The PPARy ligand rosiglitazone influences triacylglycerol metabolism in non-obese males, without increasing the transcriptional activity of PPARy in the subcutaneous adipose tissue

PPAR¿ is obligatory for fat mass generation and is thought to determine the amount of TAG stored per fat cell. We investigated whether ligand availability for PPAR¿ is rate limiting in fat mass generation and substrate metabolism. Twenty healthy men (20¿29 years) were randomly assigned to receive the PPAR¿ ligand rosiglitazone (RSG) (8 mg/d) (n 10) or a placebo (n 10) during a stay of 7 d in a respiration chamber. Food intake was ad libitum, resulting in positive energy balances of 32·2 MJ (placebo) and 44·7 MJ (RSG). Fat cell size and expression of PPAR¿, adipocyte fatty acid-binding protein (aP2), adipsin, adiponectin and fasting-induced adipose factor (FIAF) were determined in subcutaneous abdominal fat biopsies. The total amount of fat stored and the amount of TAG per fat cell were not different between groups. For the entire group, fat cell size was decreased after overeating (P = 0·02). FIAF mRNA levels were decreased after overeating in the RSG group (P = 0·01), with a trend towards a decrease in the placebo group. Unexpectedly, RSG treatment did not influence the expression levels of PPAR¿ and of the PPAR¿ responsive genes aP2, adiponectin and adipsin. In addition, RSG resulted in a larger increase in plasma TAG during overeating than placebo treatment. These results suggest that in healthy, non-obese males the PPAR¿ ligand RSG influences TAG metabolism, independent of its PPAR¿ transcriptional activity in the subcutaneous adipose tissue

The effect of the PPARgamma ligand rosiglitazone on energy balance regulation

BACKGROUND AND AIM: Fat mass generation requires an energy surplus and the activity of the peroxisome proliferator-activated receptor gamma (PPARgamma). We investigated if the PPARgamma ligand rosiglitazone influences substrate usage, energy expenditure (EE) and energy intake (EI) and, thereby, how PPARgamma activity contributes to susceptibility to obesity. METHODS: Twenty healthy males (20-29 years) were randomly assigned to receive a placebo (n = 10) or rosiglitazone (8 mg/d) (n = 10) for seven consecutive days, while staying in a respiration chamber. Food intake was ad libitum. Body composition was determined by underwater weighing (day 1) and deuterium dilution (day 1 and 8). RESULTS: Mean (+/-SE) EI was 15.9 +/- 0.9 MJ/d in the placebo group and 18.9 +/- 1.2 MJ/d in the rosiglitazone group. Mean EE was 11.3 +/- 0.3 MJ/d and 12.5 +/- 0.5 MJ/d for the placebo and rosiglitazone groups respectively. This resulted in a cumulative positive energy balance (EB) of 32.3 +/- 5.1 MJ for placebo and 44.7 +/- 6.9 MJ for rosiglitazone. There were no significant differences in EI, EE, and EB between treatments. Both groups did not adjust their fat oxidation to the increased fat intake, but fat oxidation decreased faster in the rosiglitazone group (significantly lower on days 6 and 7). During treatment with rosiglitazone, significantly more fat storage was seen in overweight subjects while this was not the case in the placebo group. CONCLUSIONS: Our results suggest a shift in substrate usage during PPARgamma stimulation leading to a preference for fat storage, especially in subjects with a higher BMI. Copyright (c) 2005 John Wiley & Sons, Ltd

Metabolic efficiency and energy expenditure during short-term overfeeding

OBJECTIVE: To investigate whether efficiency of weight gain during a short period of overfeeding is related to adaptive differences in basal metabolic rate (BMR) and physical activity. SUBJECTS: Fourteen healthy females (age 25+/-4 years, BMI 22.1+/-2.3 kg/m2). DESIGN AND MEASUREMENTS: Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Overfeeding diets provided 7% of energy from protein, 40% from fat and 53% from carbohydrates. Body composition was determined using hydrodensitometry and isotope dilution, total energy expenditure (TEE) with doubly labeled water and basal metabolic rate (BMR) with indirect calorimetry. Physical activity (PA) was recorded with a tri-axial accelerometer. RESULTS: Body weight increased by 1.45+/-0.86 kg (mean+/-S.D.) (P<0.0001), fat mass increased by 1.05+/-0.75 kg. Energy storage was 57.0+/-17.9 MJ, which is the difference between energy intake (207.2 MJ) and energy expenditure (150.2 MJ) during overfeeding. There was no difference between metabolically efficient and metabolically inefficient subjects in changes in BMR and PA. CONCLUSION: These results indicate that the metabolic efficiency of weight gain was not related to adaptive changes in energy expenditure

Preadipocyte number in omental and subcutaneous adipose tissue of obese individuals

OBJECTIVE: To determine the variation in preadipocyte isolation procedure and to assess the number and function of preadipocytes from subcutaneous and omental adipose tissue of obese individuals. RESEARCH METHODS AND PROCEDURES: The preadipocyte number per gram of adipose tissue in the abdominal-subcutaneous and abdominal-omental adipose stores of 27 obese subjects with a BMI of 44 +/- 10 kg/m(2) and an age of 40 +/- 9 years was determined. RESULTS: The assessment of the preadipocyte number was found to be labor intensive and error prone. Our data indicated that the number of stromal vascular cells (SVCs), isolated from the adipose tissue by collagenase digestion, was dependent on the duration of collagenase treatment and the size and the origin of the biopsy. In addition, the fat accumulation and leptin production by differentiated SVCs were dependent on the number of adherent SVCs (aSVCs) in the culture plate and the presence of proteins derived from serum and peroxisome proliferator-activated receptor ligands. DISCUSSION: Using our standardized isolation and differentiation protocol, we found that the number of SVCs, aSVCs, leptin production, and fat accumulation still varied considerably among individuals. Interestingly, within individuals, the number of SVCs, aSVCs, and the leptin production by differentiating aSVCs from both the subcutaneous and the omental fat depots were associated, whereas fat accumulation was not. In obese to severely obese subjects, differences in BMI and age could not explain differences in SVCs, aSVCs, leptin production, and fat accumulation

24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux

Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose- and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10-20-fold higher basal LXR alpha and -beta expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases