Peak Leptin Research Articles

Distribution, composition, and activity of airway-associated adipose tissue in the porcine lung.

Patients with comorbid asthma-obesity experience greater disease severity and are less responsive to therapy. We have previously reported adipose tissue within the airway wall that positively correlated with body mass index. Accumulation of biologically active adipose tissue may result in the local release of adipokines and disrupt large and small airway function depending on its anatomical distribution. This study therefore characterized airway-associated adipose tissue distribution, lipid composition, and adipokine activity in a porcine model. Airway segments were systematically dissected from different locations of the bronchial tree in inflation-fixed lungs. Cryosections were stained with hematoxylin and eosin (H&E) for airway morphology, oil red O to distinguish adipose tissue, and Nile blue A for lipid subtype delineation. Excised airway-associated adipose tissue was cultured for 72 h to quantify adipokine release using immunoassays. Results showed that airway-associated adipose tissue extended throughout the bronchial tree and occupied an area proportionally similar to airway smooth muscle within the wall area. Lipid composition consisted of pure neutral lipids (61.7 ± 3.5%), a mixture of neutral and acidic lipids (36.3 ± 3.4%), or pure acidic lipids (2.0 ± 0.8%). Following tissue culture, there was rapid release of IFN-γ, IL-1β, and TNF-α at 12 h. Maximum IL-4 and IL-10 release was at 24 and 48 h, and peak leptin release occurred between 48 and 72 h. These data extend previous findings and demonstrate that airway-associated adipose tissue is prevalent and biologically active within the bronchial tree, providing a local source of adipokines that may be a contributing factor in airway disease.

Postoperative Dynamic of Leptin and Fibroblast Growth Factor 21 in 123 Patients Recovering from Cardiac Surgery

BackgroundCardiac surgery triggers acute changes in serum leptin and fibroblast growth factor 21 (FGF-21). Considering their pleiotropic role in inflammation and abnormal glucose metabolism, perseverance of their abnormal serum level can have a long-term impact on recovery and end-organ failures. Long-term dynamics after cardiac surgery are unknown.Material/MethodsSerum was collected from 123 patients before cardiac surgery (tbaseline) and 24 h (t24h), 7 days (t7d), and 3 months (t3m) later. Also, interleukin 6 (IL-6) and C-reactive protein (CRP) assessed nonspecific inflammatory responses. Neurodegeneration was gauged with serum amyloid β1–40 and β1–42. Demographic and clinical information, including disposition at 28 days and t3m from admission, were collected.ResultsSerum leptin increased at t24h (leptinbaseline=613±747.9 vs leptin24h=768±718.1; P=0.0083) and decreased at t7d (leptin7d=499.5±540.2; P=0.043). FGF-21 levels increased at t24h and t7d. Cytokines normalized by t3m. Presurgical leptin levels were higher in Asians and were the primary determinant of postoperative leptin changes. Leptin levels were most elevated in patients undergoing aortic valve and arch surgery; the perioperative increase was significant only in patients with mitral valve surgery. Leptin and FGF-21 did not correlate with markers of general inflammation (CRP, IL-6), which partially resolved after t3m. Amyloid β1–42 at t3m correlated with leptin peak at t24h. Low prehospital FGF-21 level correlated with the incidence of perioperative stroke; postoperative FGF-21 correlated with discharge to facility vs home.Conclusions: Leptin and FGF-21 evolve independently from the inflammatory response in the aftermath of cardiac surgery and correlate with cardiac remodeling and neurodegeneration markers.

