Predicting changes of body weight, body fat, energy expenditure and metabolic fuel selection in C57BL/6 mice

The mouse is an important model organism for investigating the molecular mechanisms of body weight regulation, but a quantitative understanding of mouse energy metabolism remains lacking. Therefore, we created a mathematical model of mouse energy metabolism to predict dynamic changes of body weight, body fat, energy expenditure, and metabolic fuel selection. Based on the principle of energy balance, we constructed ordinary differential equations representing the dynamics of body fat mass (FM) and fat-free mass (FFM) as a function of dietary intake and energy expenditure (EE). The EE model included the cost of tissue deposition, physical activity, diet-induced thermogenesis, and the influence of FM and FFM on metabolic rate. The model was calibrated using previously published data and validated by comparing its predictions to measurements in five groups of male C57/BL6 mice (N = 30) provided ad libitum access to either chow or high fat diets for varying time periods. The mathematical model accurately predicted the observed body weight and FM changes. Physical activity was predicted to decrease immediately upon switching from the chow to the high fat diet and the model coefficients relating EE to FM and FFM agreed with previous independent estimates. Metabolic fuel selection was predicted to depend on a complex interplay between diet composition, the degree of energy imbalance, and body composition. This is the first validated mathematical model of mouse energy metabolism and it provides a quantitative framework for investigating energy balance relationships in mouse models of obesity and diabetes.     

Body mass, body composition and sleeping metabolic rate before, during and after endurance training

Metabolic rate, more specifically resting metabolic rate (RMR) or sleeping metabolic rate (SMR), of an adult subject is usually expressed as a function of the fat-free mass (FFM). Chronic exercise is thought to increase FFM and thus to increase RMR and SMR. We determined body mass (BM), body composition, and SMR before, during, and after an endurance training programme without interfering with energy intake. The subjects were 11 women and 12 men, aged 37 (SD 3) years and body mass index 22.3 (SD 1.5) kg · m^–2. The endurance training prepared subjects to run a half marathon competition after 44 weeks. The SMR was measured overnight in a respiration chamber. Body composition was measured by hydrostatic weighing. Measurements were performed at 0, 8, 20, 40, and 90 weeks after the start of the training. The BM had decreased from a mean value of 66.6 (SD 6.9) to 65.6 (SD 6.7) kg (P<0.01), fat mass (FM) had decreased from 17.1 (SD 3.9) to 13.5 (SD 3.6) kg (P<0.001), and FFM had increased from 49.5 (SD 7.3) to 52.2 (SD 7.6) kg (P<0.001) at 40 weeks. Mean SMR before and after 40 weeks training was 6.5 (SD 0.7) and 6.2 (SD 0.6) MJ · day^–1 (P<0.05). The decrease in SMR was related to the decrease in BM (r=0.62,P=0.001). At 90 weeks, when most subjects had not trained for nearly a year, BM and SMR were not significantly different from the initial value while FM and FFM had not changed since week 40 of training. In conclusion, it was found that an exercise induced increase in FFM did not result in an increase in SMR. There was an indication of the opposite effect, a decrease in SMR in the long term during training, possibly as a defence mechanism of the body in the maintenance of BM.     

Energy expenditure adjusted for body composition differentiates constitutional thinness from both normal subjects and anorexia nervosa

