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J F Caro

Publications and source records attributed to J F Caro.

At least 37 records · Page 2Linked to original sources
PubMed1997

Gender-dependent effects of exercise training on serum leptin levels in humans.

Leptin, the product of the ob gene, is elevated in obese humans and appears to be closely related to body fat content. The purpose of the present investigation was to determine the effect of aerobic exercise training on systemic leptin levels in humans. Eighteen sedentary middle-aged men (n = 9) and women (n = 9) who did not differ in aerobic capacity (29.4 +/- 1.2 vs. 27.5 +/- 1.2 ml x kg(-1) x min(-1)) or insulin sensitivity index (3.41 +/- 1.12 vs. 4.88 +/- 0.55) were studied. Fat mass was significantly lower in females vs. males (21.83 +/- 2.25 vs. 26.99 +/- 2.37 kg, P < 0.05). Despite this, fasting serum leptin was significantly higher in the females vs. males (18.27 +/- 2.55 vs. 9.88 +/- 1.26 ng/ml, P < 0.05). Serum leptin concentration decreased 17.5% in females (P < 0.05) after 12 wk of aerobic exercise training (4 day/wk, 30-45 min/day) but was not significantly reduced in males. Fat mass was not altered after training in either group. In contrast, both aerobic capacity (+13% males, +9.1% females) and insulin sensitivity (+35% males, +82% females) were significantly improved subsequent to training. These data suggest that 1) women have higher circulating leptin concentrations despite lower fat mass and 2) exercise training appears to have a greater effect on systemic leptin levels in females than in males.

Adult↗
PubMed1996

Ultradian oscillations of leptin secretion in humans.

We have recently demonstrated the nocturnal increase in leptin secretion in humans. In the present study we have examined the pulsatile pattern of leptin secretion using two different experimental protocols. The first protocol utilized blood samples withdrawn at 30 minute intervals immediately after meals, at 1 hour intervals between meals, and at 2 hour intervals during the night from 4 lean, 11 obese, and 5 obese NIDDM subjects. Analysis of circulating leptin levels by ULTRA algorithmic program and using matched intra-assay coefficient of variations demonstrated 1 to 7 ultradian oscillations with a mean of 3.25 +/- 0.36 (SEM) pulses per 24 hour period (period: 10.0 +/- 1.5 hours; mean relative amplitude: 0.52 +/- 0.06, n = 20). Significant positive correlations were observed for changes in absolute amplitude with body mass index (p < 0.025) and fasting leptin levels (< 0.0001). In the second series of experiments utilizing 15 minute blood sampling from 10 overnight fasted obese subjects (BMI 35.9 +/- 2.0 kg/m2), ultradian oscillations for leptin were more frequent, i.e., 2 to 7 oscillations (4.20 +/- 0.59), over a 12 hour duration (period: 3.44 +/- 0.49; mean relative amplitude: 0.28 +/- 0.03). The number of oscillations over a 12 hour period correlated significantly with BMI (p < 0.001), fasting leptin levels (p < 0.01), and absolute amplitude (p < 0.005) in a 15 minute sampling protocol. In summary, similar to other hormones, ultradian oscillations of leptin are observed in humans, although the physiological significance in relation to obesity or feeding behavior is not yet understood.

Blood Glucose↗
PubMed1996

Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.

