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Objective: To identify differences in amount and distribution of fat and lean soft tissue in a cross-sectional study of subjects with and without type 2 diabetes and to determine whether any differences are affected by race/ethnicity or sex., Design and Methods: Overweight and obese (body mass index, BMI > or = 25 kg m(-2)) Black, White and Hispanic men (490) and women (825) with type 2 diabetes ((mean+/-s.d.) age 58.5+/-6.6; BMI 35.3+/-5.3) who had a baseline dual energy X-ray absorptiometry whole-body scan at the time of enrollment in the Look AHEAD clinical trial, and 242 healthy controls, 91 males and 151 females (age 55.3+/-8.6 years, BMI 30.7+/-4.2 kg m(-2)) who were participating in unrelated research and were scanned on the same densitometers., Results: Adjusted for gender, age, race, clinical site and body size, total fat mass was smaller in persons with type 2 diabetes than in controls (-1.4+/-0.3 (s.e.); 34.5 vs 35.8 kg, P<0.001) while trunk fat was larger (1.3+/-0.2 (s.e.); 19.9 vs 18.6 kg, P<0.001) and leg fat was smaller (-1.5+/-0.2 (s.e.); 10.7 vs 12.3 kg, P<0.001). The arms of subjects with type 2 diabetes did not have significantly less fat compared to controls. Adjusted trunk lean mass was larger in type 2 diabetes by 0.6 kg (28.4 vs 27.8 kg, P<0.001) while leg lean was smaller by 0.5 kg (18.1 vs 18.6 kg, P<0.001)., Conclusions: Type 2 diabetes is associated with less total fat, leg fat and leg lean mass and more truncal fat and lean mass than controls. The physiological processes producing these deviations in tissue distribution and their metabolic significance warrant further investigation.

Background: Only a few published studies in children used several methods to compare body fat in large groups of fatter and leaner multiethnic children. We hypothesized that the preferred methods of determining body fat may differ in children with larger compared with smaller amounts of body fat, in boys compared with girls, and in African Americans compared with whites., Objective: Our objective was to evaluate several methods of predicting body fat in 10-12-y-old white and African American boys and girls., Design: The body fat of 129 African American and white boys and girls aged 10-12 y, distributed equally by sex and race, was measured with use of dual-energy X-ray absorptiometry (DXA), underwater weighing (densitometry), isotope dilution (H(2)18O), bioelectrical impedance, skinfold thicknesses, corporal diameters, and circumferences., Results: With use of DXA as the criterion variable, body fat was bimodally distributed in the boys and skewed to higher values in the girls. Biceps skinfold thickness had the highest predictive value of any single skinfold thickness compared with DXA fat. All formulas for estimating body fat from skinfold thicknesses, body density, or impedance performed better in the children in the upper one-half of the fat distribution (the fatter children) than in those in the lower one-half (the leaner children). Body mass index was highly correlated with body fat (R2 = 0.77); there was a good correlation for the fatter children (R2 = 0.66) and no correlation for the leaner children (R2 = 0.09). The hydration of the fat-free mass was significantly higher in the fatter children than in the leaner ones (79.2% compared with 76.7%)., Conclusions: These data are consistent with the hypothesis that all methods of estimating body fat work better in children with larger amounts of body fat. The best formulas use skinfold thicknesses, bioelectrical impedance, and a 4-compartment model.

