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Query: UNIPROT:P06889 (Mol)
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The hormone leptin is secreted by adipose tissue in proportion to fat mass to signal the repletion of body energy stores to the neuroendocrine system. Leptin acts on neurons in the hypothalamus and elsewhere in the brain to decrease appetite and regulate the activity of the thyroid, adrenal, growth, gonadal, and lactational axes. Conversely, absence of leptin signaling initiates the neuroendocrine starvation response. Leptin mediates these effects by activating the long form (LRb) of its receptor. One LRb signal, STAT3, has recently been shown to play a critical role in the regulation of body weight and some elements of neuroendocrine function (thyroid, adrenal, lactation), although the participation of STAT3 in the gonadal and growth axes is negligible. We discuss these findings in the context of the hypothalamic neuroendocrine system as it is presently understood.
J Mol Med (Berl) 2004 Jan
PMID:The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective. 1455 60

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.
Mol Cell Endocrinol 2003 Nov 28
PMID:Leptin receptors are developmentally regulated in rat pituitary and hypothalamus. 1461 55

Leptin, an adipose tissue-secreted hormone, acts via several isoforms of specific receptors (Ob-Rs), which may variously interact with the native leptin molecule and its fragments. Evidence has been provided that leptin affects rat adrenal functions, but the results were rather conflicting depending on the experimental condition examined (e.g. regenerating vs. mature or immature adrenal gland). Hence, we investigated the effects of three subcutaneous injections of murine leptin(1-147) and several leptin fragments (3 nmol/100 g body weight; 28, 16 and 4 h before the sacrifice) on the secretory activity and growth of regenerating rat adrenal cortex. The following leptin fragments were tested: murine leptin(116-130), and human leptin fragments 150-167, 138-167, 93-105, 22-56 and [Tyr]26-39. Leptin(1-147) enhanced plasma concentration of both aldosterone and corticosterone. The blood level of aldosterone was raised by leptin(116-130), leptin(138-167) and leptin(93-105), and that of corticosterone by leptin(93-105) and Tyr-leptin(26-39). Metaphase index (stachmokinetic method with vincristine) was unaffected by leptin(1-147), and lowered by leptin(116-130), leptin(150-167) and leptin(138-167). Collectively, our findings allow us to conclude that leptin and leptin fragments enhance the secretory activity and inhibit the growth of regenerating rat adrenal cortex, the biological activity of leptin being located in the C-terminal segment of its molecule.
Int J Mol Med 2004 Jan
PMID:Effects of leptin and leptin fragments on steroid secretion and proliferative activity of regenerating rat adrenal cortex. 1465 85

Leptin, the ob gene product, is an adipocyte-secreted hormone that centrally regulates weight by decreasing caloric intake and increasing energy expenditure. Expression of leptin is regulated by dietary status, insulin, glucocorticoids and catecholamines. Pancreastatin (PST), a chromogranin A-derived peptide, correlates with catecholamine levels, and may play a role in the physiology of stress, modulating endocrine secretion and metabolism. Thus, PST has been found to exert a lipolytic and anti-insulin effect in white adipocytes. The aim of the present work was to investigate a possible role of PST modulating the expression of key genes involved in lipid storage and metabolism: leptin, PPAR-gamma2, UCP-1 and UCP-2. We incubated isolated rat epididymal adipocytes with 100 nM PST for 16 and 24 h. Leptin, UCP-2 and UCP-1 mRNA levels were assessed by RT-PCR, followed by Southern blot. Leptin secretion was also measured by ELISA. PST inhibited leptin expression and secretion at 16-h incubation, but this effect was no longer observed after 24 h. On the other hand, PST stimulated the expression of UCP-2 after 16 h. However, the effect was still significant after 24 h. The inhibitory effect of PST on leptin expression and secretion and the stimulation of UCP-2 expression were prevented by blocking PKC. UCP-1 and PPR-gamma2 expression did not change after PST stimulation. Leptin differentially regulates the expression of key genes in the rat adipocyte, upregulating the expression of UCP-2 and inhibiting the expression and secretion of leptin by a mechanism that involves PKC activity. These effects may contribute to the metabolic action of catecholamines in physiological and pathophysiological conditions with increased sympathetic activity.
Cell Mol Life Sci 2003 Dec
PMID:Pancreastatin, a chromogranin A-derived peptide, inhibits leptin and enhances UCP-2 expression in isolated rat adipocytes. 1468 97

