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Biomedical subjects

A C Sullivan

Publications and source records attributed to A C Sullivan.

At least 55 records · Page 3Linked to original sources
PubMed1984

Dietary obesity and neonatal sympathectomy. I. Effects on body composition and brown adipose.

The effect of neonatal sympathectomy with guanethidine (50 mg/kg for 3 wk) on the development of diet-induced obesity (DIO) was assessed by raising guanethidine-(G) or saline-treated (S) Sprague-Dawley rats in small litters (4-5 pups/dam) and feeding a high-calorie diet from weaning (n = 29-30) or by raising similarly treated rats in normal litters (10 pups/dam) and feeding chow from weaning (n = 29-30). Sympathectomy depleted norepinephrine (NE) levels 65-98% in all organs except the adrenals and brain but had no statistically significant effect on weight gain, food intake, food efficiency, body composition, plasma glycerol, insulin, or glucose, or on basal rectal temperatures in either diet group; there was a tendency toward increased adiposity in sympathectomized rats. Despite 95-98% depletion of NE in interscapular brown adipose tissue (IBAT), sympathectomy affected only the percentage of multilocular cells that was decreased 46-69%. Rats from small litters in both treatment groups (S and G) became obese without increased food intake (increased food efficiency), had heavier IBAT pads with bigger cells and more lipid, and were also hyperlipidemic, hyperinsulinemic, and hyperglycemic compared with controls. Therefore neonatal sympathectomy was not as significant in the subsequent development of DIO as were diet and litter size.

Adipose Tissue↗
PubMed1984

Dietary obesity and neonatal sympathectomy. II. Thermoregulation and brown adipose metabolism.

Neonatal sympathectomy with guanethidine (50 mg/kg for 3 wk) in Sprague-Dawley rats was previously shown not to significantly affect body weight gain, even when rats were raised in small litters and fed a high-calorie diet from weaning to produce diet-induced obesity (15). In our study rectal temperatures of cold-stressed (24 h at 4 degrees C) sympathectomized rats (obese and lean) fell only 1.4 degrees C after 4 h and were normal by 24 h, as were plasma catecholamine, glycerol glucose, and insulin levels after 4 h at 4 degrees C. Obese rats (with or without sympathectomy) had decreased 4-h (at 4 degrees C) plasma norepinephrine (NE) and increased basal and 4-h plasma glycerol, glucose, and insulin levels. Despite greater than 95% depletion of interscapular brown adipose tissue (IBAT) NE in sympathectomized rats, there was no alteration in beta-adrenoreceptor binding and only 10 and 32% decreases in basal and maximal NE-stimulated O2 consumption, respectively. Obese rats had significant increases in IBAT beta-receptor binding (148-190%/cell, 77-155%/pad) and in basal (11-19%) but not maximal O2 consumption. These results suggest that factors other than the sympathetic nervous system can effectively control thermoregulation, IBAT metabolism, and body weight in the presence of a chronic defect in sympathetic function.

Adipose Tissue, Brown↗
PubMed1984

Regulation of thermogenesis in obesity.

Obesity results when the intake of energy exceeds that which is expended with the resultant storage of the excess energy as fat. Thermogenesis, the metabolic expenditure of energy as heat, is the primary way in which mammals loss dietarily-derived energy and some evidence suggests that certain obese humans may have defective diet-induced thermogenesis. The sympathetic nervous system is the primary effector of thermogenesis through the release of norepinephrine at its nerve terminals. During the early stages of over-eating, there is an increase in sympathetic activity in several organs, including brown adipose tissue (BAT), a major thermogenic organ in many mammals. This increased neural activity is associated with increased thermogenic capacity of the entire animal as well as in BAT and, together, these events are sufficient to prevent the development of obesity in certain young animals such as rats. However, in older rats, obesity eventually develops over several months' of exposure to high energy diets and the early increases in thermogenic capacity and sympathetic activity return to or below baseline levels. Also, genetically obese rodents generally have defective total body and BAT thermogenic capacity, especially to a dietary challenge, as well as abnormal sympathetic function in their BAT. These observations suggest that there are certain types of obesity that are associated with a diminished ability to expend dietarily-derived energy as heat and that chronic obesity in general represents an altered homeostatic state associated with increased metabolic efficiency in some humans and other mammals.

Adipose Tissue, Brown↗
PubMed1984

Anti-obesity activity of a novel lipid synthesis inhibitor.

