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Biomedical subjects

D S Weigle

Publications and source records attributed to D S Weigle.

At least 37 records · Page 2Linked to original sources
PubMed1996

Obesity genes and the regulation of body fat content.

Physiological investigation has demonstrated that the central nervous system monitors body composition and adjusts energy intake and expenditure to stabilize total adipose tissue mass. Genetic variations in the signalling molecules involved in this regulatory system account for the heritable component of body fat content. The application of molecular techniques to rodent models of Mendelian obesity has resulted in the characterization of five loci at which mutations produce an abnormal accumulation of body fat. The genes at these loci include agouti, which encodes a molecule that antagonizes the binding of alpha melanocyte-stimulating hormone to its receptor; fat, which encodes carboxypeptidase E; tubby, which encodes a putative phosphodiesterase; obese, which encodes a circulating satiety protein; and diabetes, which encodes the receptor for the obese gene product. A more detailed understanding of the functional interrelationships of these genes should lead to important new insights into the causes and potential therapies for human obesity.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Frequency of thyroid disease among Southeast Asian primary care patients.

We prospectively assessed 99 Southeast Asians for the presence of thyroid disease who were attending a primary care clinic devoted to the care of refugees. Subjects were undergoing evaluation as new patients and had no previously diagnosed thyroid abnormality. Each patient had a physical examination performed by his or her primary-care provider, was given a standardized questionnaire that focused on symptoms of thyroid disease and underwent a venipuncture for total thyroxine, triiodothyronine resin uptake and thyrotropin (TSH) concentration. Those who had an abnormal examination, calculated free thyroxine index (FT4I) or TSH level were re-examined by an endocrinologist and had repeat thyroid studies performed. Although 81% of patients reported > or = 1 symptom compatible with thyroid dysfunction, only 17% were found to have laboratory abnormalities. An abnormal FT4I and TSH level was found in 5% and 13% of subjects, respectively, but only one case of clinically significant hyperthyroidism and no cases of hypothyroidism were confirmed. TSH suppression, noted in 12% of subjects, persisted over a median follow-up of 6 months. Among seven patients with an anatomic abnormality of the thyroid, four had an abnormal FT4I or TSH. We conclude that the clinical prevalence of symptomatic thyroid dysfunction among Southeast Asians is comparable to that reported for non-Asian populations, but that the frequency of subclinical hyperthyroidism may be higher. Although symptoms suggestive of thyroid disease are common, routine screening for thyroid disease is not indicated in this study.

Adult↗
PubMed1996

Leptin is a metabolic signal to the reproductive system.

Leptin, a newly-discovered hormonal product of the obese (ob) gene, is expressed by adipocytes and thought to play a role in the regulation of food intake and metabolism. We tested the hypothesis that leptin signals metabolic information to the reproductive system by examining its effects on the reproductive system of ob/ob mice, which have a congenital deficiency in leptin and are infertile. We treated pair-fed males and females with leptin (50 microg twice daily, ip) or vehicle (n=10/group) for 14 days, after which the animals were bled and killed. Leptin-treated females had significantly elevated serum levels of LH, increased ovarian and uterine weights, and stimulated aspects of ovarian and uterine histology compared to controls. Leptin-treated males had significantly elevated serum levels of FSH, increased testicular and seminal vesicle weights, greater seminal vesicle epithelial cell height, and elevated sperm counts compared to controls. These results demonstrate that leptin stimulates the reproductive endocrine system in both sexes of ob/ob mice and suggest that leptin may serve as a permissive signal to the reproductive system of normal animals.

Analysis of Variance↗
PubMed1996

Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.

