Biomedical subjects
Publications and source records attributed to D A York.
Corticotropin stimulated brown adipose tissue mitochondrial GDP binding of young obese rats to the levels seen in lean rats. This effect was attenuated by chronic increases in corticosterone. The stimulatory response to corticotropin was absent from lean rats unless endogenous secretion of corticosterone was prevented.
Adenylate cyclase activity was determined using a purified plasma membrane fraction prepared from isolated adipocytes by a Percoll gradient centrifugation procedure. The activation of adenylate cyclase by isoprenaline was reduced by approximately 50% in membranes from obese mice, although no reduction in the sensitivity of the response was apparent. Basal and fluoride- and 5'-guanylyl-imidodiphosphate-stimulated activities were similar in both groups. However, two defects in the obese system were identified which suggested that an alteration in the properties of the regulatory protein may account for the impaired hormonal activation. The specific binding of 3H-dihydroalprenolol to membranes from obese animals also was decreased, suggesting a reduction in the number of beta-adrenergic receptors.
Arrhenius plots of fluoride- and guanine-nucleotide-stimulated adenylate cyclase activity were linear in adipocyte plasma membranes from lean and obese (ob/ob) mice. Arrhenius plots of isoprenaline-stimulated adenylate cyclase activity in hepatic plasma membranes biphasic in both groups. The results were biphasic in membranes from lean mice but linear in membranes from obese mice. In contrast, Arrhenius plots of glucagon-stimulated adenylate cyclase activity in hepatic plasma membranes were biphasic in both groups. The results suggest that the coupling between the beta-receptor and the regulatory unit of adenylate cyclase, which has been observed to be defective in adipocyte plasma membranes from obese mice, is influenced by a different lipid environment in membranes from obese animals.
Feeding adult male rats a palatable cafeteria diet stimulated energy intake and expenditure but also raised body weight and energy gains. Bilateral adrenalectomy (ADX) had little effect on stock-fed animals, but prevented the development of obesity in cafeteria-fed rats by depressing food intake and energetic efficiency. Adrenalectomy also markedly increased the thermogenic activity of brown adipose tissue, and depressed insulin levels, particularly in the cafeteria group.
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GDP binding to brown-adipose-tissue mitochondria was decreased in obese Zucker rats. Adrenalectomy restored both GDP binding and serum tri-iodothyronine of obese rats to values observed in lean rats. The effects of adrenalectomy on GDP binding and serum tri-iodothyronine were reversed by corticosterone. Decreasing food intake had no effect on brown-adipose-tissue GDP binding in obese rats. Young (5-week-old) obese rats showed a normal increase in brown-adipose-tissue mitochondrial GDP binding after housing at 4 degrees C for 7 days, but this response was attenuated in 10-week-old obese rats. Overfeeding with sucrose increased brown-adipose-tissue thermogenesis in lean, but not in obese, rats. After adrenalectomy, overfeeding with sucrose enhanced brown-adipose-tissue mitochondrial GDP binding in obese rats.
The activities of hepatic tyrosine aminotransferase, tryptophan oxygenase and serine dehydratase were increased in obese rats shortly after weaning. Immunotitration experiments showed that the increase in tyrosine aminotransferase activity resulted from an increase in enzyme protein in obese rats. No increase in hepatic tyrosine aminotransferase was observed in suckling pre-obese rats. The post-weaning increase in hepatic tyrosine aminotransferase of obese rats was only observed during the light phase of the diurnal cycle, but was prevented by pair-feeding and by starvation. Tryptophan increased hepatic tyrosine aminotransferase of lean rats to obese levels but had no effect in obese rats until tyrosine aminotransferase levels were reduced by starvation or adrenalectomy. Adrenalectomy abolished the increase in hepatic tyrosine aminotransferase activity in obese rats although serum corticosterone was normal in these animals. Hepatic and brain tyrosine concentrations were decreased in obese rats but normalized after adrenalectomy. The results suggest that the corticosteroid-dependent increase in food and tryptophan intake may be the primary cause of the increased hepatic amino acid catabolism of obese rats.