Constitutional thinness (CT) is characterized by a low and stable body mass index (BMI) without any hormonal abnormality. To understand the weight steadiness, energetic metabolism was evaluated. Seven CT, seven controls, and six anorexia nervosa (AN) young women were compared. CT and AN had a BMI <16.5 kg/m(2). Four criteria were evaluated: 1) energy balance including diet record, resting metabolic rate (RMR) (indirect calorimetry), total energy expenditure (TEE) (doubly labeled water), physical activity; 2) body composition (dual-energy X-ray absorptiometry); 3) biological markers (leptin, IGF-I, free T3); 4) psychological profile of eating behavior. The normality of free T3 (3.7 +/- 0.5 pmol/l), IGF-I (225 +/- 93 ng/ml), and leptin (8.3 +/- 3.4 ng/ml) confirmed the absence of undernutrition in CT. Their psychological profiles revealed a weight gain desire. TEE (kJ/day) in CT (8,382 +/- 988) was not found significantly different from that of controls (8,793 +/- 845) and AN (8,001 +/- 2,152). CT food intake (7,565 +/- 908 kJ/day) was found similar to that of controls (7,961 +/- 1,452 kJ/day) and higher than in AN (4,894 +/- 703 kJ/day), thus explaining the energy metabolism balance. Fat-free mass (FFM) (kg) was similar in CT and AN (32.5 +/- 2.9 vs. 34.1 +/- 1.9) and higher in controls (37.8 +/- 1.6). While RMR absolute values (kJ/day) were lower in CT (4,839 +/- 473) than in controls (5,576 +/- 209), RMR values adjusted for FFM were the highest in CT. TEE-to-FFM ratio was also higher in CT than in controls. Energetic metabolism balance maintains a stable low weight in CT. An increased energy expenditure-to-FFM ratio differentiates CT from controls and could account for the resistance to weight gain observed in CT.     

Muscle fatty acid oxidative capacity is a determinant of whole body fat oxidation in elderly people

In sedentary elderly people, a reduced muscle fatty acid oxidative capacity (MFOC) may explain a decrease in whole body fat oxidation. Eleven sedentary and seven regularly exercising subjects (65.6 +/- 4. 5 yr) were characterized for their aerobic fitness [maximal O(2) uptake (VO(2 max))/kg fat free mass (FFM)] and their habitual daily physical activity level [free-living daily energy expenditure divided by sleeping metabolic rate (DEE(FLC)/SMR)]. MFOC was determined by incubating homogenates of vastus lateralis muscle with [1-(14)C]palmitate. Whole body fat oxidation was measured by indirect calorimetry over 24 h. MFOC was 40.4 +/- 14.7 and 44.3 +/- 16.3 nmol palmitate. g wet tissue(-1). min(-1) in the sedentary and regularly exercising individuals, respectively (P = nonsignificant). MFOC was positively correlated with DEE(FLC)/SMR (r = 0.58, P < 0. 05) but not with VO(2 max)/kg FFM (r = 0.35, P = nonsignificant). MFOC was the main determinant of fat oxidation during all time periods including physical activity. Indeed, MFOC explained 19.7 and 30.5% of the variance in fat oxidation during walking and during the alert period, respectively (P < 0.05). Furthermore, MFOC explained 23.0% of the variance in fat oxidation over 24 h (P < 0.05). It was concluded that, in elderly people, MFOC may be influenced more by overall daily physical activity than by regular exercising. MFOC is a major determinant of whole body fat oxidation during physical activities and, consequently, over 24 h.     

Contributing factors and variability of energy expenditure in non-obese, obese, and post-obese adolescents

Energy expenditure (EE) is a major determinant of energy balance and body composition. The objectives of this paper were to review the contributing factors of the main components of daily EE (DEE) and the inter-individual variability in these components in non-obese (NOb), obese (Ob), and post-obese (POb) adolescents. Body composition especially fat-free mass (FFM), is the major determinant of the basal metabolic rate which contributes 50-70% of DEE, whereas fat mass (FM) is a significant factor only in obese subjects. Physical activity is the second main variation factor of DEE, whereas growth, the thermic effect of food, and thermoregulation are generally of marginal importance. The energy costs and EE associated with various sedentary and physical activities were assessed in NOb, Ob and POb subjects both in standardised and in free-living conditions. The interindividual variability of DEE is high, even after adjustment for body composition, mainly because of great differences in time devoted to the various physical activities. DEE and EE associated with sleep and sedentary activities are significantly higher in Ob than in NOb, but not after adjustment for FFM. On the contrary, EE associated with physical activities is not significantly different between Ob and NOb adolescents, but 61% lower in Ob subjects after adjustment for body composition. Multidisciplinary weight-reduction programmes including moderate energy restriction and physical training result in great FM loss, maintenance of FFM, improvement of physical capacities, but reductions in organ and tissue metabolic rate and in EE associated with the various sedentary and physical activities, which may favour body weight regain in the less active POb subjects.     

