Peak Leptin Research Articles

Leptin levels and luteinizing hormone pulsatility in normal cycling women and their relationship to daily changes in metabolic rate

To determine whether leptin and LH secretion in normal women is related to changes in metabolic rate. Academic medical center. PATIENT(S) AND DESIGN: Ten young women with normal weight and menses were studied during the early follicular phase. Leptin and LH levels were sampled every 15 minutes over a 24-hour period. Metabolic rate was frequently sampled using indirect calorimetry. Luteinizing hormone pulsatility was analyzed using a Cluster Program analysis. None. Leptin, LH, and metabolic rate levels. All subjects demonstrated a diurnal leptin curve. Luteinizing hormone pulses were increased in amplitude and slower after the leptin peak. The average (+/-SE) number of LH pulses per 6 hours slowed from 4.30 +/- 0.42 to 3.00 +/- 0.42 pulses after the leptin peak, whereas pulse amplitude increased from 1.64 +/- 0.26 to 2.51 +/- 0.42 mIU/mL after the leptin peak. The LH interpulse interval increased from 85.1 +/- 3.64 minutes to 108.8 +/- 10.26 minutes after the leptin peak. Metabolic rate began to drop approximately 4-6 hours before leptin levels peaked, going from 1.66 +/- 0.24 to 1.15 +/- 0.04 kcal/min after the leptin peak. There is a significant association between the timing of the leptin peak, the nightly slowing of LH pulses, and the fall in metabolic rate, suggesting a metabolic cycle in normal individuals.

Mammary gland leptin in relation to lactogenesis in the periparturient dairy goat

The role of leptin in development of mammary gland secretory function was studied during the periparturient period in dairy goats. Changes in mammary leptin and leptin receptor (short cytoplasmic form) expression were evaluated by real-time RT-PCR and related to changes in milk and plasma leptin concentrations from 5 weeks pre-partum to 7 weeks post-partum. It was further investigated if systemic leptin concentration in the neonate is affected by milk leptin intake. We found no evidence of accumulation of leptin in colostrum pre-partum. Pre- and post-partum milk leptin concentrations were similar, but interestingly, leptin increased markedly post-partum to reach a peak 2 days after parturition ( P = 0.01). Plasma leptin concentrations were higher pre-partum than post-partum ( P < 0.05), decreased at parturition and arterio-venous differences for leptin across the mammary gland were at no time significantly different from zero. Plasma leptin does thus not appear to be involved in regulation of milk leptin. Both leptin and the short cytoplasmic form of its receptor were expressed in the mammary gland. The highest leptin receptor expression was observed pre-partum and decreased post-partum. Expression of leptin was relatively constant except for an increase in the last week prior to parturition. Our results can neither confirm nor exclude that increased leptin and/or leptin receptor synthesis is responsible for regulation of milk leptin in the early post-partum period. The physiological significance of the distinct peak in milk leptin 2 days post-partum needs to be understood. We did not find evidence that milk leptin can be absorbed, and thus play a role in systemic regulation, of the neonatal goat.

Role of premature leptin surge in obesity resulting from intrauterine undernutrition

Intrauterine undernutrition is closely associated with obesity related to detrimental metabolic sequelae in adulthood. We report a mouse model in which offspring with fetal undernutrition (UN offspring), when fed a high-fat diet (HFD), develop pronounced weight gain and adiposity. In the neonatal period, UN offspring exhibited a premature onset of neonatal leptin surge compared to offspring with intrauterine normal nutrition (NN offspring). Unexpectedly, premature leptin surge generated in NN offspring by exogenous leptin administration led to accelerated weight gain with an HFD. Both UN offspring and neonatally leptin-treated NN offspring exhibited an impaired response to acute peripheral leptin administration on a regular chow diet (RCD) with impaired leptin transport to the brain as well as an increased density of hypothalamic nerve terminals. The present study suggests that the premature leptin surge alters energy regulation by the hypothalamus and contributes to "developmental origins of health and disease."

Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation.