The postnatal leptin surge in mice is variable in both time and intensity and reflects nutritional status

Background/objectivesThe murine postnatal leptin surge occurs within the first 4 weeks of life and is critical for neuronal projection development within hypothalamic feeding circuits. Here we describe the influence of nutritional status on the timing and magnitude of the postnatal leptin surge in mice.MethodsPlasma leptin concentrations were measured 1–3 times per week for the first 4 weeks of life in C57BL/6J pups reared in litters adjusted to 3 (small), 7–8 (normal), or 11–12 (large) pups per dam fed breeder chow or raised in litters of 7–8 by dams fed high-fat diet (HFD) ad libitum starting either prior to conception or at parturition.ResultsMice raised in small litters become fatter than pups raised in either normal or large litters. The leptin surge in small litter pups starts earlier, lasts longer, and is dramatically larger in magnitude compared to normal litter pups, even when leptin concentrations are normalized to fat mass. In mice reared in large litters, weight gain is diminished and the surge is both significantly delayed and lower in magnitude compared to control pups. Pups reared by HFD-fed dams (starting preconception or at parturition) are fatter and have augmented leptin surge magnitude compared to pups suckled by chow-fed dams. Surge timing varies depending upon nutritional status of the pup; the source of the surge is primarily subcutaneous adipose tissue. At peak leptin surge, within each group, fat mass and plasma leptin are uncorrelated; in comparison with adults, pups overproduce leptin relative to fat mass. Plasma leptin elevation persists longer than previously described; at postnatal day 27 mice continue overproducing leptin relative to fat mass.ConclusionsIn mice, small litter size and maternal HFD feeding during the perinatal period augment the plasma leptin surge whereas large litter size is associated with a delayed surge of reduced magnitude.

Malnourishment during early lactation disrupts the ontogenetic distribution of the CART and α-MSH anorexigenic molecules in the arcuate/paraventricular pathway and lateral hypothalamus in male rats

Developmental malnourishment impacts the energetic metabolism control throughout life. In rat offspring, a 0% protein diet during the first 10 days of lactation results in leptin resistance and in alterations in: feeding behavior, serum leptin and neuropeptide Y (NPY) levels in the hypothalamic arcuate nucleus (ARC)/paraventricular (PVN) pathway. Here, the distributions of alpha-melanocyte stimulating hormone (α-MSH) and cocaine and amphetamine regulated transcript (CART), anorexigenic molecules, were immunohistochemically assessed in the ARC, PVN and lateral hypothalamus (LH) nuclei. Rat dams were subjected to one of the following diet protocols from postnatal day (P) 1–10: 1) Protein-free (PFG, 0% protein chow); 2) Pair-fed (UFG, normoprotein chow); 3) Control group (CG, normoprotein chow). PFG, UFG and CG male offspring were analyzed at different time points, from P5 to P180. In the ARC, PFG α-MSH and CART were increased from P10 to P45 when compared to CG and UFG. In the PVN, α-MSH and CART peaks in PFG animals were delayed from P20 to P30 when compared to CG. In the LH, CART was more intense in PFG animals than in UFG and CG ones by P20, and, by P30, UFG immunostaining became less intense than in CG. In conclusion, aproteic diet altered the ontogenetic distribution of both anorexigenic molecules. In the PVN, the peak was delayed to P30, which coincides with the leptin peak and follows the previously described NPY (orexigenic) peak in this model. The permanent LH CART and α-MSH increase may be associated with the previously observed PFG hypophagia.

Influence of macronutrient composition of commercial diets on circulating leptin and adiponectin concentrations in overweight dogs.

Leptin and adiponectin play important roles in obesity‐related inflammation and comorbidities. Previous research suggests that alterations in dietary macronutrient composition can modify circulating leptin and adiponectin concentrations in people, but limited research on this subject has been performed in dogs. This study investigated the effects of commercial high protein (HP), high fat (HF) and high carbohydrate medium protein (HCMP) diets on baseline (T−1) concentrations, post‐prandial peak concentrations and total release in a ten‐hour time span of leptin and adiponectin in dogs, when compared to a maintenance high carbohydrate low protein (HCLP) diet. Thirty‐six overweight dogs were fed the HCLP diet in a one‐week control period, after which the animals were assigned to one of three groups. In three four‐week periods, each group was fed all test diets in a different sequence. At the last day of each period, blood was sampled at one hour before feeding (T−1) and at three (T3), six (T6) and nine (T9) hours after feeding. Feeding caused peak leptin concentrations at T6 and T9 (p < .001). No significant post‐prandial change in adiponectin concentrations was found (p = .056). The HP diet resulted in lower leptin peak concentrations (p = .004) and AUCT−1–T9 (p = .01), but none of the diets influenced baseline leptin concentrations (p = .273). Baseline adiponectin concentrations were lower for the HF diet (p = .018) and HCMP (p < .001), and the HP, HF and HCMP AUCT−1–T9 (p < .001) were lower compared with the HCLP diet. Female dogs had lower adiponectin baseline concentrations (p = .041) and AUCT−1–T9 (p = .023) than male dogs. In conclusion, the HP diet was associated with the lowest post‐prandial peak leptin concentration and the least decrease in adiponectin release, suggesting that a HP diet may improve immune‐metabolic health and post‐prandial satiety in overweight dogs.