Correction of the obese state induced by genetic leptin deficiency reduces elevated levels of both blood glucose and hypothalamic neuropeptide Y (NPY) mRNA in ob/ob mice. To determine whether these responses are due to a specific action of leptin or to the reversal of the obese state, we investigated the specificity of the effect of systemic leptin administration to ob/ob mice (n = 8) on levels of plasma glucose and insulin and on hypothalamic expression of NPY mRNA. Saline-treated controls were either fed ad libitum (n = 8) or pair-fed to the intake of the leptin-treated group (n = 8) to control for changes of food intake induced by leptin. The specificity of the effect of leptin was further assessed by 1) measuring NPY gene expression in db/db mice (n = 6) that are resistant to leptin, 2) measuring NPY gene expression in brain areas outside the hypothalamus, and 3) measuring the effect of leptin administration on hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Five daily intraperitoneal injections of recombinant mouse leptin (150 micrograms) in ob/ob mice lowered food intake by 56% (P < 0.05), body weight by 4.1% (P < 0.05), and levels of NPY mRNA in the hypothalamic arcuate nucleus by 42.3% (P < 0.05) as compared with saline-treated controls. Pair-feeding of ob/ob mice to the intake of leptin-treated animals produced equivalent weight loss, but did not alter expression of NPY mRNA in the arcuate nucleus. Leptin administration was also without effect on food intake, body weight, or NPY mRNA levels in the arcuate nucleus of db/db mice. In ob/ob mice, leptin did not alter NPY mRNA levels in cerebral cortex or hippocampus or the expression of CRH mRNA in the hypothalamic paraventricular nucleus (PVN). Leptin administration to ob/ob mice also markedly reduced serum glucose (8.3 +/- 1.2 vs. 24.5 +/- 3.8 mmol/l; P < 0.01) and insulin levels (7,263 +/- 1,309 vs. 3,150 +/- 780 pmol/l), but was ineffective in db/db mice. Pair-fed mice experienced reductions of glucose and insulin levels that were < 60% of the reduction induced by leptin. The results suggest that in ob/ob mice, systemic administration of leptin inhibits NPY gene overexpression through a specific action in the arcuate nucleus and exerts a hypoglycemic action that is partly independent of its weight-reducing effects. Furthermore, both effects occur before reversal of the obesity syndrome. Defective leptin signaling due to either leptin deficiency (in ob/ob mice) or leptin resistance (in db/db mice) therefore leads directly to hyperglycemia and the overexpression of hypothalamic NPY that is implicated in the pathogenesis of the obesity syndrome.

Animals↗
PubMed1995

Accelerated cholesteryl ester transfer in baboons with insulin-requiring diabetes mellitus.

Cholesteryl ester transfer (CET), plasma, lipoprotein lipid and phospholipid composition were studied in insulin-treated baboons with chronic streptozotocin-induced diabetes. In these diabetic animals, CET measured both as the mass (p < 0.001) and isotopic transfer (p < 0.05) of CE from HDL to the apo B-containing lipoproteins (VLDL+LDL) were significantly accelerated compared to controls and the response closely resembled that recently reported in diabetic humans. No significant differences were present in plasma triglyceride, cholesterol, or HDL-C or in lipoprotein core or surface lipid composition. Thus, despite the fact that they did not display the same spectrum of abnormalities in lipoprotein composition, these insulin-treated diabetic baboons demonstrated an abnormality in CET identical to that described in humans. These findings suggest that this non-human primate may provide a suitable diabetic animal model in which to better characterize the mechanisms that underlie this potentially atherogenic disturbance in lipoprotein transport.

Animals↗
PubMed1995

Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.

To determine whether the product of the recently cloned ob gene functions as an adipose-related satiety factor, recombinant murine ob protein was administered intraperitoneally to ob/ob mice. Monomeric ob protein given as single morning injections to groups of three animals at seven doses ranging from 5 to 100 micrograms reduced 24-h chow consumption in a dose-dependent manner from values of 81 +/- 6.8% of control (10-micrograms dose, P = 0.04) to 29 +/- 7.7% of control (100-micrograms dose, P < 0.0001). Daily injections of 80 micrograms of ob protein into six ob/ob mice for 2 wk led to an 11 +/- 1.6% decrease in body weight (P = 0.0009) and suppressed feeding to 26 +/- 4.9% of baseline (P < 0.0001), with significant reduction of serum insulin and glucose levels. The effect of recombinant ob protein on feeding was not augmented by cofactors secreted by adipose tissue, nor did exposure of adipose tissue to ob protein affect intracellular ob mRNA levels. Posttranslational modification of ob protein was not required for activity; however, addition of a hexahistidine tag to the amino terminus of the mature ob protein resulted in prolonged suppression of feeding after injection into ob/ob mice. These results demonstrate a direct effect of the ob protein to suppress feeding in the ob/ob mouse and suggest that this molecule plays a critical role in regulating total body fat content.

