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Decreased White Fat Cell Thermogenesis in Obese Individuals

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Decreased White Fat Cell Thermogenesis in Obese Individuals International Journal of Obesity (1997) 21, 439±444 ß 1997 Stockton Press All rights reserved 0307±0565/97 $12.00 Decreased white fat cell thermogenesis in obese individuals HBoÈttcher and P FuÈrst University of Hohenheim, Institute for Biological Chemistry and Nutrition, D-70593 Stuttgart, FRG Germany OBJECTIVE: To investigate whether white adipocyte thermogenesis and energy metabolism are reduced in obese individuals. SUBJECTS: Eight lean and 15 obese men and women; BMI 19±41. DESIGN: Isolated subcutaneous adipocytes were maintained in agarose gel for 20 h under basal conditions and subsequently for 10 h after stimulation with 1 mM isoprenaline. Direct microcalorimetry was performed continuously over 30 h while biochemical measures were obtained after 0, 20, 25 and 30 h. MEASUREMENTS: Total cellular thermogenesis, oxygen consumption, glycolysis, lipolysis, triglyceride/FFA substrate cycle, adenine nucleotides, DNA content as basis of reference. RESULTS: Under basal and stimulated conditions, thermogenesis (5.6 and 8.6 mW/mgDNA, respectively; P < 0.0001) correlated negatively (P < 0.01 and P < 0.05, respectively) with the BMI and positively with O2 and glucose consump- tion, lactate, glycerol, FFA release and FFA re-esteri®cation. Reduced basal lactate production with increased BMI (P < 0.05) indicates a more aerobic adipocyte metabolism in obese individuals. Negative correlation between BMI and stimulated triglyceride/FFA substrate cycle activity (P < 0.01) explains the decreased hormone induced adipocyte heat production in the obese. CONCLUSIONS: The results suggest that a reduction of total body energy expenditure, which is discussed to cause obesity, can be associated with distinct metabolic alterations at a cellular level. However, since the estimated total body fat cell thermogenesis does not exceed 7% of the resting metabolic rate, the observed decrease of adipocyte heat production in the face of augmented BMI can only in part be responsible for the development of obesity. Keywords: catecholamine-induced thermogenesis; direct microcalorimetry; energy metabolism; fat cell culture system; substrate cycle; obesity Introduction work performance. These processes include uncoup- ling of the respiration chain and increased Na/K- ATPase activity as well as various substrate cycles According to the rules of thermodynamics, obesity is (lipolysis and re-esteri®cation of free fatty acids- simply a question of energy balance. Thus, excess triglyceride/FFA cycle or the interorgan cycle of dietary energy intake over energy output (heat and glycolysis and gluconeogenesis between adipose mechanical work) will inevitably result in storage of tissue and liver-glucose/lactate cycle).4,14±19 the excess energy in the form of triglyceride in the Since the metabolic characteristics of adipose tissue white adipose tissue1±4 which is therefore considered are mainly based on the white adipocyte,20 studies as the target organ of obesity.5 Indeed, obesity is a related to energy expenditure of this cell type might major health problem and represents an obvious risk be helpful to understand the relation between obesity factor for many diseases, like diabetes, stroke, or and reduced cellular thermogenesis. In previous coronary heart disease.6±8 microcalorimetric investigations with white adipocyte Although overeating is considered as the major suspensions, reduced cellular heat production was cause for the development of obesity in overweight observed in obese subjects, compared to lean subpopulations obesity might be induced by dimin- donors.21 These results, however, are not supported ished body heat production.9±11 In contrast, a lean by simultaneous biochemical investigations of cellular person is able to compensate excess energy intake by metabolism, making the interpretation of a reduced an augmented thermogenesis, thereby keeping its thermogenesis dif®cult.19 body weight constant.4,12,13 In the human body there In the present study, white adipocytes obtained are a number of `empty' biochemical mechanisms at from lean and obese donors were cultured in agarose the level of cellular metabolism which are devoted to gel19,22 and basal and catecholamine-induced thermo- transform chemically bound energy to heat without genesis were measured by direct microcalorimetry. The underlying biochemical mechanisms were examined by parallel measurements of oxidative Correspondence: Dr H BoÈ ttcher. Received 23 October 1996; revised 7 February 1997; accepted 11 phosphorylation, glycolysis, and lipolysis, as well as February 1997 the triglyceride/FFA substrate cycle. Decreased fat cell thermogenesis in obese humans H BoÈttcher and P FuÈrst 440 Methods Biochemcial analyses Aliquots of the parallel cultures were taken 0, 20, 25 and 30 h after start of the experiment for determina- Subjects tion of oxygen content (TIA-111-LV oxygen sensor, Subcutaneous adipose tissue was obtained from 15 PBI Dansensor, Tùllùse, Danmark) and