Role of leptin in hypothalamic–pituitary function
Anna UML1997, Proceedings of the National Academy of Sciences of the United States of America
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Abstract
1028), the authors request that the following be noted. In the ''Materials and Methods'' section on page 1024, paragraph 3, line 9, the authors indicate that they used recombinant human leptin. In fact, they used recombinant murine leptin.
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Leptin is a circulating hormone secreted mainly by adipose tissue. Recent studies have shown leptin production by other tissues, including the placenta, stomach, and mammary tissues. Various reports have suggested that the anterior pituitary may have a role in the regulatory effects of leptin. We recently localized leptin in the human anterior pituitary, but analysis of leptin in rodent pituitary has not been previously reported. In this study we examined rat and mouse pituitary tissues and various cell lines for leptin by RT-PCR, immunohistochemistry, and Western blotting. Leptin receptor messenger RNA was also examined in these tissues by RT-PCR. Leptin was present in a small percentage of rat (4.8 Ϯ 0.7%) and mouse (7 Ϯ 2%) pituitary cells. Colocalization studies with leptin and pituitary hormones showed leptin expression mainly in TSH cells Anterior pituitaries obtained from female Wistar-Furth rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and female mouse pituitaries. Animals were maintained in accordance with the NIH Guide for the Care and Use of Laboratory Animals. The rat pituitary cell line GH 3 was
The effect of leptin is enhanced by microinjection into the ventromedial hypothalamus
Diabetes, 1997
To determine whether changes in food intake produced by leptin involve targeting the hormone to distinct central nervous system regions, guide cannulas were positioned stereotaxically into three brain regions-the ventromedial hypothalamus (VMH) (bilaterally, n = 6), the dorsal raphe nucleus (/i = 3), and the lateral ventricle (w = 3)-of nonobese male rats (400-500 g). Daily food intake and body weight changes were measured during twice-daily injections of saline (0.1 ul) followed by recombinant human leptin (0.05 ug) for 3 days via the brain cannulas. VMH-injected rats also were followed during a postleptin saline recovery interval. This small dose of leptin did not change food intake or body weight from that during the preceding saline injection period in ventricle-injected or dorsal raphe-injected rats. In sharp contrast, VMH-injected rats ate much less food (56 ± 8% basal) and lost 9 + 3 g/day or 5% of their body weight during 3 days of leptin administration. VMH-injected animals fully recovered from leptin-induced effects within 3 days. We conclude that small doses of leptin that do not effect eating behavior when delivered to the ventricle or the dorsal raphe (another brain region believed to regulate feeding), suppress food intake when injected into the VMH. These data suggest that the VMH or a brain region in close proximity to it is a key target for the biological actions of leptin.
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Leptin fragments induce Fos immunoreactivity in rat hypothalamus
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Systemic administration of leptin decreases plasma corticosterone levels: Role of hypothalamic norepinephrine
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Leptin, an adipocyte-derived hormone, is known to regulate a variety of neuroendocrine functions. It inhibits the hypothalamo-pituitary-adrenal axis (HPA) in several animal models, however, the exact mechanism by which it does so is not known. Since norepinephrine (NE) is a key regulator of the HPA axis, we hypothesized that leptin could suppress HPA activity by decreasing NE levels. To study this, we implanted adult male Sprague Dawley rats with both a push-pull cannula in the paraventricular nucleus (PVN) and a catheter in the jugular vein. Animals were treated with either 0 or 100 μg or 500 μg of recombinant rat leptin (Lep). Push-pull perfusion was performed from 1000-1600 h. Perfusate samples were collected every 30 min and analyzed for NE levels using HPLC-EC. Blood samples were collected every 60 min and analyzed for coticosterone (CS) levels. To further understand the role of NE in this phenomenon animals were treated with either an α-1 adrenergic agonist, phenylephrine (PHE; 0.5 mg/KgBW), an α-2 adrenergic agonist, clonidine (CLON; 0.6 mg/ Kg BW), or a β adrenergic agonist, isoproterenol (ISO; 0.2 mg/Kg BW) alone or in combination with 500 μg of Lep. Pretreatment and hourly posttreatment blood samples were collected, plasma was separated and analyzed for CS levels. Leptin administration decreased NE release in the PVN significantly by 30 min (p<0.05). It also significantly reduced plasma CS levels at 240 and 300 min (p<0.05). Administration of either PHE or CLON in combination with leptin prevented the leptininduced decrease in CS. In contrast, administration of ISO along with leptin did not prevent the leptininduced decrease in CS. These results indicate that leptin decreases hypothalamic NE and plasma corticosterone and that this effect is most probably mediated through alpha-adrenergic receptors.