Physical Activity Levels Are Low in Free‐Living Adults with Chronic Paraplegia

Objectives: To compare physical activity levels (PALs) of free‐living adults with chronic paraplegia with World Health Organization recommendations and to compare energy expenditure between persons with complete vs. incomplete paraplegia. Research Methods and Procedures: Twenty‐seven euthyroid adults (17 men and 10 women) with paraplegia (12.5 ± 9.5 years since onset; 17 with complete lesions and 10 with incomplete lesions) participated in this cross‐sectional study. Resting metabolic rate was measured by indirect calorimetry and total daily energy expenditure (TDEE) by heart rate monitoring. PAL was calculated as TDEE/resting metabolic rate. Total body water was measured by deuterium dilution and fat‐free mass (FFM) and fat mass (FM) by calculation (FFM = total body water/0.732; FM = weight ? FFM). Obesity was defined using the following percentage FM cutoffs: men 18 to 40 years >22% and 41 to 60 years >25%; and women 18 to 40 years >35% and 41 to 60 years >38%. Results: Nineteen subjects (70.4%; 13 men and six women) were obese. Fifteen subjects (56%) engaged in structured physical activity 1.46 ± 0.85 times during the observation period for a mean of 49.4 ± 31.0 minutes per session. Despite this, mean PAL of the group was 1.56 ± 0.34, indicative of limited physical activity. TDEE was 24.6% lower in subjects with complete paraplegia (2072 ± 505 vs. 2582 ± 852 kcal/d, p = 0.0372). Discussion: PAL of the group was low, indicating that persons with paraplegia need to engage in increased frequency, intensity, and/or duration of structured physical activity to achieve a PAL ≥1.75 and, thereby, to offset sedentary activities of daily living.     

Exogenous human growth hormone reduces body fat in obese women

The effects of biosynthetic methionyl human growth hormone (met-hGH) on body composition and endogenous secretion of insulin-like growth factor I (IGF-I) were studied in obese women ranging between 138 and 226% of ideal body weight. Following double-blind procedures, 12 subjects were assigned at random to either treatment with met-hGH (n = 6, 0.08 mg/kg desirable body weight) or placebo (n = 6, bacteriostatic water diluent). Treatments were delivered intramuscularly three times per week for a period of 27-28 days. Subjects were instructed to follow a weight-maintaining diet and their pre- and posttreatment kilocaloric intake was monitored for verification. The baseline peak serum GH response to L-dopa/arginine stimulation for the study population as a whole, was in the hyposecretory range (9.6 +/- 1.9 ng/ml), accompanied by a low level of circulating IGF-I (0.56 +/- 0.09 U/ml). Hydrodensitometry revealed that the met-hGH-treated subjects had a significant reduction in body fat, while an observed mean increase in fat-free mass (FFM) approached significance. The percent change in body fat was unrelated to pretreatment levels of body fat, total body weight, or initial endogenous GH status. Changes in circulating IGF-I were similar to those for FFM, with increases approaching significance. There were no significant changes in body composition or IGF-I in the placebo-treated subjects. No significant differences were observed in the self-reported dietary intake of kilocalories during the experimental period between the two groups. We conclude that exogenous GH reduces body fat in obese women in the apparent absence of significant kilocaloric restriction. The effect appears to be unrelated to endogenous GH secretion or body composition.     