Obesity is related to the risk for developing non-insulin-dependent diabetes mellitus (NIDDM), hypertension, and cardiovascular disease. Visceral adipose tissue (VAT) has been proposed to mediate these relationships. Abdominal subcutaneous adipose tissue (SAT) is divided into 2 layers by a fascia, the fascia superficialis. Little is known about the radiologic anatomy or metabolic correlates of these depots. The objective of this study was to relate the amounts of VAT, SAT, deep subcutaneous abdominal adipose tissue (DSAT), and superficial subcutaneous abdominal adipose tissue (SSAT) to gender and the metabolic complications of obesity after adjusting for total body fat and to discuss the implications of these findings on the measurement of adipose tissue mass and adipose tissue function. The design was a cross-sectional database study set in a nutrition research center. Subjects included 199 volunteers participating in nutrition research protocols who also had computed tomography (CT) and dual energy x-ray absorptiometry (DEXA) measurement of body fat. The amount of DSAT was sexually dimorphic, with women having 51% of the subcutaneous abdominal fat in the deep layer versus 66% for men (P <.05). Abdominal fat compartments were compared with metabolic variables before and after adjusting for body fat measured by DEXA using 2 separate methods. The unadjusted correlation coefficients between the body fat measures, R(2), were largest for fasting insulin and triglyceride and smaller for high-density lipoprotein (HDL) cholesterol and blood pressure. A large portion of the variance of fasting insulin levels in both men and women was explained by total body fat. In both men and women, the addition of VAT and subcutaneous abdominal adipose tissue depots only slightly increased the R(2). In men, when body fat compartments were considered independently, DSAT explained a greater portion of the variance (R(2) =.528) in fasting insulin than VAT (R(2) =.374) or non-VAT, non-DSAT subcutaneous adipose tissue (R(2) =.375). These data suggest that total body fat is a major contributor to the metabolic sequelae of obesity, with specific fat depots, VAT, and DSAT also making significant contributions., (Copyright 2001 by W.B. Saunders Company)

Objective: To determine the relationship between two common apoA-IV variants (Thr347-->Ser; Gln360-->His), and body mass index (BMI) and percentage body fat., Design: Cross-sectional study., Subjects: Eight-hundred and forty-eight subjects screened for participation in ongoing clinical studies., Measurements: ApoA-IV genotype, body mass index, waist-to-hip ratio and percentage body fat by bioelectric impedance., Results: Participants had an average age of 41+/-12 y and an average BMI of 28.2+/-5.5 kg/m2. Individuals homozygous for the Ser347 allele had higher BMI (32.3+/-6.6 vs 28.6+/-5.3 kg/m2; P<0.01) and percentage body fat (36.9+/-7.8 vs 31.0+/-9.6%; P<0.05) compared with individuals homozygous for Thr347. In contrast, the presence of at least one copy of the His360 allele was associated with lower BMI (27.2+/-5.0 vs 28.4+/-5.6 kg/m2; P<0.05) and percentage body fat (28.6+/-8.2 vs 30.7+/-9.1%; P<0.05). The genotype effects persisted after normalization of the data for the potential confounding effects of gender, age and race. When grouped by BMI percentile, the frequency of the Ser347/Ser347 genotype increased while the frequency of the His360 allele decreased with increasing BMI., Conclusions: These data suggest a role for apoA-IV in fat storage or mobilization and that genetic variations in the apoA-IV gene may play a role in the development of obesity.

Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methylpalmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. beta-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

The physiological significance of changes in uncoupling protein-2 (UCP-2) gene expression is controversial. In this study we investigated the biochemical and functional correlates of UCP-2 gene expression in sc abdominal adipose tissue in humans in vivo. UCP-2 messenger ribonucleic acid expression was quantified by nuclease protection in adipose tissue from lean and obese humans in both the fasting and postprandial states. Plasma fatty acids, insulin, and leptin were all determined in paired samples from the superficial epigastric vein and radial artery, and local production rates were calculated from 133Xe washout. In the fasting state UCP-2 expression correlated inversely with body mass index (r = -0.45; P = 0.026), percent body fat (r = -0.41; P = 0.05), plasma insulin (r = -0.47; P = 0.02), epigastric venous fatty acids (r = -0.45; P = 0.04), and leptin (r = -0.50; P = 0.018). UCP-2 expression remained inversely related with plasma leptin after controlling for percent body (r = -0.45; P = 0.038). At 2 or 4 h postprandially, there were no significant relationships between UCP-2 expression and biochemical parameters. In conclusion, 1) UCP-2 messenger ribonucleic acid expression in sc adipose tissue is inversely related to adiposity and independently linked to local plasma leptin levels; and 2) UCP-2 expression is not acutely regulated by food intake, insulin, or fatty acids. Reduced UCP-2 expression may be a maladaptive response to sustained energy surplus and could contribute to the pathogenesis and maintenance of obesity.

