Peripheral Leptin Concentrations Research Articles

Alpha-Melanocyte-Stimulating Hormone is Elevated in Hypothalamic Obesity Associated with Childhood Craniopharyngioma.

The purpose of this study was to investigate the peripheral concentrations of leptin and neuropeptides taking part in the melanocortin pathway in hypothalamic obesity (HO) associated with craniopharyngioma (CP) and to find a peripheral marker for diagnosis. Thirty-one patients (52% girls; median age 16 years) with CP were enrolled in the study group. They were grouped as CP with obesity (CPobesity , n = 17) and CP without obesity (CPnonobesity , n = 14). Two control groups without CP consisted of 27 children with obesity (OC) (55% girls; median age 13.8 years) and 25 children without obesity (normal control [NC]) (72% girls; median age 14.5 years). Obesity was defined as BMI percentile ≥ 95%. Fasting serum concentrations of leptin, brain-derived neurotrophic factor (BDNF), and alpha-melanocyte-stimulating hormone (α-MSH) were measured in the groups. Leptin and BDNF concentrations were correlated with BMI SD score (SDS) in controls (OC + NC) and CP. However, there was no correlation between α-MSH and BMI-SDS in CP or control groups. After adjusting for age, sex, and BMI-SDS, α-MSH was found to be significantly higher in CPobesity than in other groups, whereas leptin and BDNF were comparable among the four groups. Serum BDNF, just like leptin, increased with BMI, regardless of hypothalamic damage. On the contrary, α-MSH concentration was significantly high in HO, designating a potential biomarker for HO in CP.

Aberrations in peripheral inflammatory cytokine levels in substance use disorders: a meta-analysis of 74 studies.

To characterize the peripheral inflammatory cytokine profile in people with substance use disorders (SUDs). Systematic review and meta-analysis. Clinical studies that evaluated peripheral blood inflammatory cytokine levels in patients with SUDs and healthy controls PARTICIPANTS: SUD patients and healthy controls. PubMed and Web of Science were systematically searched for relevant studies. Two investigators independently selected studies and extracted data. A total of 77 articles were included in the meta-analysis, containing 5649 patients with SUDs and 4643 healthy controls. Data were pooled using a random-effects model by the Comprehensive Meta-Analysis version 2 software. Concentrations of interleukin (IL)-6) in 32 studies, tumor necrosis factor (TNF)-α in 28 studies, IL-10 in 20 studies, IL-8 in 17 studies, C-reactive protein in 14 studies, IL-4 in 10 studies, IL-12 in seven studies, monocyte chemoattractant protein (MCP)-1 in 6 studies, TNF-receptor 2 (TNF-R2) in four studies and granulocyte-macrophage colony-stimulating factor (GM-CSF) in three studies were significantly higher in patients with SUDs compared with healthy controls, while concentrations of leptin in 14 studies were significantly lower in patients with SUDs compared with healthy controls. The findings were inconclusive for the associations between interferon-γ, IL-1β, IL-2, IL-1 receptor antagonist (IL-1RA), transforming growth factor (TGF)-β1, G-CSF, C-C motif chemokine 11, TGF-α and SUDs. People with substance use disorders (SUDs) appear to have higher peripheral concentrations of IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, C-reactive protein, MCP-1, TNF-R2 and GM-CSF and lower peripheral concentrations of leptin than people without SUDs. This strengthens the view that SUD is accompanied by an inflammatory response.

Effect of passive immunization against leptin on ovarian follicular development in prepubertal mice

Leptin has been demonstrated to be essential for reproduction. However, all the relevant studies reported to date have investigated either the effect of a complete absence of leptin both centrally and peripherally, or excess leptin administration. The aim of this present study was to investigate the effect of reducing peripheral leptin concentrations on ovarian follicular development in prepubertal animals via administration of an anti-leptin antibody. Pre-pubertal female mice were administered anti-leptin antibody under the skin behind the head for four days, with or without gonadotropins, and ovaries were weighed and collected for follicle counting. Control animals were treated with non-immune serum. Passive immunization against leptin, with or without gonadotropins, resulted in a significant increase in ovarian weight compared with control ovaries. Furthermore, the ovaries from the anti-leptin group had significantly greater numbers of primary follicles per ovarian section than the control group, thus suggesting an increase in the transition of primordial to primary follicles after treatment. Interestingly, animals treated with anti-leptin plus gonadotropins had a significantly higher number of Graafian follicles in their ovaries compared with the other groups. Collectively, the results of the present study indicate that reduction of leptin in the circulation promotes ovarian follicle development in female mice, suggesting that peripheral leptin acts as an inhibitor of ovarian follicle development.