To determine the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, cortical brain temperature (Tcrt), and feeding, we determined these parameters in rats in three experimental conditions: in free-feeding rats with normal diurnal rhythms, in rats with feeding restricted to the 12-h light period (RF), and in rats subjected to 5-h of sleep deprivation (SD) at the beginning of the light cycle. Plasma ghrelin and leptin displayed diurnal rhythms with the ghrelin peak preceding and the leptin peak following the major daily feeding peak in hour 1 after dark onset. RF reversed the diurnal rhythm of these hormones and the rhythm of rapid-eye-movement sleep (REMS) and significantly altered the rhythm of Tcrt. In contrast, the duration and intensity of non-REMS (NREMS) were hardly responsive to RF. SD failed to change leptin concentrations, but it promptly stimulated plasma ghrelin and induced eating. SD elicited biphasic variations in the hypothalamic ghrelin contents. SD increased plasma corticosterone, but corticosterone did not seem to influence either leptin or ghrelin. The results suggest a strong relationship between feeding and the diurnal rhythm of leptin and that feeding also fundamentally modulates the diurnal rhythm of ghrelin. The variations in hypothalamic ghrelin contents might be associated with sleep-wake activity in rats, but, unlike the previous observations in humans, obvious links could not be detected between sleep and the diurnal rhythms of plasma concentrations of either ghrelin or leptin in the rat.

Inappropriate leptin secretion in thalassemia: a potential cofactor of pubertal timing derangement.

The objective of the present study was to gain a better understanding of the role played by scarce leptin production in the deranged sexual development observed in patients with thalassemia. We studied 101 patients at different stages of puberty. Patients of both sexes were divided into three groups according to Tanner stages: T1-2 (20 males and 12 females), T3-4 (9 males and 4 females) and T5 (48 males and 8 females). Serum levels of leptin, ferritin, testosterone and estradiol were assessed. Leptin levels were adjusted for body mass index (BMI) using reference ranges stratified on the basis of gender and pubertal development. Deviations from the mean reference values were evaluated by calculating the standard deviation scores. Mean leptin standard deviation scores were significantly lower than expected in pubertal stage T1-2 and T3-4 in males and T3-4 and T5 in females. The peak leptin level was delayed in boys (13 years). In girls, parallelism between leptin and BMI was present until age 7-10 years; thereafter, although BMI constantly increased, leptin levels fell dramatically. Mean ferritin levels were significantly higher in pubertal stage T1-2 among males and in T5 among females. These findings show that in thalassemia adipose tissue is unable to assure adequate leptin production just when the highest leptin secretion is required and suggest that this inappropriate leptin secretion may be a cofactor of the derangement in pubertal timing observed in patients with thalassemia.

Serum leptin levels are not influenced by arginine and insulin infusion and by acute changes of GH.

The aim of this study was to evaluate the relationship between GH and leptin in a group of short children and adolescents. Leptin and GH serum levels were measured before and during pharmacological stimulation tests (arginine and insulin) in a group of 45 children (30 male, 15 female), mean age 8.6+/-3.9 yr, affected by idiopathic isolated GH deficiency (GHD), and in a group of 27 children (15 male, 12 female), age 10.9+/-3.3 yr, with constitutional growth delay. Results showed that basal and peak leptin levels as well as the AUC were significantly higher in GHD patients compared to controls (p<0.05) and correlated with BMI SDS (p<0.0001) in GHD patients. No change in leptin serum levels was observed during either stimulation test. No correlation was found, however, between basal leptin serum levels and basal, peak and the AUC of GH during the tests. Moreover, no correlation was found between the acute changes of serum GH concentration during both stimulation tests and leptin serum levels. The results suggest that leptin and GH secretion is not correlated and that leptin serum levels mainly reflect the amount of fat tissue, which is higher in GHD patients.

Plasma leptin concentrations are independently associated with insulin sensitivity in lean and overweight cats

This study investigated relationships between plasma leptin, insulin concentrations, insulin sensitivity and glucose tolerance in lean and overweight cats. Leptin concentrations were measured in 16 cats during glucose tolerance tests before and after gaining weight, and after feeding a test meal in overweight cats.An important finding of this study is that in both lean (r=−0.79) and overweight (r=−0.89) cats, the higher the leptin concentrations, the more insulin resistant the cat, independent of the degree of adiposity. Leptin concentrations at baseline and after consuming a meal tended to be higher in overweight cats with glucose intolerance, compared to overweight cats with normal glucose tolerance, although the difference was not significant. After feeding the test meal to overweight cats in the early morning, plasma leptin concentrations initially decreased before subsequently rising to peak 15h later, which coincided with late evening. The leptin peak occurred 9h after the insulin peak following ingestion of the test meal.Importantly, this study suggests that increased leptin concentrations may contribute to the diminished insulin sensitivity seen in overweight cats. Alternatively, the compensatory hyperinsulinaemia found with insulin resistance in overweight cats could stimulate leptin production.