It is not known whether an inherent preference for dietary fat promotes obesity in animals allowed to self-select the proportions of fat and carbohydrate consumed. To address this question, Sprague-Dawley rats were given a choice between two diets containing either 78% fat (by energy) or 78% carbohydrate; both diets were equicaloric for protein (22%). The entire study lasted 12 weeks. After an adaptation period, macronutrient preferences were determined by measuring 24 h intake of the two diets for 5 days; fat-preferring animals were classified as those that consumed greater than 60% of total energy from the fat/protein source, and carbohydrate-preferring rats as those that consumed less than 40%. Rats with intermediate macronutrient intakes were excluded. Initial body weight was not different between preference groups. Caloric intakes and body weights were then recorded at approximate weekly intervals, and fat depots were weighed at the time of sacrifice. Measures of energy intake and body weight did not differ between the two preference groups over time. In addition, baseline macronutrient preferences remained stable across the study period. Despite similar body weights, mean epididymal fat depot weight was significantly higher in fat-preferring rats than in carbohydrate-preferring rats (12.6 vs. 10.0 g); also, mean inguinal fat depot weight in fat-preferrers was greater although not reliably different compared to carbohydrate-preferring rats (12.9 vs. 10.9 g). Thus, the preferential intake of fat led to a greater deposition of both subcutaneous and visceral fat without an increase in body weight. These data lead us to conclude that the increased fat deposition was due primarily to the ingestion of fat rather than to excess caloric intake., (Copyright 1998 Academic Press)

Although a low resting metabolic rate (RMR) has been shown to be a risk factor for future weight gain, little is known about the mechanisms determining its level. We tested the hypothesis that the composition of the fat-free mass (FFM) is a main determinant of RMR. If this hypothesis is true, a regression model including internal organ masses as independent variables should explain a larger fraction of the variance in RMR than is explained using only FFM as a predictor. We measured fat mass by hydrodensitometry, liver and kidney volumes by computed tomography (CT), heart mass by echocardiography, muscle mass by dual-energy x-ray absorptiometry (DEXA), and RMR by calorimetry in 40 subjects. FFM and fat mass explained 83% of the variability in RMR (standard error of the estimate [SEE], 420 kJ/d) in a multiple regression analysis. Combinations of organ and muscle masses performed as well as but not better than stepwise multiple regression models. The fact that the composition of the lean mass could not improve the prediction of RMR in comparison to the traditional FFM-fat mass model suggests that the weight of internal organs is not a main determinant of RMR. This may indicate that the variability in RMR is associated with variation in energy expenditure per kilogram of tissue of the individual organs.

Abdominal fat distribution is influenced by androgen levels in both men and women. The purpose of this study was to assess the effects on fat distribution of administering nandrolone decanoate (ND; an anabolic steroid with weak androgenic activity) or spironolactone (SP; an antiandrogen) in obese postmenopausal women. The design was a randomized, placebo-controlled, 9-month trial with simultaneous calorie restriction for weight loss. Women in all three groups lost comparable amounts of weight, but the ND-treated women gained lean mass relative to the other two groups (P < 0.0005) and lost more body fat than women in the SP group (P < 0.01). The resting metabolic rate also increased slightly in the ND group. ND treatment produced a gain in visceral fat, as determined by computed tomography scan, and a relatively greater loss of sc abdominal fat. SP-treated women lost significantly less sc fat than the other two groups. Serum cholesterol decreased in the placebo group, but increased slightly in the other two groups (significant for SP vs. placebo, P < 0.05). High density lipoprotein cholesterol decreased significantly in the ND-treated women. There were no significant changes in fasting glucose or insulin sensitivity. We conclude that administration of exogenous androgens modulates body composition in obese postmenopausal women and independently affects visceral and sc abdominal fat.

Obesity in humans has been associated with altered autonomic nervous system activity. The objective of this study was to examine the relationship between autonomic function and body fat distribution in 16 obese, postmenopausal women using power spectrum analysis of heart rate variability. Using this technique, a low frequency peak (0.04-0.12 Hz) reflecting mixed sympathetic and parasympathetic activity, and a high frequency peak (0.22-0.28 Hz) reflecting parasympathetic activity, were identified from 5-minute consecutive heart rate data (both supine and standing). Autonomic activity in upper body (UBO) vs. lower body obesity (LBO)(by waist-to-hip ratio) and subcutaneous vs. visceral obesity (by CT scan) was evaluated. Power spectrum data were log transformed to normalize the data. The results showed that standing, low-frequency power (reflecting sympathetic activity) and supine, high-frequency power (reflecting parasympathetic activity) were significantly greater in UBO than in LBO, and in visceral compared to subcutaneous obesity. Women with combined UBO and visceral obesity had significantly higher cardiac sympathetic and parasympathetic activity than any other subgroup. We conclude that cardiac autonomic function as assessed by heart rate spectral analysis varies in women depending on their regional body fat distribution.

