Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat.

Intracerebroventricular (ICV) administration of the hypothalamic neuropeptide neuromedin U (NMU) or the adipostat hormone leptin increases plasma ACTH and corticosterone. The relationship between leptin and NMU in the regulation of the hypothalamo-pituitary adrenal (HPA) axis is currently unknown. In this study, leptin (1 nM) significantly increased the release of CRH from ex vivo hypothalamic explants by 207 ± 8.4% (P < 0.05 vs. basal), an effect blocked by the administration of anti-NMU IgG. The ICV administration of leptin (10 μg, 0.625 nmol) increased plasma ACTH and corticosterone 20 min after injection [plasma ACTH (picograms per milliliter): vehicle, 63 ± 20, leptin, 135 ± 36, P < 0.05; plasma corticosterone (nanograms per milliliter): vehicle, 285 ± 39, leptin, 452 ± 44, P < 0.01]. These effects were partially attenuated by the prior administration of anti-NMU IgG. Peripheral leptin also stimulated ACTH release, an effect attenuated by prior ICV administration of anti-NMU IgG. We examined the diurnal pattern of hypothalamic NMU mRNA expression and peptide content, plasma leptin, and plasma corticosterone. The diurnal changes in hypothalamic NMU mRNA expression were positively correlated with hypothalamic NMU peptide content, plasma corticosterone, and plasma leptin. The ICV administration of anti-NMU IgG significantly attenuated the dark phase rise in corticosterone [corticosterone (nanograms per milliliter): vehicle, 493 ± 38; NMU IgG, 342 ± 47 (P < 0.05)]. These studies suggest that NMU may play a role in the regulation of the HPA axis and partially mediate leptin-induced HPA stimulation. Copyright © 2006 by The Endocrine Society

Effects of methamphetamine on locomotor activity and thalamic gene expression in leptin-deficient obese mice

Leptin is an adipose-derived hormone that regulates energy balance. Leptin receptors are expressed in extrahypothalamic sites and several reports showed that leptin can influence feeding and locomotor behavior via direct actions on dopaminergic neurons. The leptin deficient mouse (ob/ob) has been used as an animal model of blunted leptin action, and presents with obesity and mild type 2 diabetes. We used ob/ob mice to study the effect of repeated 7-day methamphetamine (METH) administration analyzing locomotion, behavioral sensitization, and somatosensory thalamic mRNA expression of voltage-gated calcium channels and glutamatergic receptors using RT-PCR. We observed reduced METH-mediated responses in ob/ob mice associated with enhanced in mRNA expression of key voltage-gated and glutamate receptors in the somatosensory thalamus. Results described here are important for understanding the control of locomotion and thalamocortical excitability by leptin.Fil: Gonzalez, Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gonzalez, Candela Rocio. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Effects of physical exercise on adiponectin, leptin, and inflammatory markers in childhood obesity: systematic review and meta-analysis

Background: New findings on adipose tissue physiology and obesity-Associated inflammation status suggest that modification of the adipokine level can be relevant for the long-Term prevention of obesity-Associated chronic disease. Objectives: The scope of the present study was to investigate the effectiveness of physical exercise in reducing the systemic inflammation related to obesity in children. Methods: We conducted a systematic review with meta-Analysis of controlled randomized trials, identified through electronic database search, which investigated the effect of physical exercise, without concomitant dietary intervention, on adiponectin, leptin, and/or other inflammatory markers in children up to age 18 years with a body mass index greater than the 95th percentile for age and sex. Results: Seven trials were included in the meta-Analysis, with a total of 250 participants. Compared with the control group without any lifestyle modification, the physical exercise resulted in a reduction in leptin [standardized mean difference (SMD)-1.13; 95% confidence interval (95%CI):-1.89 to-0.37; I2 = 79.9%] and interleukin-6 (SMD-0.84; 95%CI:-1.45 to-0.23, I2 = 0.9%) and an increase in adiponectin plasma concentration (SMD 0.69; 95%CI: 0.02-1.35; I2 = 74.3%). Conclusions: These results indicate that physical exercise improved the inflammatory state in children with obesity. It is unclear whether this effect can reduce the risk of cardiovascular and metabolic disease in adulthood. Clinical trials with a uniform intervention protocol and outcome measurements are required to put our knowledge on adipose tissue biology into a clinical perspective

Obesity Induces Hypothalamic Endoplasmic Reticulum Stress and Impairs Proopiomelanocortin (POMC) Post-translational Processing

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide -melanocyte-stimulating hormone ( -MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to -MSH, thereby decreasing -MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.Fil: Cakir, Isin. Brown University; Estados UnidosFil: Cyr, Nicole E.. Brown University; Estados UnidosFil: Perello, Mario. Brown University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Litvinov, Bogdan Patedakis. Brown University; Estados UnidosFil: Romero, Amparo. Brown University; Estados UnidosFil: Stuart, Ronald C.. Brown University; Estados UnidosFil: Nillni, Eduardo A.. Brown University; Estados Unido

The Bidirectional Relationship Between Obstructive Sleep Apnea and Metabolic Disease