Basal and Dynamic Leptin Secretion: Association with Cardiometabolic Risk and Body Weight Trajectories in African-Americans and European-Americans.

Fasting plasma leptin levels reflect fat mass, but dynamic leptin responses to secretagogues, and the influence of race/ethnicity, have not been well studied. Here, we compared basal and stimulated leptin levels in relation to cardiometabolic risk and weight trajectories in black and white subjects. We studied 254 (127 black and 127 white) normoglycemic adults enrolled in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. At baseline and annually, POP-ABC participants underwent physical examination, oral glucose tolerance test, and measurements of body fat (dual energy X-ray absorptiometry), fasting plasma leptin, insulin, cortisol, lipids, and leptin secretory response to single-dose (2 mg) dexamethasone (dex). The interactions among basal and stimulated leptin and changes in adiposity/cardiometabolic measures during the ensuing year were then analyzed. The mean (±SD) fasting leptin level (50.6 ± 47.7 vs. 39.5 ± 37.6 ng/mL, P = 0.004) and body mass index (BMI) (31.9 ± 7.14 vs. 29.0 ± 7.66 kg/m2, P = 0.0043) were higher in black women vs. white women, but similar in black men vs. white men (leptin: 12.4 ± 2.07 vs. 11.1 ± 1.40 ng/mL; BMI: 29.4 ± 7.68 vs. 28.1 ± 4.23 kg/m2). The peak leptin response to dex (~200% baseline) did not differ significantly by gender or race. Total body fat correlated positively with fasting leptin (r = 0.81, P < 0.0001) and inversely stimulated leptin levels (r = -0.26, P < 0.0001). Fasting leptin was unrelated to 1-year change in weight or fat mass, whereas stimulated leptin levels were significantly associated with 1-year trajectories in weight (P = 0.0016) and total fat mass (P = 0.0035). Stimulated leptin levels also had significant interactions with insulin sensitivity (homeostasis model of insulin resistance, P = 0.01), triglycerides (P = 0.0078), fasting glucose (P = 0.027), systolic blood pressure (P = 0.037), and high-sensitivity C-reactive protein (P = 0.027). We found no significant ethnic disparities in basal or dynamic leptin secretion in relation to adiposity. Fasting leptin levels were not associated with 1-year weight change, while stimulated levels showed weak though significant association with 1-year weight change.

Leptin and soluble leptin receptor in association with gestational diabetes: a prospective case-control study.

To assess the association of serum leptin and its receptor (SLeptinR) with the risk of gestational diabetes mellitus (GDM) and to evaluate the longitudinal circulation of these peptides in pregnancy. This study consisted of 53 subjects diagnosed with GDM and 43 normal glucose tolerance (NGT) pregnant women. Serum leptin and SLeptinR were measured at 24-28weeks, prior and after delivery, and post-puerperium. Lower levels of leptin and SLeptinR were observed in GDM compared to NGT. Leptin [OR 0.97 (95% CI 0.94-1.0)] and SLeptinR [OR 0.86 (95% CI 0.79-0.93]) were inversely associated with GDM. Participants in the lowest tertile for leptin and SLeptinR had a 2.8-fold (95% CI 1.0-7.6) and a 5.7-fold (95% CI 1.9-17.3) higher risk of developing GDM compared with the highest tertile, respectively. These relationships were attenuated after adjustment for covariates. In both the groups, peak leptin was observed at 24-28weeks, decreasing continuously during pregnancy (p>0.05) and after delivery (p<0.017). SLeptinR level increased (p<0.001) during pregnancy and decreased (p<0.005) after delivery in GDM, however, levels remained the same in NGT. In GDM, leptin and SLeptinR was positively and inversely correlated with BMI and HOMA-IR at 24-28weeks and post-puerperium, respectively. The cord levels of both leptin and SLeptinR were lower than maternal levels. There were no significant differences in serum cord leptin and SLeptinR levels between the groups. Leptin and SLeptinR are independently and inversely associated with GDM. Lower levels of these peptides may play an important role in the pathophysiology of GDM and pre-diabetic state in post-puerperium.