The significance of measuring plasma leptin in acute myocardial infarction.

We measured leptin concentrations in patients with acute myocardial infarction (AMI, n = 21) and in 15 age-matched controls, and compared leptin concentrations with levels of other myocardial enzymes and indicators of AMI. Blood was sampled immediately after hospital admission and at 1 h, 2 h, 3 h, 6 h and 9 h, then every 12 h until 5 days post-admission. Patients were stratified into three groups according to peak leptin concentrations: hypoleptinaemia (< 3 ng/ml); normoleptinaemia (> or = 3 - < 15 ng/ml) and hyperleptinaemia (> or = 15 ng/ml). Hypoleptinaemic AMI patients had significantly increased concentrations of plasma lactate dehydrogenase compared with normoleptinaemic patients. No significant differences in other serum markers were noted between hyperleptinaemic and normoleptinaemic AMI patients. A significant negative correlation was found between the peak concentrations of leptin and interleukin 6. Leptin may play a role in the regulation of the development of cardiac damage in patients with AMI.

Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study.

Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response--multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte-derived hormone whose levels are influenced by several cytokines and which regulates immune function, food-intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS. To assess the role of leptin in SIRS/MODS we performed a matched case control and a longitudinal study (14 days) in 35 critically ill patients with SIRS/MODS and 35 matched controls. Baseline leptin levels were positively associated with body mass index (BMI) and TNF-alpha (P < 0.01) in patients and with IGF-1 and IL-6 levels (P < 0.05) in controls. Furthermore, leptin levels exhibited a progressive increase from the first to the last day of the study and although baseline levels were not different, peak leptin levels as well as leptin levels on the last day of the study were significantly higher in cases than in controls (P < 0.05). TNF-alpha levels, IL-6 and cortisol levels were also higher, whereas IGF-1 levels were lower in cases (P < 0.05). To assess whether leptin levels are independently associated with SIRS/MODS we performed multivariate logistic regression analysis which revealed that leptin up-regulation in cases is mediated by elevated TNF-alpha and cortisol levels. Finally, there was no independent association between leptin and survival in this group of critically ill patients. We conclude that cytokines and cortisol upregulate leptin levels, which may contribute to the development of the hypercatabolism, wasting and immune dysfunction but leptin levels are not independently associated with severity or mortality of patients with systemic inflammatory response-multiple organ dysfunction.

Temporal patterns of circulating leptin levels in lean and obese adolescents: relationships to insulin, growth hormone, and free fatty acids rhythmicity.

Alterations in nutritional status, such as obesity, markedly influence insulin, leptin, GH secretion, and free fatty acid (FFA) levels. We measured every hour for 24 h circulating leptin, insulin, GH, and FFA levels in lean and obese adolescents to determine: 1) the impact of adolescent obesity on the diurnal changes in leptin concentrations; and 2) the temporal relationships between the diurnal patterns of circulating leptin levels and insulin, GH, and FFA levels. During puberty, we found that the 24-h profile of circulating plasma leptin levels follows a bimodal pattern with minimal concentrations occurring early in the afternoon and a nocturnal elevation starting after midnight and culminating early morning. The time course of the diurnal variation in leptin levels in the obese adolescents was not different from that in lean controls. Of note, however, in obese girls leptin 24-h excursion and leptin night to day ratio were lower than those found in lean girls. In obese adolescents, mean GH levels varied significantly less during the day and night than lean controls. During the day, there were distinct preprandial increases and postprandial decreases in FFA levels, whereas after midnight FFA levels rose in both lean and obese adolescents. A significant positive correlation was found between mean plasma insulin levels between 0800 h and 2000 h and peak in leptin in lean and obese girls and boys (r = 0.63, P: < 0.001). Peak leptin was inversely correlated with the area under the nocturnal GH levels in all groups (r = -0.31, P: < 0.0003), whereas it was positively correlated with the nocturnal peak in FFA levels (r = 0.45, P: < 0.004). In summary, we report in obese adolescent girls a blunted relative diurnal excursion in leptin levels. This abnormal rhythmicity may, in part, explain their leptin resistance state. The nocturnal rise in leptin was paralleled by a nocturnal rise in GH and FFA levels. Additional studies are needed to test the potential link between the adipose-derived peptide and GH axis in humans.

