Central Effects Of Leptin Research Articles

The nutrient sensing pathways FoxO1/3 and mTOR in the heart are coordinately regulated by central leptin through PPARβ/δ. Implications in cardiac remodeling

BackgroundCardiovascular disease in obese individuals with type 2 diabetes is often associated with hyperleptinemia and leptin resistance, while other studies support that leptin has cardioprotective effects. Besides, the role of leptin in regulating cardiac atrophy or hypertrophy remains to be clearly defined. In fact, in rats with normal leptin sensitivity, the molecular underpinnings of the effects of central leptin regulating cardiac structural pathways remain poorly understood. ObjectiveHence, we assessed the effects of intracerebroventricular (icv) leptin infusion on cardiac remodeling analyzing FOXO1/3 and mTORC1 pathways, focusing special attention to PPARβ/δ as mediator of central leptin's effects on cardiac metabolism. MethodsMale 3-months-old Wistar rats, infused with icv leptin (0.2 μg/day) for 7 days, were daily co-treated intraperitoneally with the specific PPARβ/δ antagonist GSK0660, at 1 mg/kg per day along leptin treatment. ResultsCentral leptin regulated dynamically, in an opposite manner, the network between FOXOs and mTORC1 and induced an atrophy-related gene program in cardiac tissue. Leptin activated the anti-hypertrophic kinase GSK3β and increased the protein levels of muscle-specific ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/Atrogin-1 involved in limiting cardiac hypertrophy. FOXO1 activity and the expression of their target genes, Sod2 and Lpl, were also increased in the heart upon central leptin infusion. Besides, Beclin-1 and LC3B-II, gene products of the autophagic pathway response, were upregulated, while the content and expression levels of phenotypic markers of cardiac hypertrophy as ANP and β-myosin heavy chain, gene product of Myh7 were significantly decreased. On the other hand, mTORC1 activity and OXPHOS protein levels were decreased suggesting a key role of central leptin preventing cardiac oxidative stress. In fact, the content of carbonylated proteins, TBARS and ROS/RSN were not increased in cardiac tissue in response to central leptin infusion. Finally, the pharmacological inhibition of PPARβ/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3, Atrogin-1, MuRF1 and GSK3β in the heart mediated by icv leptin infusion. ConclusionsOur results demonstrate that, in lean rats with normal leptin sensitivity, central leptin regulates nutrient sensing pathways in heart contributing to balance cardiac remodeling through the anti- and pro-hypertrophic programs, and in this process is involved PPARβ/δ.

SUN-570 The Crosstalk Between Central Leptin and PPARbeta/delta Protects the Heart Against Oxidative Stress Damage and the Development of Hypertrophy

Cardiovascular disease is a common cause of morbidity and mortality in obese people with type 2 diabetes, which is often associated with increased levels of leptin. While many studies hint at the existence of important roles for both hyperleptinemia and leptin resistance in obesity and diabetes-associated cardiovascular disease, others support that leptin has cardioprotective effects. Leptin action comprises direct effects on cardiac tissue and indirect effects mediated via the sympathetic nervous system. Since the molecular underpinnings of leptin-regulated pathways in cardiac tissue in normoleptinemic animals remain less well defined, we addressed the effects of central leptin infusion on cardiac function and remodeling analyzing FOXO1/3 and mTORC1 pathways, paying special attention to PPARβ/δ as a key leptin signal regulator. We found that central leptin regulated dynamically the network between PPARβ/δ, FOXOs, and mTORC1 in cardiac tissue, through antioxidant, thermogenic and autophagy programs. Intracerebroventricular (ICV) leptin infusion (0.2µg/day) for 7 days in male 3-months-old Wistar rats induced protection from hypertrophy without increasing TBARS and protein carbonylation nor ROS/RSN cardiac levels. These effects were further supported by both increased of Sod2 and Ucp1 expression and reduced Tnf-α. Atrophy-related ubiquitin ligase Atrogin-1, accompanied by Beclin-1 and LC3II, gene products of the autophagic pathway response, were all upregulated by central leptin. In addition, mTORC1 activity and OXPHOS protein levels were decreased without affecting cellular function. Moreover, the content of carbonylated proteins did not increase upon the central leptin treatment, suggesting a key role of leptin in preventing cardiac oxidative stress. Finally, the pharmacological inhibition of PPARβ/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3 and Atrogin-1 in the heart mediated by icv leptin infusion. Together these data support that PPARβ/δ may act as a mediator of central leptin effects on cardiac cellular reprogramming through the activation of FOXO1/3 and the inactivation of mTORC1 pathways, and the upregulation of Atrogin-1 and the genes involved in energy uncoupling.