Blockage of neonatal leptin signaling induces changes in the hypothalamus associated with delayed pubertal onset and modifications in neuropeptide expression during adulthood in male rats

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102–103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides.

Maternal prolactin inhibition causes changes in leptin at 22- and 30-day-old pups.

Breastfeeding is associated with obesity prevention. We showed previously that prolactin inhibition at the end of lactation causes hyperleptinemia at weaning (PN21) and programs for obesity, insulin resistance, dyslipidemia, and leptin resistance (PN180). Here, we evaluate the source of neonatal hyperleptinemia and how it develops during the nutritional transition from milk through solid food. Lactating rats were treated with bromocriptine (BRO), a prolactin inhibitor, 0.5 mg twice a day, or saline (CON) for the last 3 days of lactation. All parameters were studied at PN22 and PN30. At PN22, BRO-treated rats showed lower food intake, body mass, and body length. At PN30, only body length and mesenteric fat mass were lower. Despite normal plasma leptin levels at PN22, the adipose tissue leptin mRNA expression was lower, while plasma leptin was higher in PN30, possibly due to a higher adipose mesenteric tissue production. At PN22, the hypothalamus seems to be more sensitive to leptin, since OBR and STAT3 are higher. Conversely, at PN30 leptin signaling pathway is suggestive of leptin resistance with lower STAT3 and higher SOCS3 in hypothalamus and consequently higher NPY. Glycemia was lower at PN22 and higher at PN30, without changes in plasma insulin levels. At PN30, BRO-treated rats had other metabolic changes such as higher plasma cholesterol, lower HDL-c, higher hepatic cholesterol and AST, suggesting a liver dysfunction. Our data show that milk supply can exert a crucial role in the imprinting of a second leptin peak, which is important for survival adaptation to adverse nutritional conditions.

Multigenerational impact of maternal overnutrition/obesity in the sheep on the neonatal leptin surge in granddaughters.

Background/ObjectivesWe have reported that maternal overnutrition/obesity (OB) in sheep resulting from feeding 150% of National Research Council (NRC) requirements throughout gestation, leads to maternal hyperglycemia and hyperinsulinemia. Further, newborn lambs born to OB vs. control-fed (CON, 100% of NRC) ewes exhibited greater adiposity, increased blood cortisol, insulin and glucose and the elimination of the postnatal leptin spike seen in lambs born to CON ewes. This early postnatal leptin peak is necessary for development of hypothalamic circuits which program appetite in later life. This study evaluated the multigenerational impact of OB on insulin:glucose dynamics of mature female F1 offspring fed only to requirements throughout gestation, and on their lambs (F2 generation).Design and MethodsAdult F1 female offspring born to OB (n=10) or CON (n=7) ewes were utilized. All F1 ewes were subjected to a glucose tolerance test at midgestation and late gestation. Jugular blood was obtained from F2 lambs at birth (day 1) through postnatal day 11, and plasma glucose, insulin, cortisol and leptin concentrations determined. Dual Energy X-ray Absorptiometry (DEXA) was utilized to determine bone mineral density (BMD), bone mineral content (BMC), lean tissue mass, and fat tissue mass.ResultsFasted blood glucose and insulin concentrations were greater (P < 0.05) in OBF1 than CONF1 ewes at mid- and late gestation. Further, after glucose infusion, both glucose and insulin concentrations remained higher in OBF1 ewes (P < 0.05) than CONF1 ewes demonstrating greater insulin resistance. Blood concentrations of glucose, insulin, and cortisol, and adiposity were higher (P < 0.01) in OBF2 lambs than CONF2 lambs at birth. Importantly, OBF2 lambs failed to exhibit the early postnatal leptin peak exhibited by CONF2 lambs.ConclusionsThese data suggest that these OBF2 lambs are predisposed to exhibit the same metabolic alterations as their mothers, suggesting a multi-generational programming effect.

