BMR is found to be reduced by a magnitude which is inversely proportional to the degree of fat recovery, but is unrelated to the degree of FFM recovery. A quantitative relationship is derived between the P-ratio during refeeding, the % fat recovery, and the P-ratio during semi-starvation. CONCLUSIONS: Evidence is presented here suggesting that (i) human variability in the pattern of lean and fat tissue deposition during weight recovery is to a large extent determined by individual variations in the control of energy-partitioning, for which the initial % body fat is the most important predictor and (ii) the disproportionate gain in fat relative to lean tissue during weight recovery is contributed by a reduction in thermogenesis (i.e. increased efficiency of food utilization) for accelerating specifically the replenishment of the fat stores. These control systems, operating via energy-partitioning and thermogenesis, have been integrated into a compartmental model for the regulation of body composition during underfeeding/refeeding, and can be used to explain the individual pattern of lean and fat tissue deposition during weight recovery in situations ranging from the rehabilitation after malnutrition to the relapse of obesity.

Twenty-four-hour energy expenditure and urinary catecholamines of humans consuming low-to-moderate amounts of medium-chain triglycerides: a dose-response study in a human respiratory chamber.

OBJECTIVE: To determine whether medium-chain triglycerides, in low-to-moderate amounts consumed with meals (at breakfast, lunch and dinner), can increase daily energy expenditure (EE) and 24-h urinary excretion of catecholamines in humans. DESIGN: Dose-response study conducted under double-blind randomised design. SETTING: Respiratory chamber at the Faculty of Medicine, University of Geneva. SUBJECTS: Eight healthy young men were recruited from the student population by advertisement in our Faculty. METHODS: 24-h EE and urinary catecholamines were measured in each subject during stay in a respiratory chamber on four separate occasions. These were randomised between four different combinations of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT), a total 30g/day, which was consumed with their habitual diet in three equal parts (10g each) at breakfast, lunch, and dinner in the following ratio of MCT: LCT (g/g) 0:30, 5:25, 15:15 and 30:0. RESULTS: 24-h EE increased significantly with increasing MCT:LCT ratio (ANOVA, P < 0.001), with the diet providing a total of 15-30 g MCT per day stimulating 24-h EE by 5%: this corresponds to a mean absolute increase in daily EE of approximately 500kJ, with individual values varying between 268 kJ and 756 kJ. No significant differences were observed in respiratory quotient nor in urinary nitrogen losses across diets, but 24-h urinary noradrenaline was significantly increased (ANOVA, P < 0.025), whereas adrenaline and dopamine were unaltered. CONCLUSIONS: This study suggests that relatively low-to-moderate intake of MCT (15-30 g per day) as part of habitual diet may play a role in the control of human body composition by enhancing daily EE, and that this effect is mediated at least in part through activation of the sympathetic nervous system.

Adrenoceptor heterogeneity in human white adipocytes differentiated in culture as assessed by cytosolic free calcium measurements.

Changes in intracellular calcium concentration [Ca2+]i in response to norepinephrine (NE) and to various adrenergic agonists were monitored by dual excitation microfluorimetry in single human adipocytes differentiated in culture and loaded with fura-2 acetoxymethyl ester (fura-2 AM). The addition of NE elicited increases in [Ca2+]i that were depending on the cell, (1) either rapid (time to peak: 9 +/- 3 s), large, and transient; or (2) slow (time to peak: 125 +/- 8 s), small, and sustained. The rapid and large [Ca+]i response, which was inhibited by 90% by the alpha 1-antagonist prazosin and only by 20% by the non-specific beta antagonist (-)-propranolol, was considered to be mediated by the alpha 1-adrenoceptor. In fact, an alpha 1A-adrenoceptor was found to be expressed in human white adipose tissue. Consecutive additions of beta-agonists specific for each subtype of alpha-adrenoceptor enabled the characterization of four cell populations with different response patterns: 47% of the cells had alpha 1- and beta 1-, beta 2- and beta 3-induced [Ca2+]i responses; 29% had only beta 1-, beta 2-, beta 3-responses; 14% had alpha 1- and beta 3-responses, and 10% had only an alpha 1-response. Taken together, these results show that in differentiated human adipocytes: (1) alpha 1- and beta-adrenergic stimulations induce [Ca2+]i increases with different kinetics and amplitudes; (2) there is a beta 3-adrenergic response similar to the beta 1- or beta 2-adrenergic responses; and (3) there is a marked adrenoceptor heterogeneity.