Metabolically active portion of fat-free mass: a cellular body composition level modeling analysis

The proportion of fat-free mass (FFM) as body cell mass (BCM) is highly related to whole body resting energy expenditure. However, the magnitude of BCM/FFM may have been underestimated in previous studies. This is because Moore's equation [BCM (kg) = 0.00833 x total body potassium (in mmol)], which was used to predict BCM, underestimates BCM by approximately 11%. The aims of the present study were to develop a theoretical BCM/FFM model at the cellular level and to explore the influences of sex, age, and adiposity on the BCM/FFM. Subjects were 112 adults who had the following measurements: total body water by (2)H(2)O or (3)H(2)O dilution; extracellular water by NaBr dilution; total body nitrogen by in vivo neutron activation analysis; and bone mineral by dual-energy X-ray absorptiometry. FFM was calculated using a multicomponent model and BCM as the difference between FFM and the sum of extracellular fluid and solids. The developed theoretical model revealed that the proportion of BCM to FFM is mainly determined by water distribution (i.e., E/I, the ratio of extracellular to intracellular water). A significant correlation (r = 0.90, P < 0.001) was present between measured and model-predicted BCM/FFM for all subjects pooled. Measured BCM/FFM [mean (SD)] was 0.584 +/- 0.041 and 0.529 +/- 0.041 for adult men and women (P < 0.001), respectively. A multiple linear regression model showed that there are independent significant associations of sex, age, and fat mass with BCM/FFM.     

Effect of optimal glycaemic control with continuous subcutaneous insulin infusion on energy expenditure in type I diabetes mellitus.

To assess the role of insulin in the control of body weight energy expenditure was measured by indirect calorimetry in eight patients of normal weight with type I diabetes initially while poorly controlled during conventional insulin treatment and later during optimal glycaemic control achieved by using the continuous subcutaneous insulin infusion pump. Their response to seven days of fat supplementation was also assessed and the results compared with those in eight non-diabetic subjects. After a mean of 5.3 months of continuous subcutaneous insulin infusion the diabetic subjects had gained on average 3.5 kg. In the poorly controlled diabetic state the resting metabolic rate was raised but decreased by a mean of 374 kJ (90 kcal) per 24 hours with optimal glycaemic control. The thermic response to infused noradrenaline was reduced by 59% in the diabetic subjects, was not improved by continuous subcutaneous insulin infusion, but was improved when three of the subjects were given metformin in addition. The diabetic subjects had no abnormality in the thermic response to a meal while taking their usual diabetic diet. During fat supplementation, however, this thermic response was reduced when glycaemic control was poor but not when control was precise. Fat supplementation did not alter the resting metabolic rate or the reduced noradrenergic thermic response in the diabetic subjects. These findings suggest that precise glycaemic control could produce weight gain if energy intake remained unaltered, for diabetic subjects do not compensate for the decrease in metabolic rate by an increase in noradrenergic and dietary thermic responses. Also precise glycaemic control using continuous subcutaneous insulin infusion does not correct all the metabolic abnormalities of diabetes mellitus.     

The Grey Mouse Lemur Uses Season-Dependent Fat or Protein Sparing Strategies to Face Chronic Food Restriction

During moderate calorie restriction (CR) the heterotherm Microcebus murinus is able to maintain a stable energy balance whatever the season, even if only wintering animals enter into torpor. To understand its energy saving strategies to respond to food shortages, we assessed protein and energy metabolisms associated with wintering torpor expression or summering torpor avoidance. We investigated body composition, whole body protein turnover, and daily energy expenditure (DEE), during a graded (40 and 80%) 35-day CR in short-days (winter; SD40 and SD80, respectively) and long-days (summer; LD40 and LD80, respectively) acclimated animals. LD40 animals showed no change in fat mass (FM) but a 12% fat free mass (FFM) reduction. Protein balance being positive after CR, the FFM loss was early and rapid. The 25% DEE reduction, in LD40 group was mainly explained by FFM changes. LD80 animals showed a steady body mass loss and were excluded from the CR trial at day 22, reaching a survival-threatened body mass. No data were available for this group. SD40 animals significantly decreased their FM level by 21%, but maintained FFM. Protein sparing was achieved through a 35 and 39% decrease in protein synthesis and catabolism (protein turnover), respectively, overall maintaining nitrogen balance. The 21% reduction in energy requirement was explained by the 30% nitrogen flux drop but also by torpor as DEE FFM-adjusted remained 13% lower compared to ad-libitum. SD80 animals were unable to maintain energy and nitrogen balances, losing both FM and FFM. Thus summering mouse lemurs equilibrate energy balance by a rapid loss of active metabolic mass without using torpor, whereas wintering animals spare protein and energy through increased torpor expression. Both strategies have direct fitness implication: 1) to maintain activities at a lower body size during the mating season and 2) to preserve an optimal wintering muscle mass and function.     