Little is known about leptin's interaction with other circulating proteins which could be important for its biological effects. Sephadex G-100 gel filtration elution profiles of 125I-leptin-serum complex demonstrated 125I-leptin eluting in significant proportion associated with macromolecules. The 125I-leptin binding to circulating macromolecules was specific, reversible, and displaceable with unlabeled leptin (ED50: 0.73 +/- 0.09 nM, mean +/- SEM, n = 3). Several putative leptin binding proteins were detected by leptin-affinity chromatography of which either 80- or 100-kD proteins could be the soluble leptin receptor as approximately 10% of the bound 125I-leptin was immunoprecipitable with leptin receptor antibodies. Significantly higher (P < 0.001) proportions of total leptin circulate in the bound form in lean (46.5 +/- 6.6%) compared with obese (21.4 +/- 3.4%) subjects. In lean subjects with 21% or less body fat, 60-98% of the total leptin was in the bound form. Short-term fasting significantly decreased basal leptin levels in three lean (P < 0.0005) and three obese (P < 0.005) subjects while refeeding restored it to basal levels. The effects of fasting on free leptin levels were more pronounced in lean subjects (basal vs. 24-h fasting: 19.6 +/- 1.9 vs. 1.3 +/- 0.4 ng/ml) compared with those in obese subjects (28.3 +/- 9.8 vs. 14.7 +/- 5.3). No significant (P > 0.05) decrease was observed in bound leptin in either group. These studies suggest that in obese individuals the majority of leptin circulates in free form, presumably bioactive protein, and thus obese subjects are resistant to free leptin. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form and thus may not be available to brain receptors for its inhibitory effects on food intake both under normal and food deprivation states.

Carrier Proteins↗
PubMed1996

Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance.

BACKGROUND: A receptor for leptin has been cloned from the choroid plexus, the site of cerebrospinal-fluid (CSF) production and the location of the blood/cerebrospinal-fluid barrier. Thus, this receptor might serve as a transporter for leptin. We have studied leptin concentrations in serum and (CSF). METHODS AND FINDINGS: We demonstrated by radioimmunoassay and western blot the presence of leptin in human CSF. We then measured leptin in CSF and serum in 31 individuals with a wide range of bodyweight. Mean serum leptin was 318% higher in 8 obese (40.2 [SE 8.6] ng/mL) than in 23 lean individuals (9.6 [1.5] ng/mL, p < 0.0005). However, the CSF leptin concentration in obese individuals (0.337 [0.04] ng/mL) was only 30% higher than in lean people (0.259 [0.26] ng/mL, p < 0.1). Consequently, the leptin CSF/serum ratio in lean individuals (0.047 [0.010]) was 4.3-fold higher than that in obese individuals (0.011 [0.002], p < 0.05). The relation between CSF leptin and serum leptin was best described by a logarithmic function (r = 0 x 52, p < 0.01). INTERPRETATION: Our data suggest that leptin enters the brain by a saturable transport system. The capacity of leptin transport is lower in obese individuals, and may provide a mechanism for leptin resistance.

Biological Transport↗
PubMed1996

Mutation screening and identification of a sequence variation in the human ob gene coding region.

In the present study mRNA from the subcutaneous adipose tissue of 68 obese (defined as a body mass index > or = 27.3 for men and > or = 27.8 for women) and 38 lean subjects was screened for mutations in the ob gene coding region. No mutations in the coding region of the human ob gene were detected using Conformation Sensitive Gel Electrophoresis in 105 subjects. A first base substitution (G to A) was detected in one individual, which changed a valine to a methionine at position 94. The mRNA of all subjects contained the codon for glutamine-49, ruling out the possibility of a splice defect occurring during the removal of intron 2. These observations suggest that defects in the ob gene sequence itself are not the primary cause of obesity in humans.

Adipose Tissue↗
PubMed1996

Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.

We studied 24-h profiles of circulating leptin levels using a sensitive and specific RIA in lean controls and obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) during normal routine activity. Serum leptin levels were significantly higher in obese (41.7 +/- 9.0 ng/ml; n = 11) and obese NIDDM (30.8 +/- 6.7; n = 9) subjects compared with those in lean controls (12.0 +/- 4.4, n = 6). In all the three groups, serum leptin levels were highest between midnight and early morning hours and lowest around noon to midafternoon. The nocturnal rise in leptin levels was significant when data were analyzed by ANOVA (lean: F = 3.17, P < 0.0001, n = 4; obese: F = 2.02, P < 0.005, n = 11; and obese NIDDM: F = 4.9, P < 0.0001, n = 5). The average circadian amplitude between acrophase and nadir was 75.6% in lean, 51.7%, in obese and 60.7% in obese NIDDM groups, respectively. No significant correlations (P > 0.05) were observed between circulating levels of leptin and either insulin or glucose levels in any of the 20 subjects studied for 24-h profiles. The nocturnal rise in leptin observed in the present study resembles those reported for prolactin, thyroid-stimulating hormone, and free fatty acids. We speculate that the nocturnal rise in leptin could have an effect in suppressing appetite during the night while sleeping.