Obstructive sleep apnea (OSA) is a common sleep disorder, effecting 17% of the total population and 40–70% of the obese population (1, 2). Multiple studies have identified OSA as a critical risk factor for the development of obesity, diabetes, and cardiovascular diseases (3–5). Moreover, emerging evidence indicates that metabolic disorders can exacerbate OSA, creating a bidirectional relationship between OSA and metabolic physiology. In this review, we explore the relationship between glycemic control, insulin, and leptin as both contributing factors and products of OSA. We conclude that while insulin and leptin action may contribute to the development of OSA, further research is required to determine the mechanistic actions and relative contributions independent of body weight. In addition to increasing our understanding of the etiology, further research into the physiological mechanisms underlying OSA can lead to the development of improved treatment options for individuals with OSA

Interaction between neonatal maternal deprivation and serum leptin levels on metabolism, pubertal development, and sexual behavior in male and female rats

Background: Maternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently. We previously reported that MD during 24 h at postnatal day (PND) 9 blocks the physiological neonatal leptin surge in both sexes. It is known that modifications in neonatal leptin levels can affect metabolism in adulthood. Thus, we hypothesized that at least some of the long-term metabolic changes that occur in response to MD are due to the decline in serum leptin during this critical period of development. Hence, we predicted that treatment with leptin during MD would normalize these metabolic changes, with this response also differing between the sexes. Methods: MD was carried-out in Wistar rats for 24 h on PND9. Control and MD rats of both sexes were treated from PND 9 to 13 with leptin (3 mg/kg/day sc) or vehicle. Weight gain, food intake, glucose tolerance, and pubertal onset were monitored. Sexual behavior was analyzed in males. Rats were killed at PND90, and serum hormones and hypothalamic neuropeptides involved in metabolic control and reproduction were measured. Results were analyzed by three-way analysis of covariance using sex, MD, and leptin treatment as factors and litter as the covariate and employing repeated measures where appropriate. Results: In males, MD advanced the external signs of puberty and increased serum insulin and triglyceride levels and hypothalamic proopiomelanocortin mRNA levels at PND90. Neonatal leptin treatment normalized these effects. In contrast, MD decreased circulating triglycerides, as well as estradiol levels, in females at PND90 and these changes were also normalized by neonatal leptin treatment. Neonatal leptin treatment also had long-term effects in control rats as it advanced the external signs of puberty in control males, but delayed them in females. Neonatal leptin treatment increased serum insulin and hypothalamic mRNA levels of the leptin receptor and cocaine- and amphetamine-regulated transcript in control males and increased orexin mRNA levels in controls of both sexes. Although pubertal onset in males was advanced by either MD or neonatal leptin treatment in males and delayed by leptin treatment in females, the mRNA levels of hypothalamic neuropeptides and receptors related to reproduction were not affected by MD or neonatal leptin treatment in either sex at PND90. Conclusions: These findings indicate that some of the long-term changes in metabolic and reproductive parameters induced by MD, such as advanced pubertal onset and increased hypothalamic proopiomelanocortin (POMC) expression, hyperinsulinemia, and hypertriglyceridemia in adult males and decreased serum triglyceride and estradiol levels in females, are most likely due to the decrease in leptin levels during the period of MD

The effects of graded levels of calorie restriction : II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice

This work was supported by BBSRC BB009953/1 awarded to JRS and SEM. PK and CD were funded by the Erasmus exchange programme. JRS, SEM, DD, CG, LC, JJDH, YW, DELP, DL and AD are members of the BBSRC China Partnership Award, BB/J020028/1.Peer reviewedPublisher PD

Alterations in Lipids and Adipocyte Hormones in Female-to-Male Transsexuals

Testosterone therapy in men and women results in decreased high-density lipoprotein cholesterol (HDL) and increased low-density lipoprotein cholesterol (LDL). We sought to determine whether testosterone therapy has this same effect on lipid parameters and adipocyte hormones in female-to-male (FTM) transsexuals. Twelve FTM transsexuals provided a fasting lipid profile including serum total cholesterol, HDL, LDL, and triglycerides prior to and after 1 year of testosterone therapy (testosterone enanthate or cypionate 50–125mg IM every two weeks). Subjects experienced a significant decrease in mean serum HDL (52 ± 11 to 40 ± 7mg/dL) (P < .001). The mean LDL (P = .316), triglyceride (P = .910), and total cholesterol (P = .769) levels remained unchanged. In a subset of subjects, we measured serum leptin levels which were reduced by 25% but did not reach statistical significance (P =.181) while resistin levels remained unchanged. We conclude that testosterone therapy in FTM transsexuals can promote an increased atherogenic lipid profile by lowering HDL and possibly reduce serum leptin levels. However, long-term studies are needed to determine whether decreases in HDL result in adverse cardiovascular outcomes.National Institutes of Health (M01RR000533

The effects of graded levels of calorie restriction : III. Impact of short term calorie and protein restriction on mean daily body temperature and torpor use in the C57BL/6 mouse

GRANT SUPPORT This work was supported by BBSRC BB009953/1 awarded to JRS and SEM. PK and CD were funded by the Erasmus exchange programme. JRS, SEM, DD, CG, LC, JJDH, YW, DELP, DL and AD are members of the BBSRC China Partnership Award, BB/J020028/1.Peer reviewedPublisher PD