Fat mass, and not diet, has a large effect on postprandial leptin but not on adiponectin concentrations in cats

Leptin and adiponectin play important roles in carbohydrate and lipid metabolism in different species. Information is limited on the effects of diet, weight gain, and fat mass on their concentrations in cats. This study compared fasting and postprandial blood leptin and total adiponectin concentrations before and after 8 wk of ad libitum feeding to promote weight gain in adult cats (n = 32) fed either a low-carbohydrate, high-protein (23% and 47% ME) or a high-carbohydrate, low-protein (51% and 21% ME) diet. There were significant effects of total, abdominal, and nonabdominal fat mass, but not diet or body weight, on mean 24-h and peak leptin (P < 0.01); observed increases in mean and peak leptin were greatest for abdominal fat mass (50% and 56% increase for every extra 100 g, respectively). After weight gain, postprandial leptin concentration increased markedly relative to when cats were lean, and the duration of the increase was longer after a mean weight gain of 37% with the low-carbohydrate, high-protein diet group compared with 17% with the high-carbohydrate, low-protein group (P ≤ 0.01). Adiponectin was lower than fasting at some time points during the postprandial period in both groups (P ≤ 0.05). For both fasting and mean 24-h adiponectin, there was no significant diet effect (P ≥ 0.19) or changes in weight gain relative to when cats were lean (P ≥ 0.29). In conclusion, fat mass, and not diet, has a large effect on postprandial leptin but not adiponectin concentrations in cats.

Elevated glucocorticoids during ovine pregnancy increase appetite and produce glucose dysregulation and adiposity in their granddaughters in response to ad libitum feeding at 1 year of age

Synthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences. F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks. DEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in thefirst days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weightcompared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test. sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test.

Impaired insulin and leptin sensitivity in the offspring of moderate caloric-restricted dams during gestation is early programmed

We aimed to assess the mechanisms responsible for hyperphagia and metabolic alterations caused by maternal moderate caloric restriction during gestation. Male and female offspring of control and 20% caloric-restricted rats (CR) were studied. They were fed a normal-fat diet until 4 months of age and then moved to a high-fat diet until 6 months of age. Blood parameters and expression of selected genes in hypothalamus, retroperitoneal white adipose tissue (rWAT) and liver were analyzed at 25 days and 6 months of age. Plasma leptin was measured during suckling. Levels of proteins involved in insulin and leptin signaling were determined at 6 months of age. CR ate more calories than controls, but only males gained more weight. A peak in plasma leptin was found in 9-day-old controls, but was absent in CR. Twenty-five-day-old CR showed lower insulin receptor mRNA levels in hypothalamus, rWAT and liver, and long-form leptin receptor (ObRb) in hypothalamus. At the age of 6 months, homeostatic model assessment for insulin resistance index was higher in CR than controls, and CR males also displayed hyperleptinemia. Adult CR also showed lower ObRb mRNA levels in the hypothalamus (only females, but both showed altered neuropeptide Y/proopiomelanocortin mRNA ratio), rWAT and liver (males), and a decrease of protein kinase C zeta levels in rWAT (females) and liver (males) and of phosphorylated signal transducer and activator of transcription 3 in liver (females). These results suggest that CR animals are programmed for insulin and central leptin resistance, which may explain the dysregulation of appetite and other metabolic alterations, favoring obesity development, although only manifested in males. These early programming effects could be associated with the absence of leptin surge during lactation.