Adult↗
PubMed1996

Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice.

The obese gene product, leptin, is synthesized in adipose tissue and is a circulating factor regulating body weight. To identify the location of leptin receptors in the brain we have performed an autoradiographic study of the binding of [(125)I]leptin to frozen sections of mouse brain. Dense specific binding of [(125)I]leptin was found only in the choroid plexus which is located in the dorsal part of the third ventricle and lateral ventricles. Specific binding of [(125)I]leptin was found the ob/ob and db/db mice. These findings further our understanding of the sites and mechanism of action of leptin on brain centers regulating body weight.

Animals↗
PubMed1996

Gender differences in serum leptin levels in humans.

Leptin, the product of the ob gene, is an adipose tissue-derived hormone that appears to regulate both satiety and thermogenesis. In the present report, we have reexamined the relationship between circulating leptin concentration and body fat in humans using a more valid measure of adiposity (hydrodensitometry) and have extended these observations to examine the influence of regional body fat distribution and cardiorespiratory fitness. Fasting serum leptin concentration was 6.9 +/- 0.3 ng.ml-1 in males (N = 333) and 15.2 +/- 1.3 ng.ml-1 in females (N = 63). Interestingly, total fat mass did not differ between groups (males 20.5 +/- 0.5 kg; females 20.4 +/- 1.5 kg), suggesting that females have higher leptin levels per unit fat mass. In a multiple regression model, fat mass was the best predictor of serum leptin concentration in males, accounting for 51% of the variance in leptin concentration. In females, percentage body fat was the best predictor of leptin, accounting for 49% of the variance. In both groups, the relationship between leptin and adiposity remained significant after adjusting for age, maximal treadmill time, waist circumference, and fasting insulin concentration. These observations support previous conclusions that circulating leptin is primarily a function of adiposity and demonstrate for the first time that this relationship is independent of fat distribution or cardiorespiratory fitness. The data also suggest that there is a gender dichotomy in the relationship between leptin and body fat mass in humans.

Adult↗
PubMed1996

Preventing complications in diabetes mellitus: the role of the primary care physician.

Many Americans, knowingly or unknowingly, are afflicted with diabetes. Because of a lack of awareness or a disbelief that aggressive treatment benefits patients on the part of both patients and physicians, diabetes, particularly NIDDM, remains underdiagnosed and undertreated despite complications that can dramatically diminish quality of life. Increasing evidence that good glycemic control forestalls if not prevents these outcomes makes it the primary care physician's imperative to diagnose diabetes before complications develop. Physicians, through targeted screening and aggressive treatment of patients in whom they diagnose this chronic disease, can markedly reduce diabetes-related morbidity and mortality.

Blood Glucose↗
PubMed1996

Relationship between weight loss maintenance and changes in serum leptin levels.

Serum leptin concentrations are higher in obese humans than in lean and are decreased by initial weight loss. This study examined the effects of maintenance of weight loss on leptin concentrations and tested whether leptin concentrations at baseline or after initial weight loss are related to the ability to maintain a reduced body weight. Fifty-two overweight women [body mass index (kg/m2) averaging 31.3] were studied before and after a 4 month weight loss program and at 6 month follow-up. Subjects lost 8.1 kg over the 4 month program, and leptin concentrations decreased from 30.1 to 20.4 ng/ml. Initial leptin level per unit body mass index (r = -0.61, p < 0.0001) and weight loss during months 0 to 4 (r = 0.39, p = 0.004) were both significantly associated with initial changes in leptin, and together explained 60% of the variance in change in leptin. Subjects who maintained their weight losses over the 6-month follow-up maintained their reductions in leptin levels; again, weight changes during follow-up were correlated with changes in serum leptin levels (r = 0.41, p = 0.003). There was no evidence that baseline leptin concentration (or leptin/body mass index) or the changes in leptin which accompanied initial weight loss were predictive of subsequent weight regain. Thus, changes in leptin concentration during weight loss track with changes in weight. However, neither baseline concentrations nor initial changes in leptin predict success at weight loss or maintenance.