A novel anti-obesity agent which inhibits fatty acid synthesis and stimulates fatty acid oxidation is described. The hydrochloride salt of Ro 22-0654 (4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester) is a potent inhibitor of fatty acid and cholesterol synthesis in rat-isolated hepatocytes. Hepatic fatty acid synthesis was inhibited in vivo in a dose-dependent fashion with a duration of action of approximately 8 h. Adipose tissue fatty acid synthesis was also inhibited in vivo. Inhibition of fatty acid synthesis occurs without any apparent effect on several lipogenic enzymes, the tricarboxylic acid cycle, and the pentose phosphate shunt. Ro 22-0654 also stimulated fatty acid oxidation (in vitro) and lipolysis (in vivo). In long-term studies (2 months), Ro 22-0654 decreased body weight gain in Sprague Dawley and genetically-obese Zucker rats. Food intake was decreased following a single dose and for several days during chronic treatment. However, while food intake quickly returned to normal, body weight gain remained lower in treated rats. The effect on body weight gain can be ascribed to decreased total body lipid content in the absence of an effect on lean body mass. It is suggested that Ro 22-0654 may have utility in the treatment of human obesity.

Adipose Tissue↗
PubMed1983

Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid.

Oral administration of 13-cis-retinoic acid (40 or 160 milligrams per kilogram of body weight daily) significantly reduced the inflammation associated with developing and established adjuvant arthritis, an experimentally induced arthritis in rats that resembles human rheumatoid arthritis. The amount of collagenase secreted in tissue culture by adherent cells isolated from the inflamed joints of adjuvant rats treated with 13-cis-retinoic acid also decreased as compared to the amount secreted by cells from vehicle-treated adjuvant rats. Collagenase is important in the joint destruction accompanying rheumatoid arthritis. The successful use of retinoids in the treatment of this proliferative but nonmalignant disorder demonstrates a new application of these compounds.

Animals↗
PubMed1983

Studies of origins of abnormal sympathetic function in obese Zucker rats.

To explain previously described abnormalities of sympathetic function in the genetically obese Zucker rat, the kinetics of norepinephrine (NE) metabolism were examined. Lower stress-induced levels of plasma NE in the obese rat were shown to be due to decreased release of NE because uptake of [3H]NE tracer from plasma was 45% slower in the obese compared with the lean rat. NE levels were 15, 20, and 34% lower in heart, pancreas, and interscapular brown adipose tissue (IBAT), and NE turnover rates (determined by two independent methods) were 39-48 and 43-69% lower in the pancreas and IBAT of obese compared with lean rats. In vivo synthesis of [3H]NE from [3H]dopamine by the enzyme dopamine beta-hydroxylase was 60% lower in IBAT but was equal in hearts of obese compared with lean rats. These results suggest an organ-specific decrease of NE synthesis in the obese Zucker rat, possibly due to decreased dopamine beta-hydroxylase activity in IBAT.

Adipose Tissue↗
PubMed1983

Altered sympathetic activity during development of diet-induced obesity in rat.

Sprague-Dawley rats developed diet-induced obesity (DIO) after 3 mo on a high-fat, high-sucrose diet (DIO diet), with associated increases in total body and interscapular brown adipose tissue (IBAT) lipid content. After 7 days on the DIO diet, rats had increased levels of tyrosine hydroxylase (TH; 34%), norepinephrine (NE; 34%), and NE turnover (94%; estimated by alpha-methyl-p-tyrosine inhibition of TH) in their IBAT compared with chow-fed controls. After 3 mo on the DIO diet, NE levels and/or turnover were reduced by 27-50% in aortas, hearts, and pancreata in obese rats. While IBAT NE turnover was normal, TH inhibition failed to increase the lipid content of IBAT in obese rats as it did in controls, suggesting a postsynaptic defect in basal NE-stimulated lipolysis in this thermogenically active tissue. When obese rats were switched from the DIO diet to rat chow for 3 days, NE levels remained depressed in their hearts (25%) and aortas (14%) but were increased by 36-45% in IBAT, pancreata, and white adipose tissue. NE turnover rates and/or constants were increased by 37-110% in hearts, aortas, pancreata, and IBAT of these obese rats while there were increased IBAT TH (20%) and dopamine-beta-hydroxylase (87%) activities compared with chow-fed controls. Therefore, sympathetic activity varied markedly as a function of both dietary composition and relative body weight during the development of DIO.