Energy imbalance underlying the development of childhood obesity

Objective: To develop a model based on empirical data and human energetics to predict the total energy cost of weight gain and obligatory increase in energy intake and/or decrease in physical activity level associated with weight gain in children and adolescents. Research Methods and Procedures: One‐year changes in weight and body composition and basal metabolic rate (BMR) were measured in 488 Hispanic children and adolescents. Fat‐free mass (FFM) and fat mass (FM) were measured by DXA and BMR by calorimetry. Model specifications include the following: body mass (BM) = FFM + FM, each with a specific energy content, cff (1.07 kcal/g FFM) and cf (9.25 kcal/g FM), basal energy expenditure (EE), kff and kf, and energetic conversion efficiency, eff (0.42) for FFM and ef (0.85) for FM. Total energy cost of weight gain is equal to the sum of energy storage, EE associated with increased BM, conversion energy (CE), and diet‐induced EE (DIEE). Results: Sex‐ and Tanner stage–specific values are indicated for the basal EE of FFM (kff) and the fat fraction in added tissue (fr). Total energy cost of weight gain is partitioned into energy storage (24% to 36%), increase in EE (40% to 57%), CE (8% to 13%), and DIEE (10%). Observed median (10th to 90th percentile) weight gain of 6.1 kg/yr (2.4 to 11.4 kg/yr) corresponds at physical activity level (PAL) = 1.5, 1.75, and 2.0 to a total energy cost of weight gain of 244 (93 to 448 kcal/d), 267 (101 to 485 kcal/d), and 290 kcal/d (110 to 527 kcal/d), respectively, and to a total energy intake of 2695 (1890 to 3730), 3127 (2191 to 4335), and 3551 (2487 to 4930) kcal/d, respectively. If weight gain is caused by a change in PAL alone and PAL₀ = 1.5 at baseline t = 0, the model indicates a drop in PAL of 0.22 (0.08 to 0.34) units, which is equivalent to 60 (18 to 105) min/d of walking at 2.5 mph. Discussion: Halting the development or progression of childhood obesity, as observed in these Hispanic children and adolescents, by counteracting its total energy costs will require a sizable decrease in energy intake and/or reciprocal increase in physical activity.     

Relationship between fat-to-fat-free mass ratio and decrements in leg strength after downhill running.

The purpose of this study was to determine whether greater body fat mass (FM) relative to lean mass would result in more severe muscle damage and greater decrements in leg strength after downhill running. The relationship between the FM-to-fat-free mass ratio (FM/FFM) and the strength decline resulting from downhill running (-11% grade) was investigated in 24 male runners [age 23.4 +/- 0.7 (SE) yr]. The runners were divided into two groups on the basis of FM/FFM: low fat (FM/FFM = 0.100 +/- 0.008, body mass = 68.4 +/- 1.3 kg) and normal fat (FM/FFM = 0.233 +/- 0.020, body mass = 76.5 +/- 3.3 kg, P < 0.05). Leg strength was reduced less in the low-fat (-0.7 +/- 1.3%) than in the normal-fat individuals (-10.3 +/- 1.5%) 48 h after, compared with before, downhill running (P < 0.01). Multiple linear regression analysis revealed that the decline in strength could be predicted best by FM/FFM (r2 = 0.44, P < 0.05) and FM-to-thigh lean tissue cross-sectional area ratio (r2 = 0.53, P < 0.05), with no additional variables enhancing the prediction equation. There were no differences in muscle glycogen, creatine phosphate, ATP, or total creatine 48 h after, compared with before, downhill running; however, the change in muscle glycogen after downhill running was associated with a higher FM/FFM (r = -0.56, P < 0.05). These data suggest that FM/FFM is a major determinant of losses in muscle strength after downhill running.     