Adult↗
PubMed1996

Paracrine stimulation of preadipocyte-enriched cell cultures by mature adipocytes.

We developed a double-chamber system in which to examine the effects of mature adipocytes on the growth and differentiation of preadipocytes and other cells in the adipose tissue. In the present study we found that mature adipocytes from both lean and obese subjects release a factor that stimulates the growth of preadipocyte-enriched and dedifferentiated adipocyte-enriched cell cultures. This growth stimulation was dependent on both time of exposure to mature cells and the number of mature cells in the coculture. Proliferation of the preadipocyte-enriched (n = 4) and dedifferentiated adipocyte-enriched cultures (n = 5) in the presence of mature adipocytes from obese subjects [body mass index (BMI) > 35] was 4.1- and 2.9-fold more (P < 0.05) than that in the presence of adipocytes from lean subjects (BMI < or = 25). There was no difference in the growth of cultures enriched in preadipocytes or dedifferentiated adipocytes from lean or obese subjects in the absence of mature adipocytes. These observations demonstrate that mature adipocytes from obese patients stimulate the growth of preadipocyte-enriched cultures to a greater extent than those from lean individuals.

Adipocytes↗
PubMed1996

Leptin is related to body fat content in male distance runners.

Leptin, the product of the ob gene, has been reported to be related to body fat in humans (Considine et al. N. Engl. J. Med. 334: 292, 1996). However, little is known about the physiology of this putative satiety signal in humans. The purpose of the present study was to determine whether leptin is related to body fat content in relatively lean endurance-trained adults. In addition, the effect of acute exercise on circulating leptin concentration was studied. Thirteen male runners, whose mean age, height, weight, %fat, and maximal oxygen consumption (VO2max) were 32.2 +/- 2.5 yr, 176.2 +/- 1.6 cm, 71.9 +/- 6.9 kg, 9.7 +/- 0.9%, and 62.9 +/- 2.2 ml.kg-1.min-1, respectively, were studied. Blood samples were obtained after an overnight fast and again immediately after the completion of a 20-mile run at 70% VO2max under controlled environmental conditions. Serum leptin was closely related to fat mass (r = 0.92) in the runners. Acute exercise had no detectable effect on serum leptin levels (PRE = 2.19 +/- 0.32 ng/ml, POST = 2.14 +/- 0.36 ng/ml). These data indicate that, even at a biological extreme of body fat, circulating leptin concentration is closely related to fat content. Furthermore, the data suggest that, in trained individuals with low leptin concentrations, acute exhaustive exercise has no immediate effect on circulating leptin concentration.

Adipose Tissue↗
PubMed1996

Leptin: genes, concepts and clinical perspective.

Obesity is a complex disease which results from the interaction of multiple genes and the environment. The recently discovered genes for leptin (ob gene) and the leptin receptor appear to play a major regulatory role in body energy balance and adipose tissue deposition. Furthermore, defects in the ob gene and leptin receptor gene have been demonstrated to be the cause of obesity in several rodent models. These observations raise the possibility that human obesity may also be due to defects in the leptin signal system. This review will summarize the current findings on the ob gene, leptin and the leptin receptor in both animals and humans. These observations will be discussed in the context of potential defects in the system and the possibility that these defects result in obesity in humans.

Animals↗
PubMed1996

Response of leptin to short-term and prolonged overfeeding in humans.