Characterization of Leptin Levels in Gestating Callipyge Ewes

The callipyge mutation in sheep is a polar overdominant mutation that results in post-natal muscle hypertrophy in the loin and hindquarters of paternal heterozygotes (+/CLPG). Sheep that are homozygous for the callipyge allele (CLPG/CLPG) do not express the muscle hypertrophy phenotype, but serve as carriers for the mutation. Callipyge sheep are characterized by improved feed efficiencies and leaner carcasses. Leptin is a protein hormone secreted from adipose tissue and has been found to affect appetite and serve as an indicator of body fat mass. To date, very little knowledge is available as to the effect of the callipyge mutation on circulating leptin levels. Due to the interaction of leptin with feed intake and energy availability, and the fact that the majority of fetal growth occurs in late gestation, it is important to understand if the callipyge mutation interacts with leptin production in late gestational ewes. Therefore, our objective was to characterize serum concentrations of leptin in late gestational callipyge ewes vs. non-callipyge ewes. We evaluated genetically verified callipyge (n = 6), homozygous (n = 8) and normal (n = 8) ewes weekly during the last eight wks of gestation through one wk post-partum. Weights were taken and body condition scores were assigned by trained personnel weekly. Blood was collected via jugular venipuncture on each sampling date and subjected to an ovine-specific leptin RIA. Genotype influences on peripheral concentrations of leptin were found to be highly significant (p = 0.0005). Total leptin means for +/CLPG were 5.41±0.40 ng/ml, CLPG/CLPG 8.11±0.70 ng/ml, and +/+ 9.13±0.93 ng/ml. Sampling date was also significant (p = 0.0098) with all ewes showing a decrease in leptin levels throughout gestation and parturition. Using repeated measures, we were able to detect lower levels of plasma leptin in callipyge ewes, which may be indicative of their lower overall body fat content. These results indicate that the callipyge phenotype decreases the levels of adipose tissue and leptin production in gestating ewes.

Peripheral leptin effect on food intake in young chickens is influenced by age and strain

The acute effect of leptin on the regulation of food intake was investigated in layer and broiler chickens. In an initial study, we observed that a single intraperitoneal injection of recombinant chicken leptin (1 mg/kg BW) dramatically reduced (38%) food intake in 56-day-old layer chickens, more moderately reduced (15%) food intake in 9-day-old layer chicks, and had no significant effect in 9-day-old broiler chicks. In a subsequent study, body weight and plasma concentrations of leptin were measured weekly in layer and broiler chicks from day 1 to 35 of age and brain leptin receptor and neuropeptide Y (NPY) mRNA expression were analyzed at 1, 9, and 35 days of age. At day 1 of age, peripheral concentrations of leptin were significantly greater in layer than broiler chicks. Subsequently, despite increases in body weight and differences in growth rates between layer and broiler chicks from day 8 to day 35 of age, peripheral concentrations of leptin were constant and similar in both genotypes. Leptin receptor and NPY mRNA were expressed in brain from day 1 in chicks of both genotypes and increased significantly to day 35 of age. These observations provide evidence that the inhibitory effect of leptin on the regulation of food intake in growing chicks is an age dependent process. Furthermore, acquisition of the anorectic effect of leptin is likely to be associated with greater expression of the leptin receptor and NPY mRNAs than to changes in blood levels of leptin. Finally, this study provides evidence that chickens selected for high growth rates may be less sensitive or responsive to peripheral concentrations of leptin than chickens with low growth rates (layers), suggesting that the faster growth of broiler chicks may be related to a lessened responsiveness to anorexigenic factors.

Effects of exogenous ghrelin on feed intake, weight gain, behavior, and endocrine responses in weanling pigs.