Deficiency of MGAT2 increases energy expenditure without high-fat feeding and protects genetically obese mice from excessive weight gain

Acyl CoA:monoacylglycerol acyltransferase 2 (MGAT2) is thought to be crucial for dietary fat absorption. Indeed, mice lacking the enzyme (Mogat2(-/-)) are resistant to obesity and other metabolic disorders induced by high-fat feeding. However, these mice absorb normal quantities of fat. To explore whether a high level of dietary fat is an essential part of the underlying mechanism(s), we examined metabolic responses of Mogat2(-/-) mice to diets containing varying levels of fat. Mogat2(-/-) mice exhibited 10-15% increases in energy expenditure compared with wild-type littermates; although high levels of dietary fat exacerbated the effect, this phenotype was expressed even on a fat-free diet. When deprived of food, Mogat2(-/-) mice expended energy and lost weight like wild-type controls. To determine whether MGAT2 deficiency protects against obesity in the absence of high-fat feeding, we crossed Mogat2(-/-) mice with genetically obese Agouti mice. MGAT2 deficiency increased energy expenditure and prevented these mice from gaining excess weight. Our results suggest that MGAT2 modulates energy expenditure through multiple mechanisms, including one independent of dietary fat; these findings also raise the prospect of inhibiting MGAT2 as a strategy for combating obesity and related metabolic disorders resulting from excessive calorie intake.     

Metabolically active components of fat free mass and resting energy expenditure in nonobese adults

Resting energy expenditure (REE) and components of fat-free mass (FFM) were assessed in 26 healthy nonobese adults (13 males, 13 females). Detailed body composition analyses were performed by the combined use of dual-energy X-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), bioelectrical impedance analysis (BIA), and anthropometrics. We found close correlations between REE and FFM(BIA) (r = 0.92), muscle mass(DEXA) (r = 0.89), and sum of internal organs(MRI) (r = 0.90). In a multiple stepwise regression analysis, FFM(BIA) alone explained 85% of the variance in REE (standard error of the estimate 423 kJ/day). Including the sum of internal organs(MRI) into the model increased the r(2) to 0.89 with a standard error of 381 kJ/day. With respect to individual organs, only skeletal muscle(DEXA) and liver mass(MRI) significantly contributed to REE. Prediction of REE based on 1) individual organ masses and 2) a constant metabolic rate per kilogram organ mass was very close to the measured REE, with a mean prediction error of 96 kJ/day. The very close agreement between measured and predicted REE argues against significant variations in specific REEs of individual organs. In conclusion, the mass of internal organs contributes significantly to the variance in REE.     

Oxidation of nonplasma fatty acids during exercise is increased in women with abdominal obesity.

We evaluated plasma fatty acid availability and plasma and whole body fatty acid oxidation during exercise in five lean and five abdominally obese women (body mass index = 21 +/- 1 vs. 38 +/- 1 kg/m(2)), who were matched on aerobic fitness, to test the hypothesis that obesity alters the relative contribution of plasma and nonplasma fatty acids to total energy production during exercise. Subjects exercised on a recumbent cycle ergometer for 90 min at 54% of their peak oxygen consumption. Stable isotope tracer methods ([(13)C]palmitate) were used to measure fatty acid rate of appearance in plasma and the rate of plasma fatty acid oxidation, and indirect calorimetry was used to measure whole body substrate oxidation. During exercise, palmitate rate of appearance increased progressively and was similar in obese and lean groups between 60 and 90 min of exercise [3.9 +/- 0.4 vs. 4.0 +/- 0.3 micromol. kg fat free mass (FFM)(-1). min(-1)]. The rate of plasma fatty acid oxidation was also similar in obese and lean subjects (12.8 +/- 1.7 vs. 14.5 +/- 1.8 micromol. kg FFM(-1). min(-1); P = not significant). However, whole body fatty acid oxidation during exercise was 25% greater in obese than in lean subjects (21.9 +/- 1.2 vs. 17.5 +/- 1.6 micromol. kg FFM(-1). min(-1); P < 0.05). These results demonstrate that, although plasma fatty acid availability and oxidation are similar during exercise in lean and obese women, women with abdominal obesity use more fat as a fuel by oxidizing more nonplasma fatty acids.     