The central role of the melanocortin system in the regulation of energy balance has been studied in great detail. However, the functions of circulating melanocortins and the roles of their peripheral receptors remain to be elucidated. There is increasing evidence of a peripheral action of melanocortins in the regulation of leptin production by adipocytes. Here we investigate the interaction of alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related protein (AgRP) in the regulation of leptin secretion from cultured rat adipocytes and examine the changes in circulating alpha-MSH and AgRP in lean and obese rodents after hormonal and energetic challenge. Leptin secretion (measured by ELISA) and gene expression (by real-time quantitative PCR) of differentiated rat adipocytes cultured in vitro were inhibited by the administration of alpha-MSH (EC50=0.24 nM), and this effect was antagonised by antagonists of the melanocortin receptors MC4R and MC3R (AgRP and SHU9119). The presence of MC4R in rat adipocytes (RT-PCR and restriction digest) supports the involvement of this receptor subtype in this interaction. Leptin administered to ob/ob mice in turn increases the release of alpha-MSH into the circulation, suggesting a possible feedback loop between the site of alpha-MSH release and the release of leptin from the adipose tissue. However, the physiological significance of this putative feedback probably depends upon the underlying state of energy balance, since in the fasting state low plasma alpha-MSH is paralleled by low plasma leptin.
J Mol Endocrinol 2004 Feb
PMID:Regulation of adipose tissue leptin secretion by alpha-melanocyte-stimulating hormone and agouti-related protein: further evidence of an interaction between leptin and the melanocortin signalling system. 1476 98

Leptin has been shown to improve insulin sensitivity and glucose metabolism in obese diabetic ob/ob mice, yet the mechanisms remain poorly defined. We found that 2 d of leptin treatment improved fasting but not postprandial glucose homeostasis, suggesting enhanced hepatic insulin sensitivity. Consistent with this hypothesis, leptin improved in vivo insulin receptor (IR) activation in liver, but not in skeletal muscle or fat. To explore the cellular mechanism by which leptin up-regulates hepatic IR activation, we examined the expression of the protein tyrosine phosphatase PTP1B, recently implicated as an important negative regulator of insulin signaling. Unexpectedly, liver PTP1B protein abundance was increased by leptin to levels similar to lean controls, whereas levels in muscle and fat remained unchanged. The ability of leptin to augment liver IR activation and PTP1B expression was also observed in vitro in human hepatoma cells (HepG2). However, overexpression of PTP1B in HepG2 cells led to diminished insulin-induced IR phosphorylation, supporting the role of PTP1B as a negative regulator of IR activation in hepatocytes. Collectively, our results suggest that leptin acutely improves hepatic insulin sensitivity in vivo with concomitant increases in PTP1B expression possibly serving to counterregulate insulin action and to maintain insulin signaling in proper balance.
Mol Endocrinol 2004 Jun
PMID:Leptin increases hepatic insulin sensitivity and protein tyrosine phosphatase 1B expression. 1497 21

Leptin suppresses insulin secretion by opening ATP-sensitive K(+) (K(ATP)) channels and hyperpolarizing beta-cells. We measured the intracellular concentration of ATP ([ATP](i)) in tumor-derived beta-cells, INS-1, and found that leptin reduced [ATP](i) by approximately 30%, suggesting that the opening of K(ATP) channels by leptin is mediated by decreased [ATP](i). A reduction in glucose availability for metabolism may explain the decreased [ATP](i), since leptin (30 min) reduced glucose transport into INS-1 cells by approximately 35%, compared to vehicle-treated cells. The twofold induction of GLUT2 phosphorylation by GLP-1, an insulin secretagogue, was abolished by leptin. Therefore, the acute effect of leptin could involve covalent modification of GLUT2. These findings suggest that leptin may inhibit insulin secretion by reducing [ATP](i) as a result of reduced glucose availability for the metabolic pathway. In addition, leptin reduced glucose transport by 35% in isolated rat hepatocytes that also express GLUT2, suggesting that glucose transport may also be altered by leptin in other glucose-responsive tissues such as the liver.
J Mol Endocrinol 2004 Apr
PMID:Leptin reduces glucose transport and cellular ATP levels in INS-1 beta-cells. 1507 48