Thermogenesis associated with spontaneous activity: an important component of thermoregulatory needs in rats.

1. Quantification of the energy cost of spontaneous activity in freely moving lean and obese Zucker rats was performed at 28 degrees C and during acute cold exposure (from 28 to 5 degrees C). 2. An open-circuit metabolic chamber was supplemented with an ultrasensitive ergometric platform equipped with six undirectional accelerometers and with an opto-electronic device for location of the rat's centre of mass. 3. Resting and mean metabolic rates during control and cold-exposure periods were similar in both groups of rats. The 'extra thermogenesis' (ET), i.e. the difference between mean and resting metabolic rate, amounted to 11.7 +/- 1.1 and 8.6 +/- 0.7% of resting metabolic rate at 28 degrees C, and 39.7 +/- 2.9 and 34.1 +/- 2.9% of resting metabolic rate during cold exposure for lean and obese rats, respectively. 4. During the control period obese rats moved 3.71 +/- 0.61 m h-1 and lean rats 8.69 +/- 0.57 m h-1, but during cold exposure the distance moved by obese rats increased 3.58 +/- 0.33-fold whereas that moved by lean rats only increased 1.40 +/- 0.06-fold. The external work performed during spontaneous activity seldom reached 1.0% of the increase in metabolic rate. 5. In obese rats, weight was a good predictor of the distance covered, and cold exposure induced the same percentage increase in both distance and ET. Activity-associated thermogenesis of obese rats was the predominant thermogenic source that substituted for their atrophied brown fat thermogenesis whereas in lean rats with active brown fat these correlations were not found.

Dissociation of enhanced efficiency of fat deposition during weight recovery from sympathetic control of thermogenesis.

Studies reported here examined the extent to which conditions known to suppress or markedly increase the sympathetic control of thermogenesis influence enhanced efficiency of fat deposition during weight recovery after caloric restriction. To this end, measurements of energy balance and changes in body energy compartments during refeeding of rats pair fed with weight-matched controls were conducted over a 2-wk period at 22 degrees C, at thermoneutrality (29 degrees C), or in the cold (6 degrees C). The results indicate that, despite identical (or slightly lower) energy intake relative to the respective controls, the refed animals showed greater gain in body fat (by 2- to 2.5-fold), 10-12% lower energy expenditure, and higher energetic efficiency (60-80%) than the controls at all three environmental temperatures. In contrast, protein gain was not different between the refed and control groups. Thus the energy-conserving mechanism specific to acceleration of fat deposition during weight recovery persists when sympathetically driven thermogenesis is shifted from very low to very high intensity. These findings raise the possibility that this energy-conserving mechanism during refeeding may be distinct from sympathetic-dependent mechanisms underlying adaptive reduction in thermogenesis during severe energy deficit and weight loss.

Fish oil enhances macrophage tumor necrosis factor-alpha mRNA expression at the transcriptional level.