Adipose Tissue↗
PubMed1983

Relationship between sympathetic activity and diet-induced obesity in two rat strains.

Chronic diet-induced obesity developed in 50-60% of male Sprague-Dawley rats fed a relatively high-calorie diet for 90 days. The remaining rats decreased their caloric intake and resisted the development of obesity. All male Fischer F-344 rats fed this diet for 85 days became obese but to only half the degree of the obese Sprague-Dawley rats. The development of chronic obesity in both rat strains was associated with decreased norepinephrine (NE) levels in hearts and aortas and decreased NE turnover in aortas compared with chow-fed controls. However, 40-50% of the Sprague-Dawley rats did not become obese on this diet, yet showed similar findings suggesting an effect of dietary composition on sympathetic function. The more profoundly obese Sprague-Dawley rats additionally showed decreased or absent NE turnover in their hearts and pancreases. Since sympathetic function in both strains of rats with diet-induced obesity was either depressed or normal, it appears unlikely that the initial enhancement of sympathetic activity seen during short-term overfeeding plays an important continuing role in combating more chronic states of obesity in the rat.

Animals↗
PubMed1982

Phenethylamine inhibitors of partially purified rat and human pancreatic lipase.

Methodology for the preparation of rat and human pancreatic lipase (EC 3.1.1.3) is described, which resulted in good yield of partially purified, stable enzyme useful for kinetic studies. Apparent Km values for the rat (6.5 mM) and human (3.5 mM) enzyme were determined with triolein as the substrate. Several compounds of the phenethylamine class were found to be inhibitors of both rat and human pancreatic lipase. The structural feature in the phenethylamine series tested, which appeared to be necessary for lipase inhibition, was a halogenated substituent on the 3 or 4 position of the aromatic ring as in flutiorex, fenfluramine, N-benzyl-beta-methoxy-3-(trifluoromethyl)phenethylamine (I), chlorphentermine and p-chloroamphetamine. A chloro group at the 2 position was ineffective (chlortermine). Alterations in the ethylamine portion of the molecule did not cause significant changes in the inhibitory properties of the active phenethylamines.

Animals↗
PubMed1982

Oxidation and ketogenesis in hepatocytes of lean and obese Zucker rats.

Ketone body production and oxidation of 14C fatty acids to CO2 were measured in hepatocytes isolated from lean and obese Zucker rats. The oxidation of [1-14C]octanoate, [1-14C]palmitate and [1-14C]palmitoyl carnitine to 14CO2 was 50%--70% less in obese than in lean rats. Although ketone body production in hepatocytes from both lean and obese rats was increased by fasting, there was a significantly lower rate of ketone body production in hepatocytes from obese rats. Ketone body production was reduced to a comparable extent by increasing the glucose concentration in the incubation media of hepatocytes from both lean and obese rats. Glucagon and carnitine increased ketogenesis and the effect were additive and similar in lean and obese rats. These data suggest that beta-oxidation and ketogenesis are suppressed in the obese Zucker rat, and further that ketone bodies can be modulated similarly in hepatocytes from lean and obese rats by nutritional and hormonal intervention. It is postulated that the decreased beta-oxidation and ketone body production may play a role in the development or maintenance of obesity in the Zucker rat.

Animals↗
PubMed1982

Subtypes of unipolar depression distinguished by the dexamethasone suppression test.

The dexamethasone suppression test (DST) was administered to 54 primary unipolar depressed patients and 19 non-depressed hospitalized inpatients. Abnormal DST were found in 23 depressed patients (43%) in contrast to 2 (11%) non-depressed patients (P less than 0.05). Within the endogenously depressed group, 69% of patients categorized as familial pure depressive disease (FPDD) in contrast to 13% of depressive spectrum disease (DSD) patients had abnormal DST results (P less than 0.02). The DSD group had significantly fewer abnormal DST results than all other subtypes of unipolar depression (P less than 0.05). The distinction revealed between DSD patients and other endogenously depressed patients may be due to biological factors or due to the heterogeneous nature of the DSD subtype group.

Adult↗
PubMed1982

The TRH stimulation test in subtypes of unipolar depression.