The fat on women's thighs is more difficult to mobilize due to increased alpha-2 adrenergic receptor activity induced by estrogen. Lipolysis can be initiated through adipocyte receptor stimulation (beta adrenergic) or inhibition (adenosine or alpha-2 adrenergic) or by inhibition of phosphodiesterase. Since many women desire regional thigh fat loss, a series of clinical trials were initiated using one thigh as a double-blinded control. Trial #1: Five overweight women had injections of isoproterenol at intervals around the thigh three times a week for 4 weeks with diet and walking. Trial #2: Five overweight woman had ointment containing forskolin, yohimbine and aminophylline applied to the thigh five times a week for 4 weeks after hypertonic warm soaks with a diet and walking. Trial #3: Eighteen overweight women were divided into three groups of six and trial #2 was repeated with each agent alone vs. placebo using forskolin, yohimbine or aminophylline in separate ointments. Trial #4: Thirty overweight women had 10% aminophylline ointment applied to the thigh five times a week for 6 weeks with diet and walking. Chemistry panel, theophylline level and patch testing were performed. Trial #5: Twelve women had trial #4 repeated with 2% aminophylline cream without a diet or walking. Trial #6: Trial #5 was repeated with 0.5% aminophylline cream. All trials except yohimbine ointment gave significantly more girth loss from the treated thigh (p < 0.05 to p < 0.001). Chemistry panel showed no toxicity. Theophylline was undetectable and patch testing was negative. We conclude that topical fat reduction for women's thighs can be achieved without diet or exercise.

Objective: To compare the effects of testosterone enanthate (TE), anabolic steroid (AS) or placebo (PL) on regional fat distribution and health risk factors in obese middle-aged men undergoing weight loss by dietary means., Design: Randomized, double-blind, placebo-controlled clinical trial, carried out for 9 months with primary assessments at 3 month intervals. Due to adverse blood lipid changes, the AS group was switched from oral oxandrolone (ASOX) to parenteral nandrolone decaoate (ASND) after the 3 month assessment point., Subjects: Thirty healthy, obese men, aged 40-60 years, with serum testosterone (T) levels in the low-normal range (2-5 ng/mL)., Main Outcome Measures: Abdominal fat distribution and thigh muscle volume by CT scan, body composition by dual energy X-ray absorptiometry (DEXA), insulin sensitivity by the Minimal Model method, blood lipids, blood chemistry, blood pressure, thyroid hormones and urological parameters., Results: After 3 months, there was a significantly greater decrease in subcutaneous (SQ) abdominal fat in the ASOX group compared to the TE and PL groups although body weight changes did not differ by treatment group. There was also a tendency for the ASOX group to exhibit greater losses in visceral fat, and the absolute level of visceral fat in this group was significantly lower at 3 months than in the TE and PL groups. There were significant main effects of treatment at 3 months on serum T and free T (increased in the TE group and decreased in the ASOX group) and on thyroid hormone parameters (T4 and T3 resin uptake significantly decreased in the ASOX group compared with the other two groups). There was a significant decrease in HDL-C, and increase in LDL-C in the ASOX group, which led to their being switched to the parenteral nandrolone decanoate (ASND) after 3 months. ASND had opposite effects on visceral fat from ASOX, producing a significant increase from 3 to 9 months while continuing to decrease SQ abdominal fat. ASND treatment also decreased thigh muscle area, while ASOX treatment increased high muscle. ASND reversed the effects of ASOX on lipoproteins and thyroid hormones. The previously reported effect of T to decrease visceral fat was not observed, in fact, visceral fat in the TE group increased slightly from 3 to 9 months, although SQ fat continued to decrease. Neither TE nor AS treatment resulted in any change in urologic parameters., Conclusions: Oral oxandrolone decreased SQ abdominal fat more than TE or weight loss alone and also tended to produce favorable changes in visceral fat. TE and ASND injections given every 2 weeks had similar effects to weight loss alone on regional body fat. Most of the beneficial effects observed on metabolic and cardiovascular risk factors were due to weight loss per se. These results suggest that SQ and visceral abdominal fat can be independently modulated by androgens and that at least some anabolic steroids are capable of influencing abdominal fat.