Metabolic Consequences and Vulnerability to Diet-Induced Obesity in Male Mice under Chronic Social Stress

Social and psychological factors interact with genetic predisposition and dietary habit in determining obesity. However, relatively few pre-clinical studies address the role of psychosocial factors in metabolic disorders. Previous studies from our laboratory demonstrated in male mice: 1) opposite status-dependent effect on body weight gain under chronic psychosocial stress; 2) a reduction in body weight in individually housed (Ind) male mice. In the present study these observations were extended to provide a comprehensive characterization of the metabolic consequences of chronic psychosocial stress and individual housing in adult CD-1 male mice. Results confirmed that in mice fed standard diet, dominant (Dom) and Ind had a negative energy balance while subordinate (Sub) had a positive energy balance. Locomotor activity was depressed in Sub and enhanced in Dom. Hyperphagia emerged for Dom and Sub and hypophagia for Ind. Dom also showed a consistent decrease of visceral fat pads weight as well as increased norepinephrine concentration and smaller adipocytes diameter in the perigonadal fat pad. On the contrary, under high fat diet Sub and, surprisingly, Ind showed higher while Dom showed lower vulnerability to obesity associated with hyperphagia. In conclusion, we demonstrated that social status under chronic stress and individual housing deeply affect mice metabolic functions in different, sometime opposite, directions. Food intake, the hedonic response to palatable food as well as the locomotor activity and the sympathetic activation within the adipose fat pads all represent causal factors explaining the different metabolic alterations observed. Overall this study demonstrates that pre-clinical animal models offer a suitable tool for the investigation of the metabolic consequences of chronic stress exposure and associated psychopathologies.     

Thermogenic responsiveness to nonspecific beta-adrenergic stimulation is not related to genetic variation in codon 16 of the beta2-adrenergic receptor

Stimulation of beta-adrenergic receptors (beta-AR) by the sympathetic nervous system (SNS) modulates energy expenditure (EE), but substantial interindividual variability is observed. We determined whether the thermogenic response to beta-AR stimulation is related to genetic variation in codon 16 of the beta(2)-AR, a biologically important beta-AR polymorphism, and whether differences in SNS activity (i.e., the stimulus for agonist-promoted downregulation) are involved. The increase in EE (DeltaEE, indirect calorimetry, ventilated hood) above resting EE in response to nonspecific beta-AR stimulation [iv isoproterenol: 6, 12, and 24 ng/kg fat-free mass (FFM)/min] was measured in 46 healthy adult humans [Arg16Arg: 9 male, 7 female, 48 +/- 5 yr; Arg16Gly: 11 male, 4 female, 53 +/- 5 yr; Gly16Gly: 3 male, 12 female, 48 +/- 5 yr (means +/- SE)]. Neither FFM-adjusted baseline resting EE (P = 0.83) nor the dose of isoproterenol required to increase EE 10% above resting (P = 0.87) differed among the three groups (Arg16Arg: 5,409 +/- 209 kJ/day, 11.2 +/- 2.1 ng x kg FFM(-1) x min(-1); Arg16Gly: 5,367 +/- 272 kJ/day, 11.1 +/- 2.1 ng x kg FFM(-1) x min(-1); Gly16Gly: 5,305 +/- 159 kJ/day, 10.5 +/- 1.4 ng x kg FFM(-1) x min(-1)). Consistent with this, muscle sympathetic nerve activity and plasma norepinephrine concentrations were not different among the groups. Group differences in sex composition did not influence the results. Our findings indicate that the thermogenic response to nonspecific beta-AR stimulation, an important mechanistic component of overall beta-AR modulation of EE, is not related to this beta(2)-AR polymorphism in healthy humans. This may be explained in part by a lack of association between this gene variant and tonic SNS activity.     