Adipose Tissue↗
PubMed1994

Appetite and the regulation of body composition.

Stability of body composition requires that energy intake equals energy expenditure when integrated over prolonged periods. As recent human studies have failed to demonstrate active changes in energy expenditure with changes in body composition, it is likely that energy intake is continually adjusted to preserve a constant total adipose tissue mass. If adipose tissue mass is regulated directly, then there must be some input reflecting this quantity to the central nervous system for the purpose of making corrective changes in appetite when total body fat content fluctuates. The nature of this input has been examined in a variety of animal experiments involving induced weight change, lipectomy, plasma transfer from obese or satiated animals to hungry animals, and parabiosis between obese and lean animals. The bulk of evidence suggests that the plasma level of one or more currently unidentified stable circulating molecules increases in proportion to total body fat content and augments the effect of meal-related satiety signals in the central nervous system. The implications of this adipose tissue-related satiety factor for the pathogenesis of obesity, and the possible nature of the factor are discussed.

Animals↗
PubMed1991

Lack of evidence for improvement in long-term glycemic control by pulsatile insulin infusion in streptozocin-induced diabetic baboon.

To assess the potential therapeutic use of pulsatile intravenous insulin delivery, five streptozocin-induced diabetic baboons were treated with alternate 3- to 6-wk periods of pulsatile and continuous insulin infusion. Time-averaged insulin concentrations were matched during two pulsatile administration periods (P1 and P2) and an intervening period of continuous insulin administration (C). There were no significant differences among the overall means of four daily glucose determinations performed during the three periods (P1, 5.7 +/- 1 mM; C, 5.6 +/- 0.9 mM; P2, 5.3 +/- 0.9 mM); the mean M value, a measure of the stability of glycemic control (P1, 4 +/- 1.7; C, 3.9 +/- 1.8; P2, 3.6 +/- 1.5); the percentage of glucose values less than 2.8 mM (P1, 13 +/- 8.5%; C, 14 +/- 12%; P2, 13 +/- 9.1%); or the glycosylated hemoglobin levels determined at the end of the P1 and C (7.5 +/- 3.4 and 6.5 +/- 1.8%, respectively [all values are means +/- SD]). Fasting hepatic glucose production was suppressed to a similar degree during pulsatile and continuous insulin infusion (P1, 23 +/- 3 mumol.kg-1.min-1; C, 24 +/- 8 mumol.kg-1.min-1). Arterial glucagon levels were similar during pulsatile and continuous insulin infusion, both in the fasting state (84 +/- 29 and 84 +/- 31 ng/L, respectively) and postprandially (30 +/- 14 and 27 +/- 12 ng/L, respectively). Pulsatile insulin infusion failed to entrain a corresponding glucagon secretory rhythm. These data suggest that the metabolic consequences of long-term pulsatile and continuous insulin infusion in an animal model of human non-insulin-dependent diabetes are comparable.

Animals↗
PubMed1990

Identification of candidate genes for a factor regulating body weight in primates.