The objectives were to determine relative ADG, ADFI, behavior, and endocrine responses in weaned pigs receiving exogenous ghrelin. Twenty-four barrows weaned at 18 d of age (d 0 of the experiment) were catheterized via the jugular vein, weighed, and assigned to either a ghrelin (n = 12) or saline (control; n = 12) infusion group. Initial pig BW did not differ between treatments (7.87+/-0.39 vs. 7.92+/-0.35 kg for ghrelin and control treatments, respectively). Pig BW and feed intakes were measured once daily throughout the experiment. Starting on d 1, the ghrelin pigs were intravenously infused three times daily for 5 d with 2 microg/kg BW of human ghrelin, and the control pigs were similarly infused with saline. Activity observations and blood samples were taken at -15, 0, 15, 30, 60, 90, 120, 240, and 480 min relative to the first infusion and then three times daily (0800, 1600, and 2400) for 8 d. Weight gain during the 5-d infusion period was greater by the ghrelin than by control pigs (0.57+/-0.10 vs. 0.21+/-0.13 kg, respectively; P < 0.04); however, there was no increase in feed intake. During two behavioral observation periods, more pigs in the ghrelin treatment were observed eating compared with control pigs (P < 0.05). The initial infusion of exogenous ghrelin increased serum ghrelin, GH, insulin, and cortisol concentrations (P < 0.05). Endogenous serum ghrelin increased from d 1 to 8 of the experiment in control animals (P < 0.05). Serum IGF-I initially fell in both treatment groups from d 1 to 2 (P < 0.05) but then increased from d 5 to 8 (P < 0.05). Peripheral concentrations of glucose in the ghrelin pigs were greater on d 2, 3, 7, and 8 than on d 1 (P < or = 0.05). In both treatment groups, peripheral concentrations of leptin increased from d 7 to 8, and cortisol decreased from d 1 to 5 of the experiment. These observations provide evidence that ghrelin may positively influence weight gain and concomitantly increase GH, insulin, and cortisol secretion in weaned pigs.

Peripheral leptin effect on food intake in young chickens is influenced by age and strain

The acute effect of leptin on the regulation of food intake was investigated in layer and broiler chickens. In an initial study, we observed that a single intraperitoneal injection of recombinant chicken leptin (1 mg/kg BW) dramatically reduced (38%) food intake in 56-day-old layer chickens, more moderately reduced (15%) food intake in 9-day-old layer chicks, and had no significant effect in 9-day-old broiler chicks. In a subsequent study, body weight and plasma concentrations of leptin were measured weekly in layer and broiler chicks from day 1 to 35 of age and brain leptin receptor and neuropeptide Y (NPY) mRNA expression were analyzed at 1, 9, and 35 days of age. At day 1 of age, peripheral concentrations of leptin were significantly greater in layer than broiler chicks. Subsequently, despite increases in body weight and differences in growth rates between layer and broiler chicks from day 8 to day 35 of age, peripheral concentrations of leptin were constant and similar in both genotypes. Leptin receptor and NPY mRNA were expressed in brain from day 1 in chicks of both genotypes and increased significantly to day 35 of age. These observations provide evidence that the inhibitory effect of leptin on the regulation of food intake in growing chicks is an age dependent process. Furthermore, acquisition of the anorectic effect of leptin is likely to be associated with greater expression of the leptin receptor and NPY mRNAs than to changes in blood levels of leptin. Finally, this study provides evidence that chickens selected for high growth rates may be less sensitive or responsive to peripheral concentrations of leptin than chickens with low growth rates (layers), suggesting that the faster growth of broiler chicks may be related to a lessened responsiveness to anorexigenic factors.

Leptin administration increases nocturnal concentrations of luteinizing hormone and growth hormone in juvenile female rhesus monkeys.