Role of resting metabolic rate and energy expenditure in hunger and appetite control: a new formulation

A long-running issue in appetite research concerns the influence of energy expenditure on energy intake. More than 50 years ago, Otto G. Edholm proposed that “the differences between the intakes of food [of individuals] must originate in differences in the expenditure of energy”. However, a relationship between energy expenditure and energy intake within any one day could not be found, although there was a correlation over 2 weeks. This issue was never resolved before interest in integrative biology was replaced by molecular biochemistry. Using a psychobiological approach, we have studied appetite control in an energy balance framework using a multi-level experimental system on a single cohort of overweight and obese human subjects. This has disclosed relationships between variables in the domains of body composition [fat-free mass (FFM), fat mass (FM)], metabolism, gastrointestinal hormones, hunger and energy intake. In this Commentary, we review our own and other data, and discuss a new formulation whereby appetite control and energy intake are regulated by energy expenditure. Specifically, we propose that FFM (the largest contributor to resting metabolic rate), but not body mass index or FM, is closely associated with self-determined meal size and daily energy intake. This formulation has implications for understanding weight regulation and the management of obesity.     

Carbohydrate—Fat Interactions and Obesity Examined by a Two‐Compartment Computer Model

Objective: A systems dynamics computer model was developed to examine how the interactions between carbohydrate and fat metabolism influence body weight regulation. It reflects the operation of a two reservoir‐system: one representing the body's limited glycogen, and the other, its large fat reserves. The outflows from the reservoirs correspond to the oxidation of glucose and fat, whose relative contributions are affected by the size of the prevailing glycogen and fat reserves. Together, they meet the body's energy expenditure. Replenishments occur three times per day, in portions restoring total glycogen content to specific levels. A parameter mimicking the action of insulin is necessary to create realistic responses. Research Methods and Procedures: The model was run for 125‐day periods to establish the degree of adiposity for which rates of fat oxidation become commensurate with fat intake and the influence thereon of various dietary, environmental, lifestyle, and inherited variables. Results: Equivalent degrees of adiposity can be sustained under a variety of conditions. For instance, the impact on steady‐state body fat contents of a 10% increase or decrease in the energy provided by dietary fat is offset by a 26‐gram decrease or increase in mean glycogen levels. Discussion: Environmental factors such as food diversity, palatability, and availability can be expected to raise the range within which glycogen levels are habitually maintained. This restrains fat oxidation, until expansion of the fat mass is sufficient to promote fat oxidation to a rate commensurate with dietary fat intake. This metabolic leverage can explain why increased food offerings tend to raise the prevalence of obesity.     

Physical activity and body functionality: implications for obesity prevention and treatment

Physical activity promotes metabolic adaptations that improve body functionality and contribute to the prevention of some diseases. With respect to energy and fat balance, physical activity facilitates the equilibrium between energy intake and expenditure as well as between fat intake and fat oxidation. When combined with a healthy diet that favors satiety with a reduced energy intake, exercise can induce a substantial mass loss in obese individuals. However, even the impact of an exemplary lifestyle does not seem to have the potential to decrease body mass in obese individuals down to the mass range of lean people. Up to now, we have not been able to induce mass changes exceeding 12%-15% initial body mass in obese male subjects under tolerable exercise and dietary habits, and this moderate success was accompanied by modifications in appetite and energy expenditure susceptible to compromise subsequent mass stability. As described in this paper, many environmental factors can influence energy balance and the ability to lose body fat in response to a healthy diet and (or) physical activity program. Particular attention is given to preliminary data obtained in our laboratory that suggest that knowledge-based work does not favor the same potential mass reducing effects as physical work. In fact, the acute effects of knowledge-based work suggest that this work modality may be rather susceptible to promote a more pronounced positive energy balance compared with what we may expect from a sedentary relaxing activity. This is problematic for obesity prevention in the future since knowledge-based work now represents the main working modality in a context of modernity.