A weight gain of 20-30% above baseline, induced by gastrostomy overfeeding of subhuman primates or gavage overfeeding of rats, was found to completely suppress voluntary food consumption. When overfeeding was discontinued, body weight and oral intake returned in a coordinated fashion to baseline or "set point" values. This regulatory response could have been due to a circulating peptide that was secreted by adipocytes in proportion to the total body energy store and that mediated satiety at the level of the central nervous system. To search for this factor, a subtractive cDNA cloning strategy was developed, permitting the isolation of primate adipocyte genes with augmented expression in the overfed state. A 1.8-kb cDNA clone prepared by subtraction was found to hybridize to a 5-kb message expressed preferentially in the adipose tissue of overfed macaques and rats. This message, which was restricted in distribution among nonadipose tissues, was also detected in human subcutaneous fat. Candidate genes for satiety factors identified by this approach could be used in further studies of body weight regulation and obesity.

Adipose Tissue↗
PubMed1990

Assessment of energy expenditure in ambulatory reduced-obese subjects by the techniques of weight stabilization and exogenous weight replacement.

A technique based on a completely metabolizable liquid diet was developed rapidly to achieve weight stability (+/- 50 g/day) in experimental subjects. Weight-stabilizing caloric intake was then used as an estimate of total daily energy expenditure (24 h EE) in a study of 10 ambulatory obese subjects before and after weight loss. In five control subjects 24 h EE fell by 928 +/- 121 kcal/day (3885 +/- 507 kJ/day) or 29 +/- 3 percent after a 22.6 +/- 1.2 percent weight loss achieved on a three month 700 kcal/day (2930 kJ/day) diet. To determine how much of this decrease was due to the reduced thermic effect of exercise (TEE) at the lower body weight, the remaining five subjects underwent progressive exogenous weight replacement during dieting to compensate exactly for their 21.0 +/- 5.2 percent weight loss. In the latter group 24 h EE fell by only 392 +/- 192 kcal/day (1641 +/- 804 kJ/day) or 12 +/- 5 percent (P less than 0.001). These data, along with indirect calorimetric measurements of resting metabolic rate (RMR), permitted the decrease in 24 h EE with weight loss to be divided into its component parts. Decreases in RMR, TEE and the thermic effect of food accounted for 30 percent, 52 percent and 18 percent respectively of the fall in 24 h EE. A reduction in TEE appears to make a greater contribution to the enhanced energy efficiency of ambulatory reduced-obese subjects than has been suggested by studies based on methods requiring greater subject confinement.

Adult↗
PubMed1990

Human obesity. Exploding the myths.

This discussion was selected from the weekly Grand Rounds in the Department of Medicine, University of Washington School of Medicine, Seattle. Taken from a transcription, it has been edited by Drs Paul G. Ramsey, Associate Professor of Medicine, and Philip J. Fialkow, Professor and Chair of the Department of Medicine.

Body Constitution↗
PubMed1989

Decreased insulin- and glucagon-pulse amplitude accompanying beta-cell deficiency induced by streptozocin in baboons.

The effect of beta-cell deficiency on the spontaneous pulsatile secretory pattern of the islets of Langerhans was studied in the baboon. Measures of beta-cell function were correlated with the secretory pattern before and at intervals after streptozocin administration. The degree of insulin deficiency was variable and ranged from mild to moderate. Highly regular pulses were less prevalent in baboons compared with rhesus monkeys and humans, but the mean frequency was similar and was not affected by treatment. The principal effect of beta-cell destruction was to proportionately reduce the pulse amplitude of insulin (-39%, P less than .003) without detectable change in pulse frequency, interhormonal phase relationship, or the regularity of pulses. Glucagon-pulse amplitude also fell (-19%, P less than .09), but not significantly. However, glucagon-pulse amplitude was strongly correlated with insulin-pulse amplitude (r = -.59, P less than .002), whereas mean fasting plasma concentrations of insulin and glucagon were not significantly changed after treatment. Because streptozocin affects only the beta-cell, the data indicate a major influence of the insulin pulse on the alpha-cell secretory pulse. The data do not support the presence of a separate pacemaker for the alpha-cell but do not eliminate this possibility. The strong correlation of reduction in insulin-pulse amplitude with increasing fasting glucose and decreasing glucose disappearance lends support to growing evidence that the pattern of insulin secretion is an important determinant of normal glucose homeostasis.