THE CO-ORDINATED CYTOKINE/HORMONE RESPONSE TO ACUTE INJURY INCORPORATES LEPTIN

Recent studies have implicated leptin as a “stress” hormone and highlighted its association with increases in inflammatory cytokines, C-reactive protein and cortisol. In order to investigate the exact temporal leptin response to stress we undertook a detailed longitudinal study of circulating leptin concentrations during the well defined surgical injury of cholecystectomy. Circulating concentrations of cortisol, free fatty acids, leptin and C-reactive protein were measured at 3, 6, 9, 12, 18, 24, 48 and 72h from the start of surgery in nine patients. There was a significant correlation between baseline concentrations of leptin and BMI (r=0.893, P<0.001). Over the 72h from the start of surgery there were significant (P<0.05) increases in the concentrations of all analytes (peak median concentrations); cortisol (6h), free fatty acids (9h), leptin (18h) and C-reactive protein (48h). Interestingly the timing of the leptin peak at approximately 18h after an acute inflammatory stimulus is exactly the same as previously reported for interleukin 6. These data support the suggestion that the relationship between cortisol and leptin mirrors that of cortisol and another cytokine, interleukin 6, i.e. stimulatory in acute and suppressive in chronic situations. They also imply a physiological role for leptin in acute injury.

Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness)1

Nutritional signals strongly regulate neuroendocrine axes, such as those subserving release of LH, GH, and TSH, presumptively in part via the adipocyte-derived neuroactive peptide leptin. In turn, leptin release is controlled by both acute (fasting) and long-term (adipose store) nutrient status. Here, we investigate the neuroendocrine impact of short-term (2.5-day) fasting on leptin release in healthy young women studied in the steroid-replete midluteal phase of the normal menstrual cycle. Eight women each underwent 24-h blood sampling at 10-min intervals during a randomly ordered 2.5-day fasting vs. fed session in separate menstrual cycles. Pulsatile leptin release was quantified by model-free Cluster analysis, the orderliness of leptin patterns by the approximate entropy statistic, and nyctohemeral leptin rhythmicity by cosinor analysis. Mean (24-h) serum leptin concentrations fell by 4.6-fold during fasting; namely, from 15.2+/-2.3 to 3.4+/-0.6 microg/L (P = 0.0007). Cluster analysis identified 13.9+/-1.1 and 14.3+/-1.1 leptin peaks per 24 h in the fed and fasting states (P = NS), and unchanging leptin interpeak intervals (89+/-5.4 vs. 92+/-5.3 min). Leptin peak area declined by 4.2-fold (155+/-21 vs. 37+/-7 area units, P = 0.004), due to a reduction in incremental leptin pulse amplitude (4.4+/-0.7 vs. 1.0+/-0.13 microg/L, P = 0.0011). The cosine amplitude and mesor (mean) of the 24-h leptin rhythm decreased by 4-fold, whereas the acrophase (timing of the nyctohemeral leptin peak) remained fixed. The approximate entropy of leptin release was stable, thus indicating preserved orderliness of leptin release patterns in fasting. Cross-correlation analysis revealed both positive (fed) and negative (fasting) leptin-GH relationships, but no leptin-LH correlations. In summary, short-term (2.5-day) fasting profoundly suppresses 24-h serum leptin concentrations and pulsatile leptin release in the sex steroid-sufficient midluteal phase of healthy women via mechanisms that selectively attenuate leptin pulse area and incremental amplitude. In contrast, the pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern 24-h leptin release are not altered by acute nutrient restriction at this menstrual phase. Leptin-GH (but not leptin-LH) showed nutrient-dependent positive (fed) and negative (fasting) cross-correlations. Whether similar neuroendocrine mechanisms supervise altered leptin signaling during short-term nutrient restriction in men, children, or postmenopausal women is not known.