Leptin is a 147-amino acid adipose tissue-secreted hormone, which acts via several subtypes of receptors, the main and better known variants of which are named Ob-Ra and Ob-Rb. Structure-activity relationship studies pointed out the importance of the N-terminal and C-terminal amino-acid sequences 22-115 and 116-166, respectively, for the biological and receptor binding activities of leptin. Evidence has been provided that leptin affects corticosteroid-hormone and insulin secretion, and therefore we have investigated in the rat the expression of leptin receptor expression in adrenal cortex and pancreatic islets, as well as the effects of the acute treatment with leptin and leptin fragments 150-167, 138-167, 93-105, 22-56 and 26-39 on the plasma concentrations of aldosterone, corticosterone, insulin and glucagon. Reverse transcription-polymerase chain reaction showed the expression of both Ob-Ra and Ob-Rb mRNAs in adrenal cortex and pancreatic islets, the Ob-Rb expression in pancreas being 2-fold higher than in adrenals. Radioimmuno assay demonstrated that leptin enhanced plasma aldosterone and corticosterone concentrations, decreased plasma insulin concentration, and did not significantly affect glucagon plasma concentration. All leptin fragments tested exerted a corticosteroid-hormone secretagogue action, while only leptin fragments 116-130, 138-167 and 93-105 elicited a sizeable insulin antisecretagogue effect. Taken together these findings suggest that: i) the in vivo acute stimulating effect of leptin on adrenocortical hormone secretion is not connected to specific sequences of its molecule, while the insulinostatic effect is probably mediated by the sequence 93-105; and ii) the secretagogue and antisecretagogue effect of leptin are prevalently mediated by Ob-Ra and Ob-Rb, respectively.
Int J Mol Med 2004 Jun
PMID:Acute in vivo effects of leptin and leptin fragments on corticosteroid hormone secretion and entero-insular axis in the rat. 1513 20

Leptin is a hormone secreted by adipocytes in correlation with total body fat mass. In addition to regulating energy homeostasis, leptin modulates immune functions such as macrophage phagocytosis and cytokine synthesis. Previously, we reported defective leukotriene synthesis in macrophages from leptin-deficient mice that could be restored with exogenous leptin. In the present study, we utilized macrophages from normal rodents to explore the mechanism by which leptin could enhance cellular leukotriene synthesis. Leptin pretreatment of either rat alveolar or murine peritoneal macrophages for 16 h dose dependently increased the synthesis of leukotriene B4 and cysteinyl leukotrienes in response to calcium ionophore or the particulate zymosan. Leptin also enhanced calcium ionophore-stimulated release of free arachidonic acid. Calcium-dependent and -independent arachidonoyl-selective phospholipase activities in macrophage lysates were likewise increased following leptin treatment. Immunoblot analysis of leptin-treated cells revealed that group IVC iPLA2 (cPLA2gamma) protein expression increased approximately 80%. These data demonstrate for the first time that phospholipase A2 activity and cPLA2gamma protein levels in alveolar macrophages represent targets for upregulation by leptin and provide previously unrecognized mechanisms by which this hormone can promote inflammatory responses.
Am J Physiol Lung Cell Mol Physiol 2004 Sep
PMID:Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2gamma) protein expression. 1514 87

The present study was conducted to determine if peripheral leptin administration can alter GH secretion or feed intake in young pigs. Six, 6 kg female pigs were fasted overnight and randomly chosen to receive porcine recombinant leptin or saline injections in a crossover design. Three leptin dosages were tested over a 10 day period, 100, 200 or 500 microg/kg body mass (L100, L200 or L500). Leptin was administered in 0.2% bovine serum albumin as a bolus injection into the carotid artery. Blood samples were obtained from the jugular vein over a 24 h period. Leptin delayed feeding in pigs treated with L200 and L500 (P<0.05), while reducing overall intake in pigs treated with L100 (P<0.05). L200 or L500 depressed blood glucose (P<0.05). Plasma insulin levels were elevated by feeding in control animals, while insulin levels were depressed in pigs treated with L200 or L500 (P<0.05). L200 elevated plasma growth hormone (P<0.05) with three peaks apparent at 5, 8, and 13 h post injection. The ability for a single injection of leptin to produce significant changes in hormone and metabolite levels suggests that this peptide has a role in regulation of peripheral metabolism.
Comp Biochem Physiol A Mol Integr Physiol 2004 May
PMID:Peripheral leptin administration alters hormone and metabolite levels in the young pig. 1516 66


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