The thyrotropin releasing hormone (TRH) stimulation test was administered to 54 primary unipolar endogenously depressed and 19 non-depressed hospitalized inpatients. Blunted TSH responses to TRH infusion (delta max TSH less than 7 microunits/ml) were revealed in 18 depressed and no non-depressed patients (P less than 0.01). Augmented TSH responses (delta max TSH greater than 23 microunits/ml) were noted in 8 depressed and no non-depressed patients (P = n.s.). The TRH stimulation test did not distinguish between subtypes of unipolar depression using the familial subtyping criteria of Winokur. These findings are discussed in light of previously reported dexamethasone suppression test subtype distinctions.

Adult↗
PubMed1982

Compensatory pituitary-thyroid mechanisms in major depressive disorder.

The thyrotropin-releasing hormone (TRH) stimulation test was administered to 47 patients meeting DSM-III criteria for major depressive disorder (with melancholia) and to 19 nondepressed patients. The wide variability of pituitary responses to TRH stimulation noted in the depressed patients provides evidence for the dysregulation of compensatory hypothalamic-pituitary-thyroid function in acute depression. Blunted thyroid-stimulating hormone (TSH) responses to TRH injection were found in 16 depressed (34%) and no nondepressed patients (p less than 0.01). Depressed patients who revealed blunted TSH responses also had blunted prolactin responses to TRH relative to other depressed and nondepressed patient groups (p less than 0.01). These patients (with blunted TSH and prolactin responses) may represent a psychobiologically distinct subgroup of endogenously depressed patients. Augmented (high normal) TSH responses to TRH stimulation were found in eight depressed patients (all women), in contrast to no nondepressed patients. These patients may have a subtle thyroidal dysfunction affecting the underlying endogenous depressive diathesis.

Adolescent↗
PubMed1982

Abnormal brown adipose composition and beta-adrenoceptor binding in obese Zucker rats.

The composition, morphology, beta-adrenergic receptor binding, and in vitro lipolysis were examined in lean and obese, 5- to 6-mo-old male Zucker rat interscapular brown adipose tissue (IBAT). IBAT pads from obese rats were heavier (283%), had more lipid (700%), and more (75%)( and larger (83%) adipocytes than those from lean rats. Also, IBAT from obese rats had no multiloculated cells, and 50% of their IBAT adipocytes were the size of white fat cells. High affinity binding for (-)-[3H]dihydroalprenolol (KD, 15-18 nM), as well as the estimated KD values for binding and the 1/2 Vmax values for adrenergic agonist-induced lipolysis were similar in isolated IBAT cells from lean and obese rats. However, adipocytes from IBAT in obese rats had 75% fewer high affinity beta-adrenergic binding sites per cell (Bmax) compared to those in lean rats. These findings are most compatible with the infiltration of IBAT by white adipocytes. Such infiltration would be expected to reduce the overall thermogenic capacity of IBAT in obese Zucker rats and thereby contribute to the maintenance of their obesity.

Adipose Tissue, Brown↗
PubMed1982

Effect of phenoxybenzamine on development of adipose tissue in lean and obese Zucker rats.

Young male Zucker lean (Fa/-) and obese (fa/fa) rats were fed the alpha-adrenergic blocking agent phenoxybenzamine as a dietary admixture for 35 days. In lean and obese rats, phenoxybenzamine treatment decreased significantly body weight gain, food consumption, grams of carcass fat, and grams of carcass protein. Lean rats exhibited reduced fat cell size and number in retroperitoneal, epididymal, and inguinal fat depots. Obese rats treated with phenoxybenzamine exhibited significantly decreased numbers of fat cells in the retroperitoneal, epididymal, and inguinal fat depots and a small decreased cell size in the inguinal fat depot only. The levels of carcass fat and protein and fat cell number in obese and lean rats treated with phenoxybenzamine for 35 days were similar to pretreatment values in agreement with the lack of body weight gain. Although values in agreement with the lack of body weight gain. Although rats exhibited marked decreases in fat accumulation during phenoxybenzamine treatment, fat cell size and number returned to control values during the posttreatment period with a marked hyperplasia occurring particularly in the retroperitoneal fat depot of obese rats. Serum levels of insulin were suppressed and free fatty acid levels increased in obese rats during phenoxybenzamine treatment, suggesting a stimulation of the sympathoadrenal system. This study shows that despite severe restrictions in fat cell proliferation during the rapid-growth phase of the obese Zucker rat, the mechanisms for cellular proliferation and fat deposition remain intact.

Adipose Tissue↗