The importance of leptin in regulating sexual maturation is supported by data showing that deletions of the leptin gene or alterations in the leptin receptor result in infertility. However, attempts to define a role for leptin in normal puberty have produced equivocal results, leading to the conclusion that, if leptin is involved in puberty, its role is permissive and not obligatory. To better define the importance of leptin in primate puberty, the present study tested the hypothesis that a premature elevation in nocturnal leptin concentrations would accelerate indices of puberty, including nocturnal LH secretion in female rhesus monkeys (Macaca mulatta). Juvenile, gonadally intact females were treated daily with leptin (n = 6; 30 micro g/kg, sc at 1700 h) from 12-30 months of age and were compared with age-matched control females (n = 13). Chronic elevation in peripheral concentrations of leptin increased serum levels of both daytime and nighttime bioactive LH at a significantly younger age compared with control females. The earlier rise in LH in leptin-treated females was associated with an earlier increase in serum estradiol and occurrence of menarche. Despite this effect of leptin, nocturnal serum LH was significantly higher at each age assessed in non-leptin-treated ovariectomized controls (n = 6). In addition, leptin increased skeletal lengths and maturity that were associated with significantly higher serum levels of nocturnal GH and daytime IGF-I. Although body weights were not consistently affected by treatment, body mass index, as an index of body fat, was consistently lower in leptin-treated females. Taken together, these data indicate that the chronic elevation in serum leptin concentrations advances the nocturnal increase in serum LH as well as other parameters of female puberty. Furthermore, the observation that nocturnal LH was higher in age-matched, agonadal females compared with the leptin-treated females suggests that the nongonadal drive to LH secretion is operative in female macaques as early as 14 months of age, suggesting that the effect of leptin on puberty in female primates may involve a diminution in gonadal negative feedback suppression of LH secretion. Such a role would suggest that leptin is permissive yet critical for advancing female puberty.

Leptin in horses: tissue localization and relationship between peripheral concentrations of leptin and body condition.

Obesity has been a major concern in the horse industry for many years, and the recent discovery of leptin and leptin receptors in numerous nonequine species has provided a basis for new approaches to study this problem in equine. The objectives were to: 1) clone a partial sequence ofthe equine leptin and leptin receptor genes so as to enable the design of primers for RT-PCR determination of leptin and leptin receptor gene presence and distribution in tissues, 2) develop a radioimmunoassay to quantify peripheral concentrations of leptin in equine, 3) determine if peripheral concentrations of leptin correlate with body condition scores in equine, and 4) determine if changing body condition scores would influence peripheral concentrations of leptin in equine. In Experiment 1, equine leptin (GenBank accession number AF179275) and the long-form of the equine leptin receptor (GenBank accession number AF139663) genes were partially sequenced. Equine leptin receptor mRNA was detected in liver, lung, testis, ovary, choroid plexus, hypothalamus, and subcutaneous adipose tissues using RT-PCR. In Experiment 2, 71 horses were categorized by gender, age, and body condition score and blood samples were collected. Sera were assayed for leptin using a heterologous leptin radioimmunoassay developed for equine sera. Serum concentrations of leptin increased in horses with body condition score (1 = thin to 9 = fat; r = 0.64; P = 0.0001). Furthermore, serum concentrations of leptin were greater in geldings and stallions than in mares (P = 0.0002), and tended to increase with age of the animal (P = 0.08). In Experiment 3, blood samples, body weights, and body condition scores were collected every 14 d from 18 pony mares assigned to gain or lose weight over a 14-wk interval based on initial body condition score. Although statistical changes (P = 0.001) in body condition scores were achieved, congruent statistical changes in peripheral concentrations of leptin were not observed, likely due to the small range of change that occurred. Nonetheless, serum concentrations of leptin tended to be greater in fat-restricted mares than in thin-supplemented mares (P = 0.09). We conclude that leptin and leptin receptors are present in equine tissues and that peripheral concentrations of leptin reflect a significant influence of fat mass in equine.