Effects of Acute Changes in Neonatal Leptin Levels on Food Intake and Long-Term Metabolic Profiles in Rats

In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

Maternal obesity eliminates the neonatal lamb plasma leptin peak

A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations.We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life.

The relationship between leptin, gonadotropic hormones, and body composition during puberty in a Dutch children cohort

To investigate the relationship between leptin concentrations, gonadotropic hormone concentrations, and body composition during puberty in a Dutch children cohort. In a cohort of 98 children, we determined anthropometric measurements, body composition, and concentrations of leptin, FSH, and LH. Sex differences were observed from Tanner stage 1 onwards in weight, body fat percentage, and leptin/fat mass ratio. In boys and girls, the relationship between leptin concentrations and FM was weaker at Tanner stage 2 (R(2)=0.33 and R(2)=0.39; P<0.001), 3 (R(2)=0.27 and R(2)=0.36; P<0.002), and 4 (R(2)=0.21 and R(2)=0.28; P<0.03) than at Tanner stage 1 (R(2)=0.51 and R(2)=0.67; P<0.001) and 5 (R(2)=0.46 and R(2)=0.78; P<0.01). In girls, a peak in leptin concentrations (8.5+/-6.0 ng/ml) preceded a peak in LH and FSH concentrations (15.1+/-3.5 and 5.0+/-4.5 IU/l). A lead/lag relationship was observed of leptin at Tanner stage 1 to LH and FSH at Tanner stage 2 (R(2)=0.12, P<0.05 and R(2)=0.18, P<0.05). In boys, there was no peak in leptin, LH, and FSH; additionally, leptin at Tanner stage 3 was related FSH at Tanner stage 4 (R(2)=0.17, P<0.04). In boys and girls during puberty, factors independent of fat mass become (transiently) more important in the regulation of plasma leptin concentrations. Moreover, in girls, leptin is suggested to act as a permissive factor for the onset of puberty, while, in boys, leptin has a different timing and possibly different function.

Seasonal changes in plasma leptin concentration related to antler cycle in Iberian red deer stags

The aim of this study is to describe the leptin cycle in male Iberian red deer (Cervus elaphus hispanicus) and relate it to antler and testosterone cycles. An additional aim is to assess the relationship between the plasma leptin concentration during antlers' growth and their final size. Therefore, blood from 21 Iberian red deer males was sampled monthly to analyse leptin and testosterone. At the same time the deer were weighed and their body condition was assessed. The length of antlers was measured every 2 weeks and, after casting, their final length and perimeters were taken. Leptin showed a seasonal cycle, with a peak in June that decreased as testosterone increased. Low values were observed in autumn, winter and early spring. The relationship observed between leptin and body mass or body condition score was different in spring, when plasma testosterone concentration is low, than in autumn, when testosterone increases. Leptin peak amplitude was positively related to final antler size. In conclusion, the relationship between leptin and body mass and body condition score changes through the year, possibly due to the influence of androgens and photoperiod. There was a positive relationship between plasma concentration of leptin during antler growth and final antler length.

Leptin and leptin soluble receptor changes after pulmonary endarterectomy: relations to cortisol and cytokine network

Leptin is a hormone that regulates food intake. During inflammatory status, leptin may contribute to the anorexia and cachexia of infection. Pulmonary endarterectomy was used as a model of non-infectious cytokine network hyperstimulation. Leptin and soluble leptin receptor (SLR) were compared with evolution of cortisol and inflammatory cytokines in twenty-two patients with chronic thromboembolic pulmonary hypertension treated with pulmonary endarterectomy using cardiopulmonary bypass (CBP) and deep hypothermic circulatory arrest (DHCA). Leptin, SLR, cortisol, IL-beta, IL-6, IL-8, and TNFalpha concentrations in arterial blood were measured before/after sternotomy, last DHCA, separation from bypass, 12, 18, 24, 36, and 48 h after sternotomy. Mean duration of CPB was 338.2 min.; mean circulatory arrest time 39.9 min. The initial decline of leptin, SLR, TNFalpha, IL-6, and IL-8 was followed by an increase culminating 6-24 h after sternotomy. Leptin peak levels were detected 24 h after sternotomy (28.0 ng/ml, 21.9-37.6). IL-6 culminated after separation from CPB, IL-8 was highest 12 h after sternotomy. Leptin concentrations correlated with IL-6 (r=0.82), and TNFalpha (r=0.73). Large cardiovascular surgery caused a significant increase in serum leptin, indicating its acute regulation by stress factors. This effect may be secondary to the inflammatory response mediated via cytokine stimulation. Correlation between leptin and IL-6 indicates the role of IL-6 in leptin induction.

