Disease relevance of Lep

• Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice [1].
• In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure [2].
• Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels [2].
• The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity [3].
• In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects [4].
• Together with the finding of enhanced proliferation of T(reg) cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases [5].
• While heterozygous Lep mutations initially exacerbate obesity, in situations of severe obesity, reduced leptin levels may act oppositely and have beneficial effects on energy homeostasis [6].
• Second, we observe that ob/ob mice treated with low-dose leptin peripherally but not centrally exhibit increased thymocyte cellularity in the absence of any weight loss or significant reduction in systemic corticosterone levels [7].
• Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain [8].
• Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA [9].

Psychiatry related information on Lep

• Hypothalamic neuronal histamine as a target of leptin in feeding behavior [10].
• NPY in these hypothalamic regions of ob/ob mice was unresponsive to food deprivation or refeeding [11].
• We conclude that interruption of leptin pathways does not affect hypoxic sensitivity during sleep and wakefulness but that melanocortin 4 blockade is associated with depressed hypercapnic sensitivity in non-rapid eye movement sleep [12].
• Reductions in plasma glucose and leptin as well as rapid increases in plasma ghrelin were apparent in the neonate 4 h following maternal deprivation and maximal at 8 h [13].
• Total locomotor activity was reduced in ob/ob and C57BL/6J mice [14].

High impact information on Lep

• We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice [15].
• Partially antagonizing this inhibitory loop, leptin also upregulates AP-1 gene expression, which promotes cyclin D1 expression, osteoblast proliferation, and bone formation [16].
• Moreover, Per-deficient mice experience a paradoxical increase in bone mass following leptin intracerebroventricular infusion [16].
• The molecular clock mediates leptin-regulated bone formation [16].
• We show that expression of clock genes in osteoblasts is regulated by the sympathetic nervous system and leptin [16].

Chemical compound and disease context of Lep

• Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant alpha-smooth muscle actin staining [17].
• Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4-17 weeks age: male: -13.7%, female: -20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (-37.7%), suggesting increased insulin sensitivity [18].
• Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons [19].
• The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(-/-) double knockout mice (2KO) [18].
• Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate [19].

Biological context of Lep

• Variation in obesity phenotypes explained 49%, 40%, and 37%, respectively, of the variance in Hfe, Lep, and Trfr mRNA levels [20].
• Lep alleles derived from outbred, but not inbred, SPRET are a positional candidate for the chromosome 6 quantitative trait locus in BSB mice [20].
• Leptin differed by haplotype at the Lep locus in outbred BSB [20].
• Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism [21].
• This is the first in vivo demonstration of leptin signal transduction [21].

Anatomical context of Lep

• Leptin is the 167 amino-acid protein product of the Lep (obese) gene that is released predominantly from adipose tissue and circulates at levels related to the amount of fat [22].
• The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus [21].
• But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone [3].
• Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus [3].
• We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system [23].

Associations of Lep with chemical compounds

• RESULTS: Leptin (Lep) and adipsin expressions had the greatest fold differences between obese and lean mice [20].
• LRb-STAT3 signalling thus mediates the effects of leptin on melanocortin production and body energy homeostasis, whereas distinct LRb signals regulate NPY and the control of fertility, growth and glucose homeostasis [24].
• Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus [25].
• The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone [26].
• Leptin regulation of the mesoaccumbens dopamine pathway [27].
• Direct control of leptin receptor expression by insulin could also be demonstrated in isolated hepatocytes from normal mice [28].
• Leptin also stimulated tyrosine phosphorylation of kinase-inactive JAK2(K882E) in JAK2-null cells [29].

Physical interactions of Lep

• Here, we show that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin) [30].
• ET-1 and insulin positively interact with each other in increasing leptin production in adipocytes [31].
• The data suggest that JAK-2 and IRS-2 couple the leptin signalling pathway to the insulin signalling chain [32].
• Activation of urocortin transport into brain by leptin [33].
• Thus DEX acts in the hypothalamus of ob/ob mice in a phenotype-specific manner to evoke rapid transport of NPY from cell bodies within the arcuate nucleus to terminal regions including the dorsomedial and ventromedial hypothalamic regions for release [34].

Enzymatic interactions of Lep

• We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin [35].
• Immunoblot experiments showed that tyrosine phosphorylation of Stat3 increased in total cellular extracts and that the phosphorylated protein translocated into the nucleus upon leptin treatment [36].
• The stimulation by leptin was not accompanied by recruitment of any tyrosine phosphorylated proteins to PI3K-C2alpha and no shift in electrophoretic mobility was noted [37].
• We conclude that, although the metabolic adaptations to fasting and CR include changes in plasma leptin concentration and phosphorylated acetyl-CoA carboxylase, these effects occur without changes in AMPK activity [38].

Co-localisations of Lep

• We reported previously that leptin was co-localized with oxytocin and vasopressin [39].

Regulatory relationships of Lep

• Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling [40].
• Five daily injections of urocortin significantly lowered body weight and improved glycemic control in ob/ob mice [41].
• Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity [42].
• Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c [43].
• Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice [18].
• Coimmunoprecipitation analysis revealed that leptin promoted immune complex formation between Akt and the IkappaB kinase subunits as well as STAT-1alpha [44].
• Analysis of signal transduction pathways revealed that leptin stimulated phosphorylation of Akt and STAT3 but not ERK1/2 [45].
• Leptin induced phosphorylation of signal transducer and activator of transcription-3 in 100% of GLP-1 cells in the caudal brainstem of mice [46].

Other interactions of Lep

• These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling [47].
• Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do [47].
• Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes [21].
• These results suggest that NPY is a central effector of leptin deficiency [4].
• An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice [40].

Analytical, diagnostic and therapeutic context of Lep

• Sequence analysis revealed that the coding region of Lep in KK/Ta mice was identical to that in BALB/c mice [48].
• Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc) [27].
• To investigate the basis for this effect, we used in situ hybridization (ISH) to determine whether leptin alters expression of hypothalamic neuropeptides involved in energy homeostasis [49].
• To assess whether the effect of leptin in intestinal inflammation is mediated by corticosteroids we performed adrenalectomy experiments in db/db and wild-type mice [50].
• The ob gene product, leptin, has been shown in several studies to be involved in weight control and recombinant leptin recently has entered clinical trials to treat obesity [51].

References