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Leptin Activates Hypothalamic CART Neurons Projecting to the Spinal Cord
Neuron, 1998
This is thought to be the result of increased activity of Program in Neuroscience the sympathetic nervous system. Indeed, evidence for Harvard Medical School these physiological processes exists, as leptin adminis-Boston, Massachusetts 02215 tration increases sympathetic nerve activity (Haynes et † Department of Medicine and al., 1997), norepinephrine turnover in brown adipose tis-Division of Endocrinology sue (BAT) (Collins et al., 1996), and body temperature Beth Israel Deaconess Medical Center of ob/ob mice (Pelleymounter et al., 1995). Thus, activa-Harvard Medical School tion of sympathetic preganglionic neurons in the spinal Boston, Massachusetts 02215 cord by leptin is likely an obligate step for leptin to ‡ Yerkes Regional Primate Center regulate diverse processes, such as thermoregulation, Emory University metabolic rate, and cardiovascular status. Leptin recep-Atlanta, Georgia 30329 tors are highly localized in hypothalamic cell groups, especially in the mediobasal hypothalamus (Mercer et al., 1996; Schwartz et al., 1996; Fei et al., 1997; Elmquist Summary et al., 1998a). Therefore, it is plausible that leptin may activate sympathetic preganglionic neurons through a The adipocyte-derived hormone leptin decreases body neuronal relay originating in the hypothalamus (Loewy, weight in part by activating the sympathetic nervous 1991; Saper , 1995). Several hypothalamic cell groups system, resulting in increased thermogenesis and endirectly innervate the sympathetic preganglionic cell ergy expenditure. We investigated hypothalamic pathcolumn, including the lateral hypothalamic area, the ways underlying leptin's effects on stimulating the paraventricular nucleus (PVH), the dorsal hypothalamic sympathetic nervous system. We found that leptin acarea, and the retrochiasmatic area RCA) (Saper et al., tivates neurons in the retrochiasmatic area (RCA) and 1976; Swanson and Kuypers, 1980; Cechetto and Saper, lateral arcuate nucleus (Arc) that innervate the tho-1988; Strack et al., 1989). However, the hypothalamic racic spinal cord and also contain cocaine-and ampathways engaged by leptin that regulate sympathetic phetamine-regulated transcript (CART). We also found outflow are still unclear. that most CART-containing neurons in the RCA and Recent studies have identified several neuropeptides Arc of the hypothalamus also contain proopiomelanoresiding in the arcuate nucleus (Arc) and RCA of the cortin (POMC) mRNA. The finding that leptin activates hypothalamus as targets of leptin (Campfield et al., 1998; CART/POMC neurons innervating sympathetic pre-Woods et al., 1998). One of these is cocaine-and amganglionic neurons in the thoracic spinal cord sugphetamine-regulated transcript (CART) (Douglass et al., gests that this pathway may contribute to the in-1995), which is found throughout the CNS, including a creased thermogenesis and energy expenditure and prominent population in the Arc and the RCA (Koylu et decreased body weight observed following leptin adal., 1997, 1998). CART neurons in the Arc are regulated ministration. by leptin, as CART mRNA levels are decreased during times of low leptin, such as starvation or in ob/ob mice. Introduction This reduction in CART mRNA is reversed by leptin administration (Kristensen et al., 1998). Intracerebroven-The identification of leptin greatly increased the undertricular (icv) injection of CART peptides also inhibits standing of the pathophysiology of obesity and related feeding, including that induced by neuropeptide Y (NPY) disorders (Zhang et al., 1994). Leptin is produced by administration. Moreover, icv injections of CART-blockwhite adipose tissue and affects food intake, body ing antisera induces feeding in rats (Lambert et al., 1997, weight, neuroendocrine status, and thermogenesis. The 1998; Kristensen et al., 1998). Therefore, engagement total absence of leptin as seen in ob/ob mice causes of central CART-containing systems may underlie many obesity, diabetes, inactivity, and dysregulation of multiof the physiological effects of leptin. However, the speple neuroendocrine axes (Ahima et al., 1996; Spiegelman cific neuroanatomic pathways underlying these effects and Flier, 1996). The repletion of leptin to ob/ob mice are unknown. decreases feeding; normalizes body weight, activity lev-In addition to CART-containing systems, several other els, and body temperature; and also corrects neuroenneuropeptide systems play a role in regulating metabodocrine abnormalities (Campfield et al., 1995; Halaas et lism. Recent evidence suggests that central melanocortin receptor systems are critical in the regulation of body weight and food intake, including that mediated by leptin § To whom correspondence should be addressed: (e-mail: jelmquis@ bidmc.harvard.edu). (Fan et al.