Disease relevance of Lep

• The circulating peptide leptin, which is the product of the ob gene, provides feedback information on the size of fat stores to central Ob receptors that control food intake and body-weight homeostasis [1].
• To investigate the physiological role of leptin in the control of meal size and the response to satiety signals, and to identify brain areas mediating this effect, we studied Koletsky (fa(k)/fa(k)) rats, which develop severe obesity due to the genetic absence of leptin receptors [2].
• This process could contribute to the limiting of hyperphagia, primarily when leptin signaling is altered, as in the obese state [3].
• To determine whether these effects may be altered in hypertension, we assessed the effect of leptin on angiotensin II-induced vascular response in the aorta of 10-week-old spontaneously hypertensive rats (SHR) [4].
• These data raise the possibility that high leptin levels may contribute to infertility in some women with PCOS by counteracting the sensitizing effects of IGF-I in dominant follicles [5].
• Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups [6].

Psychiatry related information on Lep

• Leptin acts on specific populations of hypothalamic neurons to regulate feeding behavior, energy expenditure, and neuroendocrine function [7].
• Leptin deficiency induced by fasting impairs the satiety response to cholecystokinin [8].
• Leptin reduces food intake but does not alter weight regain following food deprivation in the rat [9].
• Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin [10].
• These findings suggest that: (i) impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, (ii) the hippocampus is a brain site mediating leptin's antidepressant-like activity, and (iii) elevating leptin signaling in brain may represent a novel approach for the treatment of depressive disorders [11].

High impact information on Lep

• Leptin-regulated endocannabinoids are involved in maintaining food intake [12].
• Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity [12].
• Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance [12].
• Moderate increases in circulating leptin considerably decreased Lep expression in adipose tissue and induced lep expression in skeletal muscle, a tissue that normally does not express this gene [13].
• Here, we demonstrate tissue-specific autoregulation of Lep [13].

Chemical compound and disease context of Lep

• Maternal exposure to the high-fat diet increased pregnancy leptin levels and offspring's birth weight, but had no effect on pregnancy estradiol or insulin-like growth factor 1 levels [14].
• Leptin induces nitric oxide synthase type II in C6 glioma cells. Role for nuclear factor-kappaB in hormone effect [15].
• Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation [16].
• Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity [17].
• On the other hand, perivagal capsaicin prevented the protective effects of both CCK-8s and leptin on colitis [18].

Biological context of Lep

• These results indicate that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety [1].
• Despite the identification of leptin as a key mediator of this process, the mechanism whereby changes of body adiposity are coupled to adaptive, short-term adjustments of energy intake remains poorly understood [2].
• To determine if the hypothalamic arcuate nucleus (ARC) (a key forebrain site of leptin action) mediates this leptin effect, we used adenoviral gene therapy to express either functional leptin receptors or a reporter gene in the area of the ARC of fa(k)/fa(k) rats [2].
• We conclude that leptin stimulates leukemic cell growth in vivo by promoting angiogenesis [19].
• The weight-reducing action of leptin is thought to be mediated primarily by signal transduction through the leptin receptor (LR) in the hypothalamus [20].

Anatomical context of Lep

• Leptin has so far been reported to be secreted only by adipocytes and the placenta [1].
• Here we show that leptin messenger RNA and leptin protein are present in rat gastric epithelium, and that cells in the glands of the gastric fundic mucosa are immunoreactive for leptin [1].
• We identified leptin-sensitive neurons in the arcuate nucleus of the hypothalamus (Arc) that innervate the LHA using retrograde tracing with leptin administration [21].
• Restoration of leptin signaling to this brain area normalized the effect of CCK on the activation of neurons in the nucleus of the solitary tract and area postrema, key hindbrain areas for processing satiety-related inputs [2].
• Leptin action in the forebrain regulates the hindbrain response to satiety signals [2].

Associations of Lep with chemical compounds

• These data indicate that a supply of calories via glucose infusion induces a hypophagic response independent of leptin signaling in the rat, and support the hypothesis that a rise in central malonyl-CoA, triggered by increased glucose and insulin concentrations, participates in this adaptation [3].
• Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01) [22].
• Insulin alone (P < 0.01), but not leptin, increased autophosphorylation of nonreceptor tyrosine kinases (pp59(Lyn) + pp125(Fak)) [23].
• Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells [5].
• In order to address this question, the present study examined the effects of direct intrahypothalamic perfusions with leptin on the in vivo release of GnRH in ovarian steroid-primed ovariectomized rats utilizing the push-pull perfusion technique [24].
• Within the physiological range of brain glucose levels, leptin has a differential effect on VMN vs. ARC neurons, and acts on both glucosensing and non-glucosensing VMN neurons in a glucose-independent fashion with inhibition primarily dependent upon activation of the ATP-sensitive K+ channel [25].
• We therefore hypothesized that a longer exposure time to high concentrations of progesterone might be required to mimic the leptin resistance that occurs on d 14 of pregnancy [26].