Leptin in Pregnancy

Leptin is a polypeptide hormone that aids in the regulation of body weight and energy homeostasis and is linked to a variety of reproductive processes in both animals and humans. Thus, leptin may help regulate ovarian development and steroidogenesis and serve as either a primary signal initiating puberty or as a permissive regulator of sexual maturation. Perhaps significantly, peripheral leptin concentrations, adjusted for adiposity, are dramatically higher in females than in males throughout life. During primate pregnancy, maternal levels that arise from adipose stores and perhaps the placenta increase with advancing gestational age. Proposed physiological roles for leptin in pregnancy include the regulation of conceptus growth and development, fetal/placental angiogenesis, embryonic hematopoiesis, and hormone biosynthesis within the maternal-fetoplacental unit. The specific localization of both leptin and its receptor in the syncytiotrophoblast implies autocrine and/or paracrine relationships in this endocrinologically active tissue. Interactions of leptin with mechanisms regulating pre-eclampsia and maternal diabetes have also been suggested. Collectively, therefore, reports suggest that a better understanding of the regulation of leptin and its role(s) throughout gestation may eventually impact those causes of human perinatal morbidity and mortality that are exacerbated by intrauterine growth retardation, macrosomia, placental insufficiency, or prematurity.

Serum leptin concentrations and expression of leptin transcripts in placental trophoblast with advancing baboon pregnancy.

Leptin is a polypeptide hormone originally thought to be produced exclusively by adipocytes. Recently, however, both leptin messenger ribonucleic acid (mRNA) and leptin protein were identified in human placental trophoblast cells, suggesting a potential role in primate pregnancy. In the present study, venous blood samples were collected at 5-day intervals during gestation from baboons (Papio sp), an established model for the study of human pregnancy, as well as from nonpregnant baboons, and leptin concentrations were determined by RIA. Additionally, placental villous tissue was collected upon cesarean delivery at early (days 60-62; n = 5), mid (days 98-102; n = 5), and late (days 159-167; n = 5) gestation (term = approximately 184 days), and leptin mRNA was quantitated by competitive RT-PCR. Finally, in situ hybridization was employed to localize transcripts to specific placental cell types. Results determined that maternal leptin levels (mean +/- SEM), which were dramatically greater (P<0.01) than those in nonpregnant cycling baboons (1.4+/-0.1 ng/mL), increased (P<0.005) with gestational age from 63.6+/-10.4 ng/mL on day 60 of gestation to 157.8+/-16.1 near term. Levels declined to those found in cycling baboons by 15 days postdelivery. In contrast to maternal leptin concentrations, placental leptin mRNA decreased (P<0.02) with advancing pregnancy, as transcript abundance declined approximately 8-fold from early to late gestation. Maternal peripheral leptin concentrations were positively correlated (r = 0.66; P<0.001) whereas placental leptin mRNA levels were negatively correlated (r = -0.64; P<0.01) with gestational age. Expression of leptin mRNA transcripts, as evidenced by RT-PCR in villous tissue, was localized principally within syncytiotrophoblast by in situ hybridization. In summary, changes in maternal peripheral leptin concentrations and placental leptin mRNA abundance that occur commensurate with advancing gestational age may imply evolving roles for the polypeptide with advancing primate pregnancy. In this capacity, localization of leptin transcripts within the baboon syncytiotrophoblast suggests the potential for autocrine or paracrine interactions within this endocrinologically active tissue. Finally, both the similarities in leptin ontogeny in baboon and human pregnancy and the singular enhancement of maternal leptin levels inherent throughout baboon gestation emphasize the potential of this nonhuman primate model for the study of leptin action in the maternal-fetoplacental unit.

Leptin

Leptin is an adipocyte hormone that signals nutritional status to the central nervous system (CNS) and peripheral organs. Leptin is also synthetized in the placenta and in gastrointestinal tract, although its role in these tissues is not yet clear. Circulating concentrations of leptin exhibit pulsatility and circadian rhythmicity. The levels of plasma leptin vary directly with body mass index and percentage body fat, and leptin contributes to the regulation of body weight. Leptin plasma concentrations are also influenced by metabolic hormones, sex, and body energy requirements. Defects in the leptin signaling pathway result in obesity in animal models. Only a few obese humans have been identified with mutations in the leptin gene or in the leptin receptor; however, most cases of obesity in humans are associated with high leptin levels. Thus, in humans obesity may represent a state of leptin resistance. Minute-to-minute fluctuations in peripheral leptin concentrations influence the activity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes, indicating that leptin may be a modulator of reproduction, stress-related endocrine function, and behavior. This suggests potential roles for leptin or its antagonists in the diagnosis, pathophysiology and treatment of several human diseases.