(1998a). Distributions of leptin receptor mRNA isoforms in the rat brain. . Leptin activates distinct projections from the dorsomedial References and ventromedial hypothalamic nuclei. Proc. Natl. Acad. Sci. USA 95, 741-746. A., Hruby, V.J., and Cone, R.D. atos-Flier, E., and Flier, J.S. (1996). Role of leptin in the neuroendo-(1997). Role of melanocortinergic neurons in feeding and the agouti crine response to fasting. Nature 382, 250-252. obesity syndrome. Nature 385, 165-168. . (1992). Distribution and characterization Friedman, J.M. (1997). Anatomic localization of alternatively spliced of cyclooxygenase immunoreactivity in the ovine brain. J. Comp. leptin receptors (Ob-R) in mouse brain and other tissues. . Recombinant mouse OB protein: evidence for a peripheral the sympathetic innervation of rat interscapular brown adipose tissignal linking adiposity and central neural networks. Science 269, sue via intercostal nerves. Can. Weight-reducing effects of the plasma protein encoded by the obese of the hypothalamic projection to the spinal cord in the rat. J. Comp. gene. Science 269, 543-546. Neurol. 272, 579-604. (1995). Hemodynamic regulation (1997). Receptor-mediated regional sympathetic nerve activation by of tyrosine hydroxylase messenger RNA in medullary catecholamine leptin. J. Clin. Invest. 100, 270-278. neurons: a c-fos-guided hybridization histochemical study. et al. (1997). Targeted disruption of the melanocortin-4 recep-P.E. (1993). A comparison of two immediate-early genes, c-fos and tor results in obesity in mice. Cell 88, 131-141. NGFI-B, as markers for functional activation in stress-related neuro-Jacobowitz, D.M., and O'Donohue, T.L. (1978). ␣-Melanocyte stimuendocrine circuitry. J. Neurosci. 13, 5126-5138. lating hormone: immunohistochemical identification and mapping Cheung, C.C., Clifton, D.K., and Steiner, R.A. (1997). Proopiomelanoin neurons of rat brain. Proc. Natl. Acad. Sci. USA 75, 6300-6304. cortin neurons are direct targets for leptin in the hypothalamus. Joseph, S.A., Pilcher, W.H., and Bennett-Clarke, C. (1983). Immuno-Endocrinology 138, 4489-4492. cytochemical localization of ACTH perikarya in nucleus tractus soli-Collins, S., Kuhn, C.M., Petro, A.E., Swick, A.G., Chrunyk, B.A., and tarius: evidence for a second opiocortin neuronal system. Neurosci. dehydrationon the anatomical distribution of CART by in situ hybridization. J. induced peptidergic gene expression in the rat lateral hypothalamic Chem. Neuroanat. 12, 229-241. area by forebrain afferent projections. J. Comp. Neurol. 370, 231-246. Dawson, R., Pelleymounter, M.A,, Millard, W.J., Liu, S., and Eppler, B. (1997). Attenuation of leptin-mediated effects by monosodium Koylu, E.O., Couceyro, P.R., Lambert, P.D., Ling, N.C., DeSouza, glutamate-induced arcuate nucleus damage. Am. J. Physiol. 273, E.B., and Kuhar, M.J. (1997). Immunohistochemical localization of E202-E206. novel CART peptides in rat hypothalamus, pituitary and adrenal gland.
Leptin and the brain
Hormone Molecular Biology and Clinical Investigation, 2011
Leptin, which comes from the Greek root leptos meaning thin, has been the focus of intense investigation since its discovery in 1994. This hormone belongs to the cytokine family and is produced by adipocytes and circulates in proportion to fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. However, it participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of its various receptor isoforms. Leptin is involved in brain development, most notably in development of hypothalamic centers that control metabolism, but also in other brain areas. It acts as a nutritional cue to indicate adequacy of energy stores for pubertal development and reproductive capacity. The effects of this hormone on behavior and cognition are less well studied, but it clearly is involved in specific aspects of these physiological phenomena. As obesity is a major health problem in many areas of the world, the search for pharmacological treatments to decrease appetite and increase energy expenditure is intense. Understanding the mechanisms of actions of all physiological effects of this hormone is of great interest in the pursuit of such treatment.