Physical interactions of Lep

• Only when leptin was infused into the median eminence-arcuate nucleus complex was PRL secretion also stimulated, although its onset was 1 h behind that of LH [24].
• Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat [27].
• These data indicate an extremely high turnover of leptin receptors in hypothalamic target sites, but also raise the possibility that leptin may interact with the Golgi apparatus-related mechanisms to alter intracellular mechanisms [28].
• Megalin bound leptin in the presence of Ca(2+) and mediated its cellular internalization and degradation [29].
• Leptin binding to its functional receptor leads to activation of the JAK-STAT-signaling pathway and especially to the activation of the signal transducer and activator of transcription factor 3 (STAT3) [30].

Enzymatic interactions of Lep

• Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion [31].
• Leptin increased mammalian target of rapamycin (mTor) that phosphorylates 4E-BP1 [32].
• The effect of leptin is abolished when insulin secretion is induced with cAMP analogues that cannot be hydrolyzed by PDE3B [33].

Co-localisations of Lep

• Leptin accumulation in hypothalamic nuclei was partially colocalized with neuropeptide Y fibres [34].

Regulatory relationships of Lep

• Conversely, NPY-induced obesity results in raised circulating leptin concentrations [22].
• Physiological leptin concentrations (0.1-5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280-954%; P < 0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P < 0.003) [23].
• In contrast, in 3-day fasted rats leptin was effective in stimulating the secretion of GnRH, alpha-MSH, and LH, regardless of the site of perfusion [24].
• Additionally, AGE-induced mitogenesis and type I collagen protein expression were dependent on leptin-induced CTGF [35].
• Pyrrolidine dithiocarbamate (PDTC) and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), two inhibitors of NF-kappaB activation, as well as the specific proteasome inhibitor MG132, blocked leptin-induced iNOS [15].
• Altogether, our data show that leptin inhibits division of prepubertal Leydig cells via a cyclin D-independent mechanism and suggest that cyclin D1 might be involved in leptin-induced differentiation of Leydig cells [36].

Other interactions of Lep

• Hypocretin-immunoreactive terminals originating from the lateral hypothalamus make direct synaptic contact with neurons of the arcuate nucleus that not only express NPY but also contain leptin receptors [37].
• Our data indicate that a direct interaction between leptin, hypocretin, and NPY exists in the hypothalamus that may contribute to the central regulation of metabolic and endocrine processes in both rodents and primates [37].
• Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2 [23].
• OBJECTIVE: The anti-obesity properties of a new beta3-adrenergic agonist (Trecadrine) were examined in a diet-induced obesity model, including the effects on OB and uncoupling protein (UCP-1 and -2) gene expression [38].
• SOCS3 mRNA induction in response to leptin was lower in the Lou/C rat [39].
• ICV infusion of leptin potentiated signal transducer and activator of transcription 3 phosphorylation and attenuated AMP kinase in the hypothalamus, but resistin had less potent effects than leptin [40].

Analytical, diagnostic and therapeutic context of Lep

• To examine the chemical nature of target cells for leptin, direct double-labeling immunofluorescence histochemistry was applied [20].
• RESEARCH METHODS AND PROCEDURES: Leptin mRNA expression in the gastric mucosa and in adipose tissue depots (epididymal, retroperitoneal, mesenteric, and inguinal) was assessed by reverse transcriptase-polymerase chain reaction and serum and stomach leptin content by enzyme-linked immunosorbent assay [41].
• By comparison, leptin-mediated activation of hypothalamic STAT3 signaling, as measured by induction of both phospho-STAT3 immunohistochemistry and suppressor of cytokine signaling-3 (Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment [42].
• Western blot analysis confirmed the presence of leptin receptor-immunoreactive proteins in extracts from the vagal trunk [43].
• Hypothalamic NPY gene expression, estimated by Northern blot analysis, was significantly increased in fasting rats, and decreased in leptin-treated, fasting rats [44].

References