Circulating Leptin in Women

OBJECTIVE To investigate whether leptin is linked to reproduction, circulating levels were measured longitudinally throughout spontaneous menstrual cycles and during pregnancy in normal women. DESIGN Longitudinal blood samples were collected from normal volunteers, either during regular menstrual cycles or during successful singleton pregnancies. PATIENTS Six healthy, regularly cycling, women volunteers (31.5 ± 3.0 years old, BMI = 21.6 + 0.5) were recruited for serial venous blood sampling throughout one complete menstrual cycle. In addition, five healthy, women (31.8 ± 1.2 years old, pre-pregnant BMI = 30.0 ± 3.1) provided serial venous blood samples throughout one complete singleton pregnancy. MEASUREMENTS Circulating venous oestradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), leptin and (pregnant group only) human chorionic gonadotrophin (hCG). RESULTS In spontaneously cycling women, changes in circulating leptin levels were associated with menstrual phase (P < 0.001) and correlated with progesterone levels (P < 0.05). Peak leptin concentrations were recorded during the luteal phase (P < 0.01), coincident with maximal progesterone levels (P < 0.05). Leptin concentrations were elevated throughout gestation (P < 0.05), and especially during the second trimester (P < 0.05). Post-partum, circulating leptin levels fell sharply to below pre-pregnant values. Leptin correlated with oestradiol (P < 0.05) and human chorionic gonadotrophin (hCG, P < 0.01) levels during pregnancy. First trimester (P < 0.05) and postpartum (P < 0.05) oestradiol concentrations and post-partum hCG levels exhibited the greatest correlation with circulating leptin. CONCLUSIONS We conclude that the relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. This, together with the correlation between circulating oestradiol, hCG and leptin levels during pregnancy, strongly suggests a dynamic relationship between leptin and reproductive events in women.

Leptin levels in patients with anorexia nervosa are reduced in the acute stage and elevated upon short-term weight restoration

Circulating leptin concentrations are known to be low in acute anorexia nervosa (AN), which is characterized by low weight, amenorrhea and specific psychopathological features. In this study plasma leptin concentrations were determined during inpatient treatment of 23 adolescent females with AN using a sensitive radioimmunoassay (RIA) and set into relationship to leptin levels of females matched for age, body mass index (BMI; kg m-2) and/or percent body fat. At referral patients had leptin concentrations well below the female controls. Weight gains led to steep increases of leptin levels which peaked at values well in excess of those observed in controls matched for BMI. In patients who reached the final treatment stage and who were followed-up after discharge, levels subsequently fluctuated and finally dropped into or below the control range. The low leptin levels at referral are likely to be involved in the pathogenesis of amenorrhea and the reduced metabolic state of acutely ill patients. Peak leptin levels reached after weight gain are possibly the cause of increased energy expenditure during this stage of the disorder.

Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy.

To investigate whether leptin is linked to reproduction, circulating levels were measured longitudinally throughout spontaneous menstrual cycles and during pregnancy in normal women. Longitudinal blood samples were collected from normal volunteers, either during regular menstrual cycles or during successful singleton pregnancies. Six healthy, regularly cycling, women volunteers (31.5 +/- 3.0 years old, BMI = 21.6 +/- 0.5) were recruited for serial venous blood sampling throughout one complete menstrual cycle. In addition, five healthy, women (31.8 +/- 1.2 years old, pregnant BMI = 30.0 +/- 3.1) provided serial venous blood samples throughout one complete singleton pregnancy. Circulating venous oestradiol, progesterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), leptin and (pregnant group only) human chorionic gonadotrophin (hCG). In spontaneously cycling women, changes in circulating leptin levels were associated with menstrual phase (P < 0.001) and correlated with progesterone levels (P < 0.05). Peak leptin concentrations were recorded during the luteal phase (P < 0.01), coincident with maximal progesterone levels (P < 0.05). Leptin concentrations were elevated throughout gestation (P < 0.05), and especially during the second trimester (P < 0.05). Post-partum, circulating leptin levels fell sharply to below pregnant values. Leptin correlated with oestradiol (P < 0.05) and human chorionic gonadotrophin (hCG, P < 0.01) levels during pregnancy. First trimester (P < 0.05) and postpartum (P < 0.05) oestradiol concentrations and post-partum hCG levels exhibited the greatest correlation with circulating leptin. We conclude that the relationship between body mass index and circulating leptin varies during the course of spontaneous cycles in women, the best correlation occurring during the luteal phase when progesterone and leptin concentrations are highest. This, together with the correlation between circulating oestradiol, hCG and leptin levels during pregnancy, strongly suggests a dynamic relationship between leptin and reproductive events in women.