Central Effects of Leptin on Glucose Homeostasis are Modified during Pregnancy in the Rat

Despite increased leptin concentrations during pregnancy, fat mass and food intake are increased. The satiety response to central leptin is suppressed, indicating a state of leptin insensitivity in the hypothalamus. Although the regulation of food intake is a major function of leptin, this hormone also influences a wide range of functions within the body. These actions include the regulation of glucose homeostasis, which undergoes major adaptation in the maternal body to generate optimal conditions for foetal development and growth. The present study aimed to investigate the effects of central leptin treatment on glucose homeostasis in pregnant rats to determine whether pregnancy-induced leptin insensitivity is functionally specific, and to further investigate changes in glucose homeostasis during pregnancy. After an overnight fast, nonpregnant and day 14 pregnant rats received an i.c.v. injection of leptin (100ng or 4μg) or vehicle then underwent a glucose tolerance test (GTT). Further groups of nonpregnant and day 14 pregnant rats were killed 30min after leptin (doses ranging from 40ng-4μg) or vehicle i.c.v. injections for western blot analysis of phospho-signal transducer and activator of transcription 3 (STAT3) and phospho-Akt in various hypothalamic nuclei. Central leptin injection prior to a GTT lead to lowered basal insulin concentrations and impaired glucose tolerance in nonpregnant female rats, whereas the same doses of leptin had no significant effect on glucose tolerance in day 14 pregnant rats, indicating that, similar to the satiety actions of leptin, the effects of leptin on glucose homeostasis are suppressed during pregnancy. Furthermore, in the arcuate nucleus and ventromedial and dorsomedial nuclei of the hypothalamus, comprising three leptin-sensitive areas, there was no evidence that leptin induced Akt phosphorylation despite significant increases in phospho-STAT3, suggesting that leptin does not act through phospho-Akt in these areas in female rats.

Male gonadal axis function in patients with type 2 diabetes.

Patients with type 2 diabetes have lower serum testosterone levels and a higher prevalence of hypogonadism than non-diabetic patients, independently of the metabolic control of disease. The mechanisms underlying a decrease in testosterone might be related to age, obesity and insulin resistance, often present in patients with type 2 diabetes. The increase in estrogens due to higher aromatase enzyme activity in increased adipose tissue might exert negative-feedback inhibition centrally. Insulin stimulates gonadal axis activity at all three levels and therefore insulin resistance might account for the lower testosterone production. Leptin exerts a central stimulatory effect but inhibits testicular testosterone secretion. Thus, resistance to leptin in obese subjects with type 2 diabetes determines lower central effects of leptin with lower gonadotropin-releasing hormone (GnRH) secretion and, on the other hand, hyperleptinemia secondary to leptin resistance inhibits testosterone secretion at the testicular level. However, lower testosterone levels in patients with diabetes are observed independently of age, weight and body mass index, which leads to the assumption that hyperglycemia per se might play a role in the decrease in testosterone. Several studies have shown that an overload of glucose results in decreased serum testosterone levels. The aim of this review is to assess changes in the male gonadal axis that occur in patients with type 2 diabetes.