Adrenalectomy reduced food intake and the rate of weight gain in the Zucker (fatty) rat to levels indistinguishable from normal. The size of adipocytes in the retroperitoneal and perimetrial fat pads also decreased after adrenalectomy but the number of fat cells in each of these depots increased to reach levels not different from those in the sham-operated fatty rat. Fat accretion in the intact fatty rat was characterized by both hyperplasia and hypertrophy of the fat cells, but in the adrenalectomized Zucker rats, weight gain was accompanied by hyperplasia and decreased fat cell size. These data show that adrenalectomy can prevent most of the phenotypic expression of the genetic defect in the fatty rat and challenge the concept that reduced food intake can prevent hyperplasia of fat cells.

The activity of lipoprotein lipase (LPL) released from human adipose tissue was measured before and after an oral glucose load in obese (n = 8) and normal (n = 7) weight subjects. The enzymatic activity of LPL release from fat tissue by heparin rose significantly one hour after glucose in the normal subjects. There was no such rise in LPL in adipose tissue from obese subjects. Serum triglyceride, insulin and glycerol were higher in the obese than in the lean subjects.

[1-(14)C]glucose oxidation to CO(2) and conversion into glyceride by adipose tissue from nonobese and obese subjects has been studied in vitro in the presence of varying medium glucose and insulin concentrations as functions of adipose cell size, the composition of the diet, and antecedent weight gain or loss. Increasing medium glucose concentrations enhance the incorporation of glucose carbons by human adipose tissue into CO(2) and glyceride-glycerol. Insulin further stimulates the conversion of glucose carbons into CO(2), but not into glyceride-glycerol. Incorporation of [1-(14)C]glucose into glyceride-fatty acids by these tissues could not be demonstrated under any of the conditions tested. Both adipose cell size and dietary composition influence the in vitro metabolism of glucose in, and the response to insulin by, human adipose tissue. During periods of ingestion of weight-maintenance isocaloric diets of similar carbohydrate, fat, and protein composition, increasing adipose cell size is associated with (a) unchanging rates of glucose oxidation and increasing rates of glucose carbon incorporation into glyceride-glycerol in the absence of insulin, but (b) decreasing stimulation of glucose oxidation by insulin. On the other hand, when cell size is kept constant, increasing dietary carbohydrate intake is associated with an increased basal rate of glucose metabolism and response to insulin by both small and large adipose cells. Thus, the rate of glucose oxidation and the magnitude of the insulin response of large adipose cells from individuals ingesting a high carbohydrate diet may be similar to or greater than that in smaller cells from individuals ingesting an isocaloric lower carbohydrate diet.The alterations in basal glucose metabolism and insulin response observed in adipose tissue from patients with spontaneous obesity are reproduced by weight gain induced experimentally in nonobese volunteers; these metabolic changes are reversible with weight loss. The relationships among adipose cell size, dietary composition, and the metabolism of adipose tissue are similar in spontaneous and in experimental obesity.

Injection of picomolar quantities of insulin into the ventromedial hypothalamus of rats significantly reduced the firing rate of sympathetic nerves that supply interscapular brown adipose tissue. The minimal firing rate was reached in 2 min, and the effect was gone within 4 min. The effect of insulin was dose-related and did not occur when comparable volumes of physiological saline were injected into the ventromedial hypothalamus. Destruction of neurons in the ventromedial hypothalamus by injection of kainic acid abolished the inhibitory effects of insulin. These data suggest that insulin may play a role in modulating the sympathetic firing rate to thermogenically important tissues.