subsequent obese (8 f/7 m; mean BMI 30.6; range 27.7±40.4 kg/ analyses of glucose, lactate, pyruvate, glycerol and m2) and 8 lean (4 f/4 m; mean BMI 22.1; range 19.5± FFA concentrations, and cellular contents of adenine 24.7 kg/m2) patients undergoing a minor uncompli- nucleotides and DNA. These methods were previously cated surgery of inguinal hernia. The patients had no described and evaluated in detail.19,23 Re-esteri®cation identi®ed metabolic or endocrinological disorders. rate of FFA (RRE) was calculated from the lipolytic After an overnight fast, general anaesthesia was rate (RGLL) and the rate of FFA release (RFFA) 15 given with Iso¯urane, oxygen and nitrous oxide. according to the formula RRE 3 6 RGLL 7 RFFA. Tissue samples were taken at commencement of the surgical procedure. Statistics The rates of oxygen and glucose uptake as well as release of lactate, pyruvate and glycerol were esti- Fat cell culture mated by regression analysis after testing the linearity. White fat cells were isolated by collagenase diges- The mean FFA release and re-esteri®cation rates were tion20 and embedded in 1% agarose gel (type VII, calculated for the time intervals 0±20 h and 20±30 h. Sigma, St. Louis, MO) containing Medium 199 Comparisons between groups were made by the paired (Gibco Ltd., Paisley, U.K.) and 2% human serum rank-test. All results are expressed as mean Æ s.e. albumin (Behringwerke, Marburg, FRG). The gel cultures were prepared in 3 ml glass ampoules and sealed with metal caps (Macherey-Nagel, DuÈren, Results FRG). From each preparation, up to 20 parallel cultures were established and kept at 37C. The procedure was described earlier in detail.19,22,23 The age of the subjects did not correlate with BMI, Under these culture conditions, basal rates of fat heat production rate or biochemical indices, and sex cell thermogenesis, lipolysis, glycolysis and oxidative had no in¯uence on the results. Therefore, the com- phosphorylation are constant for more than 72 h, while bined data from men and women are evaluated. FFA release declines continuously.19,23 Stimulated and unstimulated thermogenesis were virtually constant throughout the experiment. Mean basal heat production was 5.64 Æ 0.44 mW/mgDNA, and correlated negatively with the BMI (r 70.56; Microcalorimetry P < 0.01). Isoprenaline induced thermogenesis Two identical microcalorimeters of the thermopile (8.60 Æ 0.61 mW/m P < 0.0001) was also negatively heat conduction type (2277-BioActivityMonitor, correlated with the BMI (r 70.44; P < 0.05; LKB, Bromma, Sweden and 2277-ThermalActivity- Figure 1). The absolute increase of heat production Monitor, ThermoMetric, JaÈrfaÈlla, Sweden) were used. after isoprenaline addition was independent from In this system Peltier elements are sandwiched BMI; the relative increase being positively correlated between the measuring ampoule containing the with BMI (r 0.53; P < 0.01). sample and tempered heat sinks. The produced vol- The rates of oxygen and glucose consumption as tage is proportional to the heat production rate which well as lactate, pyruvate and glycerol release (Table 1) is continuously monitored.22,24 In every experiment, were stable not only under basal, but also under unstimulated heat production of six parallel cultures stimulated conditions (Table 2), whereas with the from one patient was monitored continuously for 20 h. time elapsed, FFA release decreased and re-esteri®ca- Subsequently, isoprenaline (®nal concentration tion increased. The degree of increase or decrease was 1076 M) was injected into the cultures without inter- independent from BMI, thermogenesis or FFA con- rupting the measurement by using a special micro- centrations. None of the metabolic events appeared to catheter as described previously.25 Stimulated be affected by the FFA concentration. Correlations thermogenesis was measured for a further 10 h. with cellular heat production rate under basal and After isoprenaline addition the heat production rate stimulated conditions are shown in Table 3. Under increased, the maximum being reached after basal conditions, correlations with the subjects' BMI 150 Æ 50 min. 10 h after stimulation, thermogenesis were observed only with glucose consumption was decreased by only 9 Æ 7% of the maximum (r 70.58; P < 0.01) and lactate production value.25 In the parallel cultures not used for micro- (r 70.52; P < 0.05; Figure 2), while after iso- calorimetry, hormone injection was performed after prenaline stimulation a correlation with FFA re- 20 h with a syringe and cannula pierced through the esteri®cation was observed (r 70.63; P < 0.01; rubber sealing of the closed vessels. Figure 3). Decreased fat cell thermogenesis in obese humans H BoÈttcher and P FuÈrst 441 Cellular contents of ATP, ADP, and total adenines after 20 h of culture (3.80 Æ 0.28; 0.22 Æ 0.02 and 4.12 Æ 0.29 nmol/mgDNA, respectively) were inver- sely correlated with the BMI (P < 0.05), while the AMP content (0.10 Æ 0.02 nmol/mgDNA) and the ATP/ADP ratio (19.1 Æ 1.7) were independent from the BMI. Correlations with heat production rates are shown in Table 3.
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