Abstract 12582: The Origin of Hypertension and Sympathetic Regulation in Diet Induced Obesity

Obesity is closely associated with a greater risk of developing hypertension and there is a strong link between bodyweight gain and greater blood pressure (BP). Plasma leptin levels correlate with BP and renal sympathetic nerve activity (RSNA). The central effects of leptin are mediated primarily through the arcuate (ARC) nucleus of the hypothalamus from which peripheral signals are relayed downstream, to other hypothalamic nuclei, via a network of second order neurons. Dense projections of both Neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (α-MSH) containing neurons ascend from the ARC and terminate in several hypothalamic nuclei such as the ventromedial hypothalamus (VMH) which are the key centres of energy homeostasis, hemodynamics and sympathetic tone to brown adipose and renal vasculature. It is therefore possible that a change in the activity of either POMC or, NPY neurons or both may underlie the mechanism by which sympathetic output is increased in obesity, leading to hypertension. In the present study we assessed the contribution of α-MSH and NPY neurons in the VMH on development of diet-induced neurogenic hypertension. New Zealand White rabbits were instrumented with a VMH cannula and a renal sympathetic nerve electrode. Blood pressure (BP) was measured by means of an intra-arterial catheter. Rabbits were injected with α-MSH, SHU9119 (MC3/4R antagonist), NPY or Leptin receptor antagonist into the VMH, 60 minutes apart using an injector. Following 3 weeks of a high fat diet (HFD, 13.5% fat), conscious rabbits had higher BP (+7.6 ± 0.5mmHg, P<0.001) and RSNA (+4.6 ± 0.4nu, P<0.001) compared to control group (3.5% fat). α-MSH injection into the VMH increased BP (+7%) and RSNA (+35%) (P<0.001) and SHU9119 injection showed reduction (P<0.05) in BP (-7%), HR (-5%) and RSNA (-23%) in HFD rabbits. Leptin antagonist or NPY injection showed dose dependant reduction in BP (-7%), HR (-5%) and RSNA (-11%) (P<0.05) when given to HFD rabbits. NPY injection reduced BP in all groups. We conclude that the HFD feeding may induce pathway-specific changes in the VMH and VMH is the likely origin of leptin-mediated sympathoexcitation, α-MSH hypersensitivity and altered central responsiveness to NPY.

Teasaponin improves leptin sensitivity in the prefrontal cortex of obese mice.

Obesity impairs cognition, and the leptin-induced increase of brain-derived neurotrophic factor (BDNF) and neurogenesis. Tea consumption improves cognition and increases brain activation in the prefrontal cortex. This study examined whether teasaponin, an active ingredient in tea, could improve memory and central leptin effects on neurogenesis in the prefrontal cortex of obese mice, and in vitro in cultured prefrontal cortical neurons. Teasaponin (10 mg/kg, intraperitoneal) for 21 days improved downstream leptin signaling (JAK2 and STAT3), and leptin's effect on BDNF, in the prefrontal cortex of high-fat diet (HFD) fed mice. Prefrontal cortical neurons were cultured with teasaponin and palmitic acid (the most abundant dietary saturated fatty acid) to examine their effects on neurogenesis and BDNF expression in response to leptin. Palmitic acid decreased leptin's effect on neurite outgrowth, postsynaptic density protein 95, and BDNF expression in cultured cortical neurons, which was reversed by teasaponin. Teasaponin improved the leptin sensitivity of prefrontal cortical neurons in obese mice or when treated by palmitic acid. This in turn increased BDNF expression and neurite growth. Therefore, teasaponin supplementation may be used to prevent obesity-associated neurodegeneration and improve cognitive function.