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In vitro pituitary and testicular effects of the leptin-related synthetic peptide leptin(116-130) amide involve actions both similar to and distinct from those of the native leptin molecule in the adult rat
European Journal of Endocrinology, 2000
The obese gene (ob) product, leptin, has recently emerged as a key element in body weight homeostasis, neuroendocrine function and fertility. Identification of biologically active, readily synthesized fragments of the leptin molecule has drawn considerable attention, as they may provide a powerful tool for detailed characterization of the biological actions of leptin in different experimental settings. Recently, a fragment of mouse leptin protein comprising amino acids 116-130, termed leptin(116-130) amide, was shown to mimic the effects of the native molecule in terms of body weight gain and food intake, and to elicit LH and prolactin (PRL) secretion in vivo. As a continuation of our previous experimental work, the present study reports on the effects of leptin(116-130) amide on basal and stimulated testosterone secretion by adult rat testis in vitro. In addition, a comparison of the effects of human recombinant leptin and leptin(116-130) amide at the pituitary level on the patterns of LH, FSH, PRL and GH secretion is presented. As reported previously by our group, human recombinant leptin(10 ¹9 -10 ¹7 M) significantly inhibited both basal and human chorionic gonadotrophin (hCG)-stimulated testosterone secretion in vitro. Similarly, incubation of testicular tissue in the presence of increasing concentrations of leptin(116-130) amide (10 ¹9 -10 ¹5 M) resulted in a dose-dependent inhibition of basal and hCG-stimulated testosterone secretion; a reduction that was significant from a dose of 10 ¹7 M upwards. In addition, leptin (116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130) amide, at all doses tested (10 ¹9 -10 ¹5 M), significantly decreased LH and FSH secretion by incubated hemi-pituitaries from adult male rats. In contrast, in the same experimental protocol, recombinant leptin(10 ¹9 -10 ¹7 M) was ineffective in modulating LH and FSH release. Finally, neither recombinant leptin nor leptin(116-130) amide were able to change basal PRL and GH secretion in vitro. Our results confirm the ability of leptin, acting at the testicular level, to inhibit testosterone secretion, and map the effect to a domain of the leptin molecule that lies between amino acid residues 116 and 130. In addition, we provide evidence for a direct inhibitory action of leptin(116-130) amide on pituitary LH and FSH secretion, a phenomenon not observed for the native leptin molecule, in the adult male rat.
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American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
Leptin, a hormone produced by adipocytes, has been shown to affect a number of central functions, such as regulation of the hypothalamo-pituitary-adrenal axis, feeding, and body weight regulation. Because hypothalamic monoamines are intricately involved in the regulation of these functions, we hypothesized that leptin may produce its effects by altering the activity of these neurotransmitters. To test this hypothesis, male rats received peripheral (0, 100, or 500 μg ip), or central (0 or 5 μg icv) injections of leptin. The animals were killed 5 h later, and their brains were removed, frozen, and sectioned. Serum was collected to measure leptin and corticosterone by RIA. The paraventricular nucleus (PVN), arcuate nucleus (AN), ventromedial hypothalamus (VMH), dorsomedial dorsal nucleus (DMD), median eminence (ME), and medial preoptic area (MPA) were obtained using Palkovits' microdissection technique, and monoamine concentrations in these areas were determined using HPLC-EC. Intr...
Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice
The Journal of Nutrition, 2000
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Trends in Endocrinology and Metabolism, 1998
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Journal of Neuroendocrinology, 2020
Leptin is a hormone produced by the adipose tissue and its circulating levels reflect the amount of fat stored in the body. 1,2 The brain is the main site where leptin acts to influence numerous metabolic functions, including food intake, energy expenditure and nutrient oxidation. 3 Loss-of-function mutations in the genes encoding leptin or the leptin receptor (LepR) lead to severe obesity, hyperphagia,
Leptin modulates the expression of its receptors in the hypothalamic-pituitary-ovarian axis in a differential way
Journal of Endocrinology, 2008
To investigate the expression of leptin receptors (Ob-R) in the rat hypothalamus-pituitary-ovarian axis, immature rats were treated with eCG/hCG and Ob-R expression was evaluated by western blot analysis. The Ob-R expression increased 24 h after eCG administration in all the tissues assayed. In the hypothalamus, these levels immediately decreased to those obtained without treatment. In the pituitary, the Ob-R expression continued to be elevated 48 h after eCG administration, whereas the hCG injection did not modify these levels. Similar results were obtained with the ovarian long isoform. To assess the effect of leptin on its receptors, Ob-R was assessed in hypothalamus, pituitary and ovarian explants cultured in the presence or absence of leptin (0 . 3-500 ng/ml). In the hypothalamus, we found a biphasic effect: the Ob-R expression was either reduced or increased at low or high concentrations of leptin respectively. LH-releasing hormone secretion increased at 1 ng/ml. In the pituitary, Ob-R increased at 10 or 30 ng/ml of leptin for the long and short isoforms respectively. Leptin also induced an increase in LH release at 30 ng/ml. In the ovarian culture, the presence of leptin produced an increase in Ob-R expression at different ranges of concentrations and a dosedependent biphasic effect on the progesterone production. In conclusion, all these results clearly suggest that leptin is able to modulate the expression of its own receptors in the reproductive axis in a differential way. Moreover, the positive or negative effect that leptin exerts on the ovulatory process may be dependent on this regulation.