Biopsies of adipose tissue, liver and small bowel mucosa obtained from grossly obese and control subjects were used to study absolute rates of fatty acid, cholesterol, and other nonsaponifiable lipid synthesis using glucose as substrate and 3H2O as the isotopic marker. Fatty acid synthesis in subcutaneous adipose tissue expressed on a cell basis was greater in obese than control subjects and was stimulated by a high concentration of insulin (1000 micro U/ml), but not by a lower amount (100 micro U/ml). Fatty acid synthesis in omental adipose tissue exceeded by 3-fold that of subcutaneous fat. Fatty acid synthesis in obese liver was twice that of control liver and 20 times greater than obese adipose tissue. In terms of total organ activity fatty acid synthesis in fat tissue equalled or exceeded that of liver in both obese and control subjects. The cholesterol content of obese adipose tissue 1.86 +/- 0.11 mg/g exceeded that of controls 1.47 +/- 0.07 mg/g. All tissues examined synthesized cholesterol and nonsaponifiable lipids, liver greater than adipose tissue greater than small bowel mucosa. Nonsaponifiable lipid synthesis per gram of adipose tissue or liver was similar in obese and control tissue. The synthesis of total nonsaponifiable lipids including sterols, hydrocarbons and squalene was appreciable in adipose tissue and was approximately 15% of that of liver. However, cholesterol synthesis in the liver exporessed in terms of total organ activity was 50 times that in adipose tissue. The study demonstrates by direct comparison that liver is the dominant cholesterogenic organ in man and also shows that adipose tissue is a significant site of formation of fatty acids and nonsaponifiable lipids.

Subcutaneous fat cells were isolated from genetically obese rats and from rats with obesity produced by hypothalamic lesions. Insulin did not augment the oxidation of fatty acids or their synthesis from glucose-1-(14)C or glucose-1-(3)H by fat cells from either group. Radioactivity from pyruvate-3-(14)C was incorporated into fatty acids to the same degree by fat cells from these two groups. The presence of 5 mm glucose in the incubation medium containing fat cells and pyruvate-3-(14)C or aspartate-3-(14)C stimulated the synthesis of fatty acids to a greater extent in cells of genetically obese rats. Fasting, in contrast, reduced the incorporation of radioactivity from pyruvate and glucose into fatty acids by fat cells from the genetically obese animals. In all experiments the fat cells from genetically obese rats converted more radioactivity into glyceride-glycerol relative to CO(2) than did fat cells from hypothalamic obese rats. Parabiosis between one thin and one genetically obese litter mate was performed in three pairs of rats without influencing growth of either rat. Thus in the present studies fat cells from genetically obese rats showed two differences from normal fat cells: they channeled more radioactivity from pyruvate into fatty acids in the presence of glucose, and they uniformly converted more radioactivity into glyceride-glycerol.

Lipogenesis and the metabolism of sn-glycerol-3-phosphate were studied in 23 fat biopsies from eight grossly obese patients. The first biopsy was obtained after a minimum of 12 days on a 3500 cal diet, the second biopsy after 2 wk on a 900 cal diet, and the third biopsy after an additional 2 wk on 900 cal supplemented with thiiodothyronine, 250 mug/day.Oxygen consumption and respiratory quotient declined during caloric restriction. Oxygen consumption was restored to the initial level during treatment with triiodothyronine, and the respiratory quotient rose somewhat.Lipogenesis from glucose and pyruvate was demonstrated in fat obtained from the first biopsy but could not be detected in the other biopsies. The incorporation of radioactivity from pyruvate into fatty acids was stimulated by the addition of glucose. Insulin stimulated lipogenesis in pieces of fat from the first biopsy, but isolated fat cells were unaffected by insulin. After caloric restriction no effects of insulin could be detected. The activity of both the cytoplasmic and mitochondrial sn-glycerol-3-phosphate dehydrogenase in homogenates of adipose tissue declined with caloric restriction. Treatment with triiodothyronine enhanced the activity of the mitochondrial sn-glycerol-3-phosphate dehydrogenase but did not affect the cytoplasmic enzyme.