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

Alzheimer's disease is the leading cause of dementia and the most prevalent neurodegenerative disease. It is an aging-related multi-factorial disorder and growing evidence support the contribution of metabolic factors to what was formerly thought to be a centrally mediated process. Obesity has already been recognized as an important player in the pathogenesis of this type of dementia, independently of insulin resistance or other vascular risk factors. Although the exact underlying mechanisms are still unknown, adipocyte dysfunction and concomitant alteration in adipocyte-derived protein secretion seem to be involved, since these adipocytokines can cross the blood-brain barrier and influence cognitive-related structures. Very few studies have assessed the role of adipocytokines dysfunction on cognitive impaired patients and yielded contradictory results. Interestingly, extensive research on the central effects of leptin in Alzheimer's disease-transgenic mice has demonstrated its capacity to enhance synaptic plasticity and strength, as well as to prevent beta-amyloid deposition and tau phosphorylation. In addition, adiponectin, the most abundant adipocytokine whose levels are inversely correlated to adiposity, has shown to be neuroprotective to hippocampal cells. Many other adipose-derived cytokines have mainly pro-inflammatory properties, being able to trigger and/or enhance central inflammatory cascades and also to influence the secretion of other adipocytokines involved in cognition. This paper pretends to review the existing evidence on the contribution of adipocytokines dysfunction to the increased risk of dementia associated with mid-life obesity, unraveling its insulin-independent effects on cognition.

Interaction Between Energy Homeostasis and Reproduction: Central Effects of Leptin and Ghrelin on the Reproductive Axis

Reproductive maturation and function are sensitive to the metabolic state of the organism and the magnitude of body fuel reserves; hence, conditions ranging from energy insufficiency to morbid obesity impact the timing of puberty and are frequently linked to fertility problems. This phenomenon is the result of the close interplay between a diversity of nutritional cues and metabolic signals (including hormones) with different elements of the so-called hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will focus our attention on the 'reproductive' roles of 2 key metabolic hormones, namely, the adipose signal, leptin, and the gut hormone, ghrelin. These 2 factors, which have been proposed to operate as functional antagonists in the control of metabolism and energy homeostasis, are also provided with important, and in many cases opposite, roles in the regulation of puberty onset and gonadal function. We will provide herein an update view of the reproductive effects of leptin and ghrelin, with a major emphasis on the actions of these 2 key hormones upon the central elements of the HPG axis, including their putative effects on Kiss1 and other reproductive neuronal networks. This will help to understand the mechanisms whereby reproductive function is gated and dynamically regulated by metabolic signals at different key developmental stages, such as puberty and adulthood.

A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis

Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells. The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice. The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin. Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.

Lateral hypothalamic serotonin is not stimulated during central leptin hypophagia

Whether leptin targets the hypothalamic serotonergic system to inhibit food intake is not established. We examined the effect of a short-term i.c.v. leptin treatment on serotonin microdialysate levels in rat lateral hypothalamus. Adipose tissue gene expression was also evaluated.Male rats received four daily injections of leptin (5μg) or vehicle (with pair-feeding to leptin-induced intake) and a fifth injection during collection of LH microdialysates. We found that serotonin and 5-HIAA levels were not affected by the leptin pre-treatment, as basal levels were similar between the leptin and the pair-fed group. These levels remained unaltered after the acute leptin injection.For gene expression studies, rats were pre-treated with five daily injections of either leptin (5μg) or vehicle (with either pair-feeding or ad libitum intake). mRNA levels of resistin, adiponectin, lipoprotein lipase, and PPAR-gamma were unaltered by either leptin or pair-feeding. Leptin gene expression was significantly reduced by leptin but not by pair-feeding, in both the retroperitoneal (−74%) and the epididymal (−99%) depots while no differences were observed in the subcutaneous depot.The observations confirmed the absence of an acute stimulatory effect of central leptin on serotonin release in the lateral hypothalamus and showed that the pre-treatment with leptin failed to modify this pattern. This indicates that components of the serotonergic system are probably not directly affected by leptin. Additionally, the central effect of leptin was able to downregulate its own adipose tissue gene expression in a depot-specific manner while other adipokine genes were not affected.