Leptin Inhibits Directly Glucocorticoid Secretion by Normal Human and Rat Adrenal Gland**This work was supported by a grant from the Swiss National Science Foundation (No. 3100–050748.97/1)
Endocrinology, 1998
Different interactions have been described between glucocorticoids and the product of the ob gene leptin. Leptin can inhibit the activation of the hypothalamo-pituitary-adrenal axis by stressful stimuli, whereas adrenal glucocorticoids stimulate leptin production by the adipocyte. The present study was designed to investigate the potential direct effects of leptin to modulate glucocorticoid production by the adrenal. Human adrenal glands from kidney transplant donors were dissociated, and isolated primary cells were studied in vitro. These cells were preincubated with recombinant leptin (10 Ϫ10-10 Ϫ7 M) for 6 or 24 h, and basal or ACTH-stimulated cortisol secretion was subsequently measured. Basal cortisol secretion was unaffected by leptin, but a significant and dose-dependent inhibition of ACTH-stimulated cortisol secretion was observed [down by 29 Ϯ 0.1% of controls with the highest leptin dose, P Ͻ 0.01 vs. CT (unrelated positive control)]. This effect of leptin was also observed in rat primary adrenocortical cells, where leptin inhibited stimulated corticosterone secretion in a dose-dependent manner (down by 46 Ϯ 0.1% of controls with the highest leptin dose, P Ͻ 0.001 vs. CT). These effects of leptin in adrenal cells are likely mediated by the long isoform of the leptin receptor (OB-R), because its transcript was found to be expressed in the adrenal tissue and leptin had no inhibitory effect in adrenal glands obtained from db/db mice. Therefore, leptin inhibits directly stimulated cortisol secretion from human and rat adrenal glands, and this may represent an important mechanism to modulate glucocorticoid levels in various metabolic states.
Leptin receptors are developmentally regulated in rat pituitary and hypothalamus
Molecular and Cellular Endocrinology, 2003
We have previously reported that leptin is expressed in adult rat brain and pituitary gland, though the role of leptin in these sites has not been determined. Leptin mRNA is developmentally regulated in the brain and pituitary of male and female rats during early postnatal development, suggesting a role in the maturation of the brain-pituitary system. Here, we sought to extend our previous studies by evaluating (1) the ontogeny of leptin receptor mRNA levels in rat brain and pituitary and (2) pituitary leptin protein levels in neonatal and pre-pubertal rats.Pituitary leptin concentration was highest shortly after birth (postnatal day (PD) 4, 25 ng/mg protein) and fell significantly throughout postnatal development and into adulthood (PD 60, 3.5 ng/mg protein; P<0.005) coincident with a decline in pituitary leptin mRNA levels. Significant age-related effects on leptin receptor mRNA levels were also observed in the pituitary and the hypothalamus of male and female rats using semi-quantitative RT-PCR analysis. In the pituitary, the short form (OBRa) mRNA levels were highest in neonatal rats (PD 4) but declined throughout postnatal development (PD 4–22) paralleling the fall in pituitary leptin mRNA and protein levels. The long form (OBRb) mRNA levels were unaffected by age between PD 4 and 22. In contrast, hypothalamic, levels of OBRb mRNA were very low to undetectable shortly after birth (PD 4) and rose significantly between PD 4 and 14/22 while levels of OBRa mRNA were not significantly different between PD 4 and 22. Immunohistochemical detection of leptin receptor immunoreactivity (all forms) revealed the presence of OBR-like protein in pituitary and hypothalamus as early as PD 4. Cortical leptin receptor mRNA levels were similar throughout early postnatal development. No gender-related differences in leptin receptor mRNA levels were noted in brain or pituitary.In conclusion, these data, together with our previous work, indicate that the neonatal pituitary gland expresses leptin and leptin receptors at levels far in excess of those observed in mature rats. The pituitary is thus quite different from adipose tissue, hypothalamus and cerebral cortex, in which neonatal leptin expression is lowest at birth. Since neonatal pituitary leptin receptor expression is also elevated, it is possible that pituitary-derived leptin plays some role in the development of the hypothalamic-pituitary system.
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