A highly sensitive enzyme-linked immunosorbent assay for measurement of leptin secretion in human adipocytes

To establish a highly sensitive and specific ELISA method for measurement of leptin and further to study the secretion of leptin during human preadipocytes differentiation and effects of troglitazone. Rabbits Balb/c mice were immunized by recombinant human leptin and Balb/c mice were immunized by human leptin so as to produce rabbit anti-human leptin polyclonal antibodies (PAb) and mouse anti-human leptin monoclonal antibodies (MAb). Combination of the PAb as coating antibody, with a carefully paired biotinylated MAb as detector, and the avidin-horseradish peroxidase as the amplifier of detecting signals, a sandwich method, biotin-avidin ELISA (BA-ELISA) was established. Human omental preadipocytes were cultured, introduced to differentiate, and treated with 10 micromol/L troglitazone; the leptin secretion in the supernatant was detected by BA-ELISA. Peripheral blood samples were collected from 114 healthy persons and the serum leptin was detected by BA-ELISA. The sensitivity of BA-ELISA was 0.03 ng/ml with a working range of 0.05 - 5 ng/ml and a exogenous leptin recovery rate of 97.8%, and the intra- and interassay coefficients of variation (CVs) were less than 7.4% and 9.3% respectively. The assay detected only a single free leptin peak in gel chromatographic fractions from the mixed human sera or adipocytes culture media. The leptin secretion level detected by BA-ELISA showed that the leptin secretion of the preadipocytes increased strongly when the cells differentiated into mature adipocytes. The peak leptin secretion level of the troglitazone treated group was 2 times as that of the control group. The leptin concentration of women was than 7.6 ng/ml, significantly higher than that of the men (3.2 ng/ml, P < 0.001), and the serum leptin level was significantly correlated with body mass index both for men (r = 0.67, P < 0.001) and for women (r = 0.61, P < 0.001). A highly sensitive BA-ELISA specific for free leptin has been developed that is especially suited for the accurate measurement of the rather low leptin levels of clinical blood specimens and for basic research use.

Feeding and stress interact through the serotonin 2C receptor in developing mice

Feeding and stress neurocircuits are intertwined. Among the neurotransmitters and receptors common to both circuits, the serotonin 2C receptor is particularly intriguing because its distribution is limited to the central nervous system. Hence, deficits in energy balance and stress responses in mice lacking this gene are likely due to defects in central regulation. The phenotype of the serotonin 2C receptor null (KO) mouse is adult-onset hyperphagia, depressed metabolic rate, and disruption in satiety, with a progression to midlife obesity. A provocative feature of this obese model is our recent finding of a childhood component where the KO mouse is heavier at weaning, a distinction that only returns in adulthood. To determine when the KO mouse becomes heavier, longitudinal and cross-sectional timecourse studies followed weight gain and found significantly heavier body weight, higher plasma leptin, and rectal temperature, only in unhandled KO compared to sibling wildtype controls. To map what metabolic compensations cause the KO weight increase, we launched thermal and behavioral studies in 10 day old mice before there was any genotype difference in body weight, corticosterone levels, or the levels leptin during the developmental leptin peak. The heavier KO weanling is, in part, explained by hyperphagia, lower metabolic rate and activity, and behavioral thermogenesis measured at 10 days of age. However, the infant KO mouse is stress-sensitive and growth is impaired with handling. The serotonin 2C receptor has a role in fine-tuning energetic and stress demands even as neurocircuits are developing, and unbalanced compensations in infancy may program responses in adulthood that are “off target” from optimal function.