Ten years of leptin replacement therapy

Leptin is a pleiotropic cytokine-like hormone that is involved in the regulation of energy intake and expenditure, neuroendocrine function, immunity and lipid and glucose metabolism. The few humans with genetically based leptin deficiency provide a unique model to assess those effects. We have identified five Turkish patients (one male and two female adults; one boy and one girl) with congenital leptin deficiency due to a missense mutation in the leptin gene. Four of these patients were treated with physiological doses of recombinant methionyl human leptin. Body composition, brain structure and function, behaviour, immunity and endocrine and metabolic parameters were evaluated before and during treatment. Our results showed that leptin has peripheral, hypothalamic and extra-hypothalamic effects. Within the endocrine system, leptin regulates the circadian rhythms of cortisol, thyroid-stimulating hormone, luteinizing hormone and follicle-stimulating hormone. In the brain, leptin controls energy balance and body weight, and plays a role on neurogenesis and brain function. Leptin is a key element of the adiposinsular axis, enhances immune response, and regulates inflammation, coagulation, fibrinolysis and platelet aggregation. Our 10-year experience in treating these unique patients provided valuable data on the peripheral and central effects of leptin. Those results can be taken into account for the development of leptin-based therapies for other diseases.

Chronic central leptin infusion differently modulates brain and liver insulin signaling

Recent studies reported the impact of leptin on peripheral insulin sensitivity and glucose utilization. However, little is known concerning the effect of central leptin on hypothalamic and hepatic insulin efficiency. This study aimed to determine the consequence of chronic intra-cerebroventricular (ICV) leptin or murine leptin antagonist (MLA) infusion on hypothalamic and hepatic insulin signaling pathways, in rats. A 2-week central leptin infusion enhanced insulin-dependent Akt phosphorylation in the liver without changing PTP-1B protein expression, associated to insulin receptor (IR) upregulation and reduced IRS-1 phosphorylation on Ser302 residue. In the hypothalamus, a chronic ICV leptin infusion induced PTP-1B associated with a specific decrease in insulin-dependent Akt phosphorylation. In contrast, a chronic MLA infusion did not alter IR and PTP-1B expressions in hypothalamus and liver. Our results underline a brain leptin-dependent increase in hepatic insulin efficiency as mirrored by IR up-regulation, increased insulin-dependent Akt phosphorylation and reduced IRS-1 phosphorylation on Ser302 residue.

Hepatic Gene Expression Profiling Reveals Key Pathways Involved in Leptin-Mediated Weight Loss in ob/ob Mice

BackgroundLeptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.Methodology/Principal FindingsWe utilized microarray technology to compare hepatic gene expression changes after two types of leptin administration: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.Conclusions/SignificanceIn this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.

Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected Into Medial Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues

OBJECTIVEThe medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues.RESEARCH DESIGN AND METHODSLeptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[3H]deoxy-d-glucose method.RESULTSLeptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect.CONCLUSIONSThe VMH mediates leptin- and MT-II–induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II–induced glucose uptake in peripheral tissues.

A Case of Pseudopseudohypoparathyroidism with Normal Stature

Pseudopseudohypoparathyroidism (PPHP) is characterized by the phenotype of Albright hereditary osteodystrophy (AHO) alone without biochemical evidence of multihormone resistance, which is unlike pseudohypoparathyroidism. AHO is associated with characteristic developmental abnormalities that include a short stocky stature, a short neck, brachydactyly, a round face, central obesity, mental retardation and subcutaneous ossifications. AHO is an autosomal dominant disease that’s caused by heterozygous inactivating mutations in the Gsα gene (GNAS1). Melanocortin-4 receptor (MC4R) is a hypothalamic Gs-coupled receptor that is thought to mediate the central effect of leptin on satiety. MC4R mutations cause morbid obesity starting in infancy, as well as an elevated leptin level. A 62 year old man with a height of 171.5 cm, a round face, a short neck, central obesity and brachydactyly had normal ranges of serum calcium, phosphorus and PTH and a normal Ellsworth-Howard test. GNAS1 gene analysis revealed substitution of alanine to cysteine in the 165 codon of exon 6 and substitution of alanine to cysteine in the 231 codon of exon 9. Two known SNPs (Cyt-1042Thy, Gua-719Ade) in the MC4R were detected in the patient. We report here on a case of PPHP and the patient had normal stature. We propose that MC4R may have contributed to the obesity & normal