Dietary supplementation with fish oil has previously been shown to enhance in vivo and in vitro (macrophage) synthesis of tumor necrosis factor-alpha (TNF-alpha) in response to bacterial lipopolysaccharide (LPS) stimulation. The studies reported here were conducted to gain insight into the molecular mechanisms of this nutrient-immune interaction by comparing the concentration, rate of synthesis, and rate of decay of TNF-alpha mRNA upon LPS stimulation of macrophages obtained from mice fed high-fat diets, rich in either fish oil, corn oil, or coconut oil, or a low-fat diet for a period of 4 weeks. The results indicate that compared with the other diet groups, LPS stimulation of macrophages from mice fed fish oil resulted in (1) enhanced levels of mRNA and protein for TNF-alpha, and (2) increased transcription of TNF-alpha mRNA as assessed by nuclear run-on assays. Posttranscriptional studies showed that the rate of decay of TNF-alpha mRNA did not vary significantly for macrophages from mice fed with fish oil as compared with corn oil. Further studies using actinomycin D and cycloheximide suggested that RNA synthesis, but not protein synthesis, was necessary for TNF-alpha mRNA accumulation. Taken together, the present studies suggest that fish oil enhances macrophage TNF-alpha mRNA expression at the transcriptional level. Although such TNF-alpha upregulation may provide a mechanism for the beneficial effects of fish oil in certain inflammatory and immune disorders, it can also underlie its potential deleterious effects if the degree of upregulation leads to exaggerated TNF-alpha production that exceeds the limits of benefit to reach toxic levels.

Differential effects of high-fat diets varying in fatty acid composition on the efficiency of lean and fat tissue deposition during weight recovery after low food intake.

The energetics of body weight recovery after low food intake was examined in the rat during refeeding for 2 weeks with isocaloric amounts of high-fat (HF) diets providing 50% of energy as either lard, coconut oil, olive oil, safflower oil, menhaden fish oil, or a mixture of all these fat types. The results indicate that for both body fat and protein, the efficiency of deposition was dependent on the dietary fat type. The most striking differences were found (1) between diets rich in n-3 and n-6 polyunsaturated fatty acids (PUFA), with the diet high in fish oil resulting in a greater body fat deposition and lower protein gain than the diet high in safflower oil; and (2) between diets rich in long-chain (LCT) and medium-chain triglycerides (MCT), with the diet high in lard resulting in a greater gain in both body fat and protein than the diet high in coconut oil. Furthermore, the diet high in olive oil (a monounsaturated fat) and the mixed-fat diet (containing all fat types) were found to be similar to the fish oil diet in that the efficiency of fat deposition was greater (and that of protein gain lower) than with the diet high in safflower oil. Neither the efficiency of fat gain nor that of protein gain were found to correlate with fasting plasma insulin, the insulin to glucose ratio, or plasma lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Paraxanthine (metabolite of caffeine) mimics caffeine's interaction with sympathetic control of thermogenesis.

The notion that paraxanthine (the major dimethylated by-product of caffeine) may be a biologically active metabolite that could mediate some of the effects of caffeine was tested in relation to the well-established property of caffeine as a thermogenic stimulant. From studies measuring the in vitro respiration rates of rat brown adipose tissue in the basal state and in response to ephedrine (an enhancer of norepinephrine release from sympathetic nerve endings), it is shown that paraxanthine has the same potency as its parent compound, caffeine, in interacting with the adrenergic system to potentiate thermogenesis. These data provide the first direct demonstration of a physiological effect of the main metabolite of caffeine and raise the possibility that paraxanthine may contribute importantly to the ability of caffeine to potentiate the thermogenic effects of well-known stimuli of the sympathetic nervous system such as cold exposure, moderate exercise, and sympathomimetic drugs.

[Autoregulation of body weight and body composition in man. A systematic approach through models and simulation]. / L'auto-régulation du poids et de la composition corporelle chez l'homme. Une approche systémique par modélisation et simulation.

The regulation of body weight and its composition in humans is examined from the standpoint of system analysis. It is based upon the hypothesis that the ultimate purpose for modulating body energy stores is to ensure the maximum duration for survival of the individual in the face of calorie deficit. A mathematical model, which is built on this hypothesis, allows quantitative simulation of variations in body weight and composition which occur during cycles of underfeeding/refeeding, and is achieved with the use of three global parameters. One of them controls the partitioning of body energy stores between fat and lean tissues, and the other two are concerned with the control of adaptive thermogenesis. The first of these two parameters for thermogenesis modulates the efficiency of fat storage by a function which is inversely proportional to the level of replenishment of the adipose tissues, and the other one controls regulatory thermogenesis which is a direct function of energy imbalance. These two forms of adaptive thermogenesis operate independently of each other and their amplitude depends upon the nutritional background of the individual. This model can be used as a theoretical framework for integrating numerous data in the literature on physiological processes that are involved in the regulation of body weight and body composition.