As one of the postulated roles of the ob gene product, leptin, is regulation of energy balance and preservation of normal body composition, we investigated the effect of acute and chronic calorie excess (weight gain) on serum leptin in humans. Two protocols were employed: 1) acute (12-h) massive (120 Cal/kg) voluntary overfeeding of eight healthy individuals; and 2) chronic overfeeding to attain 10% weight gain, with its subsequent maintenance for additional 2 weeks, involving six normal males. In the acute experiments (protocol 1), circulating leptin rose by 40% over baseline (P < 0.01) during the final hours of overfeeding; this increase persisted until the next morning. At the point of achievement and the 2-week maintenance of 10% weight gain (protocol 2), a more than 3-fold rise in the basal leptin concentration was observed (P < 0.01). A direct linear relationship was found between the magnitude of the leptin response to weight gain and the percent gain of body fat (r = 0.88; P < 0.01). In summary, 1) in contrast to normal food intake (8), short term massive overfeeding is associated with a moderate elevation of circulating leptin levels that persists until next feeding cycle is initiated; and 2) a 10% weight gain causes different changes in the body composition, and the resulting rise in circulating leptin parallels the increase in the percentage of body fat. In conclusion, these studies document acute elevation of leptin in response to positive energy balance and suggest that developing resistance to leptin is associated with bigger fat deposition during weight gain in humans.

Adipose Tissue↗
PubMed1996

Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves.

We investigated the response of leptin to short-term fasting and refeeding in humans. A mild decline in subcutaneous adipocyte ob gene mRNA and a marked fall in serum leptin were observed after 36 and 60 h of fasting. The dynamics of the leptin decline and rise were further substantiated in a 6-day study consisting of a 36-h baseline period, followed by 36-h fast, and a subsequent refeeding with normal diet. Leptin began a steady decline from the baseline values after 12 h of fasting, reaching a nadir at 36 h. The subsequent restoration of normal food intake was associated with a prompt leptin rise and a return to baseline values 24 h later. When responses of leptin to fasting and refeeding were compared with that of glucose, insulin, fatty acids, and ketones, a reverse relationship between leptin and beta-OH-butyrate was found. Consequently, we tested whether the reciprocal responses represented a causal relationship between leptin and beta-OH-butyrate. Small amounts of infused glucose equal to the estimated contribution of gluconeogenesis, which was sufficient to prevent rise in ketogenesis, also prevented a fall in leptin. The infusion of beta-OH-butyrate to produce hyperketonemia of the same magnitude as after a 36-h fast had no effect on leptin. The study indicates that one of the adaptive physiological responses to fasting is a fall in serum leptin. Although the mediator that brings about this effect remains unknown, it appears to be neither insulin nor ketones.

3-Hydroxybutyric Acid↗
PubMed1996

Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro.

This study was undertaken to investigate the changes in obesity (OB) gene expression and production of leptin in response to insulin in vitro and in vivo under euglycemic and hyperglycemic conditions in humans. Three protocols were used: 1) euglycemic clamp with insulin infusion rates at 40, 120, 300, and 1,200 mU / m / min carried out for up to 5 h performed in 16 normal lean individuals, 30 obese individuals, and 31 patients with NIDDM; 2) 64-to 72-h hyperglycemic (glucose 12.6 mmol/l) clamp performed on 5 lean individuals; 3) long-term (96-h) primary culture of isolated abdominal adipocytes in the presence and absence of 100 nmol/l insulin. Short-term hyperinsulinemia in the range of 80 to > 10,000 microU/ml had no effect on circulating levels of leptin. During the prolonged hyperglycemic clamp, a rise in leptin was observed during the last 24 h of the study (P < 0.001). In the presence of insulin in vitro, OB gene expression increased at 72 h (P < 0.01), followed by an increase in leptin released to the medium (P < 0.001). In summary, insulin does not stimulate leptin production acutely; however, a long-term effect of insulin on leptin production could be demonstrated both in vivo and in vitro. These data suggest that insulin regulates OB gene expression and leptin production indirectly, probably through its trophic effect on adipocytes.

Adipocytes↗