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Hepatic plasma membrane lipids of lean (+/?) and obese (ob/ob) mice have been investigated using 1,6-diphenylhexatriene (DPH). Arrhenius plots of DPH fluorescence polarization in membranes showed the breakpoint in obese mice was reduced from 21 to 15 degrees C, whereas the breakpoint of 5'-nucleotidase activity was raised from 23 to 32 degrees C. Arrhenius break temperatures of DPH polarization and 5'-nucleotidase activity responded differently to housing mice at 34 degrees C and triiodothyronine (T3) treatment. Studies of DPH polarization in liposomes and phospholipid fatty acid composition suggested that differences in sphingomyelin acyl composition determine Arrhenius characteristics of hepatic 5'-nucleotidase in lean and obese mice.
The activity of hepatic [Na+ + K+]ATP-ase showed a gene-dosage relationship in 6 week old mice. Before weaning hepatic [Na+ + K+]ATP-ase activity was normal in preobese mice but fell within 7 days of weaning to the low levels observed in older ob/ob mice. Brain [Na+ + K+]ATP-ase activity was unchanged in ob/ob mice although [3H]-ouabain binding was reduced. Arrhenius plots of [Na+ + K+]ATP-ase activity in liver and brain and of [3H]-ouabain binding to brain preparations showed breakpoints at lower temperatures in ob/ob than lean mice. These breakpoints were altered by pretreatment of tissue with deoxycholate. It is suggested that changes in membrane lipid composition might be an important factor regulating [Na+ + K+]ATP-ase in ob/ob mice.
Five-week-old male, lean (+/?) and genetically obese (fa/fa) Zucker rats received either bilateral adrenalectomy or sham operations, and energy balance was measured over the subsequent 21 days. Body weight and energy intake were similar for intact lean and obese rats, but the latter group showed a marked increased in body energy gain and energetic efficiency, and reduced energy expenditure. Adrenalectomy did not significantly influence energy balance in lean rats but caused decreases in food intake and body weight gain in obese rats, and restored their energetic efficiency and body energy gain to the level of lean animals. The lower thermic response to a single meal (40 kJ) in intact obese rats was restored to normal by adrenalectomy. Brown adipose tissue (BAT) mass was larger in sham-operated obese rats, but tissue protein concentration, mitochondrial yield and mitochondrial GDP binding were all markedly reduced in obese rats. BAT mass, composition and GDP binding were almost identical in adrenalectomized obese and all lean rats. These findings demonstrate that the reduced fat deposition in Zucker rats after adrenalectomy is mainly due to the large decrease in the efficiency of energy utilization associated with a restoration of brown fat activity.
Resting metabolic rate (RMR) and the thermic effect of feeding (TEF) two meals of differing energy densities were measured in 8 healthy elderly men aged 63-74 years. Similar measurements were made on 8 healthy young men aged 22-28 years. TEF was related to the meal size in both groups. Metabolic rate increased by 20.7 and 27.9% in the elderly group (EG) and 25.8 and 37.7% in the control group (CG) in response to the 2.0-and 4.0-MJ meals, respectively. Although the EG were fatter than the CG, they consumed a smaller daily food intake: we suggest that the decline in RMR and TEF as indicated by the study would explain his paradox.
GDP binding to brown-adipose-tissue mitochondria of young obese Zucker rats (fa/fa) was significantly lower than in lean control rats, as a result of a decrease in the number of binding sites. Adrenalectomy of fa/fa rats restored GDP binding to control values. Corticosterone replacement suppressed GDP binding in adrenalectomized obese rats.