Autonomic nervous control of heart rate at altitude (5050 m).

To investigate possible changes in autonomic regulation of heart rate as a result of acclimatization to high altitude, indexes of autonomic nervous activity were obtained non invasively by spectrum analysis of heart rate variability on five healthy male subjects [age, 31 (SEM 2) years] during a postural change from supine to seated, both at sea level and after 1 month of exposure to an altitude of 5050 m. Heart rate fluctuations at the respiratory frequency (high frequency, HF) are mediated by the parasympathetic system whereas fluctuations at about 0.1 Hz (low frequency, LF) are due to both sympathetic and parasympathetic nervous systems. Maximal heart rate, as measured during an incremental exercise test, decreased from 184 (SEM 5) beats.min-1 at sea level to 152 (SEM 2) beats.min-1 at 5050 m. At sea level, the change in posture from supine to seated induced an increase in LF amplitude accompanied by an increase or a decrease in HF amplitude, whereas after 1 month at altitude the HF amplitude decreased in all subjects, with little or no change in LF amplitude. These results indicate a changed strategy of heart rate regulation after acclimatization to high altitude. At sea level, the postural change induced an increase in sympathetic activity in all subjects with different individual vagal responses, whereas at altitude the postural change induced a net decrease in vagal tone in all subjects, with little or no change in sympathetic activity. These results corroborate the reported reduced sensitivity of the heart to adrenergic drive in chronic hypoxia, which may, at least in part, explain the decreased maximal heart rate in altitude-acclimatized human subjects.

Adaptive role of energy expenditure in modulating body fat and protein deposition during catch-up growth after early undernutrition.

After 10 or 30 d of growth arrest due to undernutrition during the early weaning period, rehabilitated rats fed ad libitum showed the phenomenon of catch-up growth, ie, gains in body weight and body protein were greater by 50% and 25%, respectively, (P < 0.001) than those of controls with similar starting body weight [ie, weight-matched (WM) controls]. These increases, however, were entirely dependent on the higher food intake because they failed to occur when food intakes were maintained at similar amounts to those for WM controls. In contrast, independent of whether the rehabilitated groups were spontaneously hyperphagic relative to WM controls or made normophagic by pair-feeding to WM controls, the gross energetic efficiency was increased (P < 0.01) and body fat gain was more elevated (2-2.5 fold, P < 0.001) during the first 2 wk of refeeding compared with WM controls--differences that were uninfluenced by the duration of growth arrest. Taken together, these studies suggest that the often reported impressive gains in body fat during recovery from malnutrition may result not only from unbalanced diets or excess dietary intake, but also from a transitory enhancement in the efficiency of food utilization and a shift in energy partitioning in favor of an acceleration for the replenishment of fat stores.

Real-time measurement of the contribution of the muscular activity to the metabolic rate in freely moving rats.

A new real-time ergometric system, ERGORAT, for measuring the energy expenditure due to muscular activity of small mammals is described. The method is based on measuring the vibrations induced by a freely moving rat to a platform on which it is living. Six accelerometers placed on the platform detect all the vibrations produced by the rat. The co-ordinates of the centre of mass of the animal are located by an optoelectronic device. This location and the six accelerations are fed to a microprocessor-based data acquisition and processing system. Using a Lagrangian dynamic model, the values of the mechanical energy transferred to the platform are computed every second. ERGORAT is used as part of an experimental setup allowing the measurement of the energetic balance of lean and obese rats. The results clearly show that the increase in metabolic rate of obese rats during cold exposure can be entirely explained by the cost of their increase in locomotor activity, whereas for lean rats, this cost accounts for only 41.5 per cent of their metabolic increase, the remaining being the contribution of their active brown adipose tissue.