The Effect of Leptin on Bone - an Evolving Concept of Action

Leptin, a cytokine-like hormone secreted by adipocytes, is known to regulate food intake but has also emerged as a significant factor in the regulation of bone mass. In humans, states of energy deprivation with low serum leptin have been associated with low bone mass. In mice, leptin deficiency led to increased trabecular bone mass with overall decrease in cortical bone. Leptin regulates bone metabolism indirectly in the hypothalamus thereby activating the sympathetic nervous system (SNS). In addition to the SNS, leptin also interacts with various hypothalamic neuropeptides, such as cocaine- and amphetamine-regulated transcript, neuropeptide Y and/or neuromedin U, which might modulate the effects of leptin on bone. In osteoblasts sympathetic signaling is further gated by the transcriptional factors called molecular clock. As a result, bone loss is accelerated showing that the central effect of leptin seems to be antiosteogenic. Additionally, leptin has a direct anabolic effect within the bone driving the differentiation of bone marrow stem cells into the osteoblastic cell lineage. Besides the interaction between the central and peripheral pathways, the overall effect of leptin on bone might be bimodal depending on leptin serum concentrations. Regulatory pathways triggering osteoblast activity might open new possibilities for anabolic treatment of osteoporosis.

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.

Leptin Signaling in the Central Nervous System and the Periphery

The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.

Peripheral actions of leptin and its involvement in disease.

The discovery of leptin is broadening our understanding of the mechanisms underlying neuroendocrine function. To date, most investigations have focused on the effects of leptin on food intake control and body weight homeostasis with attention primarily focused on the central effects of leptin. However, the almost ubiquitous distribution of leptin receptors in peripheral tissues provides a fertile area for investigation and a more dynamic view of leptin is starting to unfold. Thus, leptin has generated enormous interest in the interaction as well as integration between brain targets and peripheral signals. The scientific evidence supporting the direct peripheral effects of leptin on angiogenesis, wound healing, lipolysis, blood pressure homeostasis, and satiety control is reviewed.

Central leptin stimulates ingestive behavior and urine flow in the near term ovine fetus.

Leptin inhibits ingestive behavior and induces diuresis and natriuresis. To examine whether leptin influences fetal physiologic functions, we investigated the effect of central leptin on ovine fetal swallowing activity and urine flow. Six pregnant ewes with singleton fetuses (130 +/- 2 d gestation) were prepared with maternal and fetal arterial and venous catheters, fetal lateral intra-ventricle cannula, fetal bladder and amniotic fluid catheters. Electromyogram wires were placed in the fetal thyrohyoid muscle and upper and lower nuchal esophagus and electrodes were implanted on the parietal dura. Five days after surgery, recombinant human leptin was infused into the lateral ventricle and the fetus monitored for 8 h. Central leptin increased fetal swallowing activity during low-voltage electrocortical activity from basal values (0.96 +/- 0.08 swallows/min) at 2 h (1.41 +/- 0.24 swallows/min), 4 h (2.81 +/- 0.57 swallows/min), 6 h (2.53 +/- 0.59 swallows/min) and 8 h (2.08 +/- 0.39 swallows/min, p < 0.05). In comparison to basal values, low voltage electrocortical activity decreased (57 +/- 5% to 42 +/- 4%) and high voltage electrocortical increased (43 +/- 5% to 61 +/- 4%). In response to leptin, fetal urine flow initially decreased from basal values at 2 h (0.12 +/- 0.03 to 0.08 +/- 0.02 ml/kg/min, p < 0.05) then subsequently increased at 4 h and 6 h (0.20 +/- 0.04; 0.21 +/- 0.04 ml/kg/min, respectively, p < 0.05). Central leptin significantly increases near term ovine fetal swallowing activity and urine output, suggesting that leptin contributes to in utero development of ingestive behavior.