Animals↗
PubMed1989

Preliminary assessment of very low calorie diets by conventional and signal-averaged electrocardiography.

Fatalities accompanying the use of very low calorie diets have been attributed to cardiac arrhythmias, which may have been associated with myocardial catabolism and hypokalemia. Delayed activation of damaged regions of myocardium may result in low amplitude potentials late in the QRS complex which have been associated with sustained ventricular tachycardia. We used the techniques of routine electrocardiography, signal averaging of the surface electrocardiogram and ambulatory electrocardiographic (Holter) monitoring to evaluate a group of 11 obese men (116 +/- 14 kg) who consumed a potassium-supplemented 660 kcal/day (2763 kJ/day) milk-based liquid diet for 95 +/- 14 days. Electrocardiographic measurements were made before beginning the diet, during the final week on the diet, and after refeeding. Corrected QT interval, QRS voltage and duration, absence of signal-averaged late potentials and ventricular ectopy during 24 h Holter monitoring during the diet and refeeding did not differ from baseline determinations at any point in the obese subjects. In this study, which involved only 11 subjects, neither standard electrocardiographic techniques nor a newer signal-averaging technique revealed any electrocardiographic changes from the diet. A very large population would have to be studied to evaluate the usefulness of these techniques in predicting myocardial damage serious enough to cause arrhythmias. Until such studies are available, the safety of such diets remains unknown.

Arrhythmias, Cardiac↗
PubMed1988

Weight loss leads to a marked decrease in nonresting energy expenditure in ambulatory human subjects.

The extent to which the resting and nonresting components of 24-hour energy expenditure decrease after weight reduction has not been prospectively assessed in ambulatory, weight-stable, reduced-obese humans. Accordingly, 24-hour energy expenditure was estimated as the weight-stabilizing (+/- 50 g/d) daily caloric intake of a defined liquid diet in a cross-sectional study of ten reduced-obese subjects after a 23.2% +/- 9.4% weight loss and 18 obese subjects at baseline weight. A regression analysis demonstrated an 18% decrease in the mean daily energy requirement of the reduced-obese subjects compared with that of subjects of the same relative body weight who had never dieted. Strong linear relationships were noted between estimated 24-hour energy expenditure and fat-free mass (FFM), and between resting metabolic rate (RMR) and FFM in the subjects at baseline weight. In six reduced-obese men, the 24-hour energy expenditure was only 75.7% +/- 5.6% of the value predicted by regression analysis for the decreased FFM. In these six subjects the RMR was 97.4% +/- 7.5% of that predicted for the decreased FFM, suggesting that essentially all the energy savings relative to FFM in the reduced-obese state occurred in nonresting energy expenditure. In a subsequent group of seven subjects studied longitudinally before and after a 21.5% +/- 2.3% weight loss, the decrease in nonresting energy expenditure accounted for 582 +/- 276 kcal/d or 71% of the decrease in estimated 24-hour energy expenditure. These data suggest a decrease in the nonresting energy expenditure of ambulatory reduced-obese individuals, which is greater than previously appreciated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Contribution of decreased body mass to diminished thermic effect of exercise in reduced-obese men.

Reduced energy expenditure after weight loss contributes to the difficulty which obese individuals face in maintaining a lower body weight. To evaluate the contribution of decreased energy cost of physical activity at a lower body weight to diminished total energy expenditure, two groups of unconfined obese men were studied before and after a 22 percent weight loss. A control group received a 700-cal diet alone whereas the experimental group, while consuming an identical diet, wore a vest into which weights were inserted twice weekly to exactly compensate for body weight loss. In the control group the total daily caloric requirement for weight maintenance fell by 916 +/- 121 kcal/day (3834 +/- 507 kJ/day) in contrast to only a 404 +/- 192 kcal/day (1691 +/- 804 kJ/day) fall in the experimental group at full exogenous weight replacement (P less than 0.001). Body composition, maximal exercise performance, and resting metabolic rate were unaffected by weight replacement. Activity levels decreased at the same rate in both subject groups with progressive weight loss. In conclusion, loss of body weight reduces the energy cost of physical activity sufficiently to account for more than half of the major fall in energy expenditure noted in free-living men after weight loss.