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1. Sixteen adult male volunteers were selected on the basis of body size and customary food intake: half could be described as "lean' and habitually consuming large amounts of food (group mean +/- SEM: 15.03 +/- 1.13 MJ/d), the high-energy-intake group (HEI group), and half though "lean' admitted to a weight problem and regularly consumed a lower than average food intake (group mean +/- SEM: 6.90 +/- 0.39 MJ/d), the low-energy-intake group (LEI group). 2. Energy expenditure was measured by open-circuit indirect calorimetry. Resting metabolic rate (RMR) was recorded. A meal (Complan, either 2.1 MJ or 4.2 MJ), ephedrine hydrochloride (0.25 mg and 0.50 mg/kg body-weight) or a water control were then administered and metabolic rate (MR) was measured for 4 h. Blood was collected before and 1 h after the meal or drug, and the serum analysed for various hormones and blood metabolites. 3. The size of the thermic response to feeding but not the time-course was related to meal size in both groups. MR increased by 21.6 and 28.6% in the HEI group and by 8.2 and 20.0% in the LEI group in response to the 2.1 and 4.2 MJ Complan meals respectively. Fasting insulin levels were similar in both groups but showed a significantly higher level in the LEI than HEI group after the Complan meals. 4. The mean RMR increased by 5.2 and 10.3% in the LEI in response to ephedrine and by 15.7 and 11.2% in the HEI groups after 0.25 mg and 0.50 mg ephedrine/kg respectively. The rise in serum-free fatty acids in response to ephedrine was significantly higher in the HEI group than in the LEI group. 5. These results suggest (1) the meal size required to promote a maximum thermic effect is smaller in energetically-inefficient individuals (2) the sensitivity to a sympathomimetic drug is also increased in energetically-inefficient individuals. 6. We conclude that in energetically-efficient individuals both the thermic response to a meal and the sympathetic-mediated thermogenesis are lower than in energetically-inefficient ones.
The characteristics of microsomal membrane lipids in obese (ob/ob) mice have been probed by studies on the microsomal enzyme NADPH-cytochrome P450 oxidoreductase and by investigation of their fluidity using the fluorescence probe 1,6 diphenylhexatriene. Arrhenius plots of NADPH-cytochrome P450 oxidoreductase activity were biphasic with the break temperature in obese mice reduced from 9.5 to 6.5 degrees C. The activation energy of NADPH-cytochrome P450 oxidoreductase was increased in obese microsomes below the Arrhenius breakpoint. Normalising the body temperature of ob/ob mice did not rectify the Arrhenius plot of NADPH-cytochrome P450 oxidoreductase activity of ob/ob mice. DPH fluorescence polarisation indicated that the gross phospholipids from ob/ob mouse microsomes were more fluid than those from lean mice. Phosphatidylethanolamine (PE) of ob/ob microsomes contains a higher proportion of unsaturated fatty acids resulting mainly from an increase in 22:6 and a fall in 16:0. Phosphatidyl choline (PC) of ob/ob microsomes contains an increased proportion of saturated fatty acids. Phospholipid vesicles of obese microsomal PE were more fluid and obese microsomal PC less fluid than the equivalent phospholipids from lean mice microsomes. The changes in Arrhenius plots of NADPH-cytochrome P450 oxidoreductase activity of obese microsomes are interpreted in relation to the reported phospholipid changes.
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Preobese 'fatty' fa/fa rats identified by their decreased rectal temperature were either given access to high carbohydrate chow or maintained on a suckling only diet til 20 days of age. Serum insulin, hepatic and adipose tissue fatty acid synthesis and lipogenic enzyme activities were low in suckling preobese fa/fa. In animals with access to chow diet, hepatic lipogenesis was unaltered, serum insulin rose to similar levels in lean and preobese fa/fa (lean 62 +/- 5; preobese 69 +/- 4 microU/ml), but adipose tissue lipogenesis was increased to higher levels in the preobese than lean rats (lean 0.56 +/- 0.12; preobese 1.80 +/- 0.22 mumol. tissue-1. h-1). The activities of glucose-6-phosphate dehydrogenase, acetyl coenzyme A carboxylase and fatty acid synthetase were increased in adipose tissue of preobese fa/fa rats. Neither streptozotocin treatment nor pretreatment with Triton WR 1339 abolished the difference in adipose tissue lipogenesis between lean and preobese fa/fa rats. Preobese fa/fa rats showed an enhanced insulin secretory response to a glucose load.