Six grossly obese patients were fed 5000 calorie diets for 4 wk. During one period of 2 wk, the calories were consumed over 4 hr (gorging) and during the other 2 wk, the dietary intake was spread over 20 hr (nibbling). Each of these periods followed a low caloric intake which lasted at least 10 days. Three male patients (group I) were studied at or near their maximal weight and three females (group II) after a weight loss of 50-70 kg. The patients in group II gained more weight than those in group I. Lipogenesis from pyruvate was greater in group II than in group I. Rapid ingestion of food (gorging) was accompanied by a significant increase in glyceride-glycerol-(14)C and fatty acids-(14)C from pyruvate-(14)C. The enzymatic activity of sn-glycerol 3-phosphate dehydrogenase and mitochondrial glycerophosphate oxidase paralleled the rate of formation of glyceride-glycerol. Lipogenesis from pyruvate was significantly lower when the bicarbonate concentration was reduced from 25 to 10 mM. Citrate and acetate were also converted to fatty acids but there was no difference between gorging and nibbling. An inhibitor of carbonic anhydrase significantly reduced the conversion of pyruvate into CO(2), glyceride-glycerol, and fatty acids. These data on gorging and nibbling have been related to other studies suggesting that the frequency of food intake may be inversely related to obesity.

Epinephrine increases the oxidation of glucose in adipose tissue even when its lipolytic effects are markedly reduced or abolished by propranolol, nicotinic acid, ouabain, or thyroidectomy. In order to locate the site(s) at which epinephrine stimulates glucose utilization, we studied the effects of epinephrine on the oxidation of various metabolites of glucose. Epinephrine neither increased the production of (14)CO(2) from 1- or 3-(14)C-pyruvate nor affected pyruvate conversion to glyceride-glycerol. To assess the possibility that epinephrine might accelerate the entry of glucose into adipocytes, we studied the accumulation of the nonmetabolized sugar l-arabinose in the intracellular water of adipose tissue. Epinephrine increased arabinose penetration into adipocytes to a degree comparable with that caused by 0.1 mU/ml of insulin. Virtually identical results were obtained in tissues from thyroidectomized rats in which the lipolytic effects of epinephrine were significantly reduced. It is concluded that epinephrine increases glucose oxidation by promoting its entry into adipose tissue and that the effect is independent of lipolysis.

(Log dose)-response curves have been determined for lipolysis and for the conversion of glucose-(14)C to (14)CO(2) by adipose tissue from rats in the presence of epinephrine, corticotropin, and thyrotropin. The stimulatory effect of epinephrine on lipolysis was greater than that of corticotropin or thyrotropin. Lipolysis induced by epinephrine was inhibited by propranolol but only slightly by phenoxybenzamine, whereas lipolysis induced by corticotropin was inhibited by phenoxybenzamine to a much greater extent than by propranolol. Neither blocking drug had a pronounced effect on the response to thyrotropin. Epinephrine stimulated the oxidation of glucose-(14)C to CO(2) more than did either thyrotropin or corticotropin. Moreover, epinephrine stimulated the conversion of glucose-(14)C to CO(2) and fatty acids even when lipolysis was not increased. These studies indicate that epinephrine can affect glucose utilization independently of its effect on lipolysis.

Epinephrine stimulated lipolysis and the uptake of oxygen by subcutaneous adipose cells of man. When glucose-(14)C was present in the medium, its utilization was not increased by epinephrine, although lipolysis was accelerated. Insulin did not reduce the production of fatty acids that had been stimulated by epinephrine. The combination of human growth hormone and cortisol stimulated the production of fatty acids by isolated human adipose cells to a lesser extent than epinephrine. When human growth hormone or cortisol was used singly, or when bovine growth hormone was added in combination with cortisol, no effect on fatty acid production was observed. Furthermore, an acetone-dried preparation of human pituitary glands, which was shown to stimulate lipolysis in rat adipose cells, had no effect on fatty acid formation in human adipose cells. This suggested that the human pituitary gland contained no more potent lipolytic agents than growth hormone and was supported by the lack of response of human adipose cells to purified corticotropin.

The mobilization of fatty acids has been studied in genetically obese rats of the Zucker strain and in control obese animals with bilateral destructive lesions in the hypothalamus. The body weight and size of adipose cells did not differ significantly between the genetically obese rats and the obese controls. Weight loss in control and genetically obese rats was identical during a 1 month fast. The release of glycerol and the rise in free fatty acids in adipose tissue incubated in vitro were similar in tissue from genetic and hypothalamic obese rats. Epinephrine, theophylline, and dibutyryl cyclic adenosine monophosphate all augmented lipolysis, and the effects were usually greater in the tissues from genetically obese rats.