Adipose Tissue↗
PubMed1987

A kinetic analysis of hepatocyte responses to a glucagon pulse: mechanism and metabolic consequences of differences in response decay times.

Pulsatile administration of glucagon to perifused rat hepatocytes stimulates hepatocyte glucose production (HGP) more effectively than continuous administration. Having established that this effect was due to delayed relaxation of glucagon-stimulated HGP (t1/2 for decay = 3.54 +/- 0.60 min) we wished to examine the mechanism of response termination. Delayed dissociation of glucagon from its receptor was excluded by the brisk washout of [125I]glucagon from perifusion columns (t1/2 = 1.00 +/- 0.13) and the rapid decay in glucagon-stimulated cAMP released into the perifusion medium (t1/2 = 1.14 +/- 0.12). The relaxation of the HGP response to a pulse of administered cAMP was comparable to the decay in glucagon-stimulated HGP (t1/2 = 3.28 +/- 0.22). Furthermore, the phosphodiesterase inhibitor isobutyl-methylxanthine did not alter the decay of the HGP response to glucagon despite increasing the amplitude of the response (t1/2 = 3.04 +/- 0.36). These data place the rate-limiting step for HGP relaxation distal to cAMP generation and degradation. The decay of the beta-hydroxybutyrate response to a glucagon pulse was not different from the cAMP response (t1/2 = 1.14 +/- 0.23), whereas the decay of gluconeogenesis from lactate was not significantly different from HGP relaxation (t1/2 = 1.94 +/- 0.08). We conclude that rate-limiting events for HGP relaxation occur distal to the second messenger cascade; however, ketogenesis is more closely coupled to the kinetics of cAMP. These results may help to explain the absence of excessive ketosis during fasting in normal humans, who secrete glucagon episodically at 10- to 14-min intervals.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Evidence that the physiological pulse frequency of glucagon secretion optimizes glucose production by perifused rat hepatocytes.

We have reported that glucagon administered to perifused rat hepatocytes as a series of pulses at 15-min intervals is a more effective stimulus for hepatocyte glucose production (HGP) than is continuous glucagon infusion. To test whether the efficiency of HGP depends upon the frequency of pulsatile glucagon delivery, we administered glucagon to perifused rat hepatocytes as a series of pulses of fixed amplitude [922 +/- 30 (+/- SE) pg/ml] at eight separate pulse intervals ranging from 3-45 min. Compared to continuous infusion of the same total amount of hormone, pulsatile glucagon administration clearly enhanced HGP in a frequency-dependent fashion. At pulse intervals between 10 and 20 min, pulsatile HGP exceeded continuous HGP by a factor of 1.5-2. This range of optimal intervals compared favorably with the glucagon secretory period of 10 min observed in nonhuman primates and that of 13-20 min observed in humans. We noted a desensitization of the hepatocyte response to glucagon that was directly proportional to the log of the time-averaged hormone concentration. Since the magnitude of the desensitization elicited by pulsatile glucagon delivery exceeded the desensitization elicited by continuous hormone delivery regardless of pulse frequency, differential desensitization could not explain the frequency dependency of the pulse enhancement effect. A mathematical simulation of our data demonstrated that the asymmetry of the HGP waveform elicited by a brief glucagon pulse could account for the observed frequency dependency of HGP. Pulse to pulse summation and the desensitization phenomenon modulated both the magnitude of the pulse enhancement effect and the frequency range over which the effect was manifest. We conclude that the enhancement of HGP by glucagon pulses is a frequency-dependent phenomenon and that the physiological glucagon secretory period optimizes HGP.

Animals↗