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Journal articles on the topic 'Recombinant Leptin'

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Published: 4 June 2021

Last updated: 4 February 2022

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Gertler, A., Y. Sandowski, and N. Raver. "Recombinant leptin mutants and leptin binding proteins aimed to block leptin action in vivo." Proceedings of the British Society of Animal Science 2002 (2002): 48. http://dx.doi.org/10.1017/s1752756200007043.

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Obese protein (OB) also known as leptin serves as a protein signal secreted from adipose tissue and acts on a central nervous system that regulate ingestive behavior and energy balance (Campfield, 2000). The sequence of various leptins from 10 mammalian species was compiled and the 3D structure of human leptin mutant W100E was elucidated (Zhang et al., 1997). We have prepared recombinant leptins of sheep, chicken, cow and pig. Mammalian and chicken leptins are respectively 146 and 145 amino acid containing proteins found in circulation. Leptin in blood is found in both free and bound form; the main binding protein is the extracellular domain (ECD) of leptin receptor (Liu et al., 1997). One of the established functions of leptin, is its attenuating effect on the expression of NPY and other neuropeptides in hypothalamus that subsequently leads to decreased food intake (Campfield, 2000). Therefore it seems logical that blocking leptin receptors that are responsible for transferring it through the blood-brain barrier or for its action in hypothalamus will lead to increase in food intake. Leptin receptor belongs to cytokine receptor superfamily. Its ECD consists of ∷ 800 amino acids but it was suggested that only the cytokine homology subdomain II (CHD) consisting of ∷ 200 amino acids is responsible for binding (Fong et al., 1997). The objective of the present work is to prepare recombinant proteins aimed to block leptin action. We suggest two approaches (a) preparation of leptin antagonists capable of binding but not homodimerizing leptin receptors and (b) subcloning and preparing CHD II of leptin receptor responsible for binding of the hormone.

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Dridi, S., N. Raver, E. E. Gussakovsky, et al. "Biological activities of recombinant chicken leptin C4S analog compared with unmodified leptins." American Journal of Physiology-Endocrinology and Metabolism 279, no. 1 (2000): E116—E123. http://dx.doi.org/10.1152/ajpendo.2000.279.1.e116.

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The chicken leptin sequence, in contrast to mammalian leptins, contains an unpaired Cys at position 3 of the original cDNA ( AF012727 ). The presence of an extra Cys may confer a different structure and affect the leptin's biological activity. To address this, we studied the effects of wild-type and mutated (C4S) chicken leptins in vitro and in vivo and compared them with mammalian leptin prepared from ovine leptin cDNA. The prokaryotic expression vector pMON, encoding full-size A(−1) chicken leptin ( AF012727 ), was mutated using a mutagenesis kit, yielding the C4S analog. Escherichia coli cells transformed with this vector overexpressed large amounts of chicken leptin C4S upon induction with nalidixic acid. The expressed protein, found in the inclusion bodies, was refolded and purified to homogeneity on a Q-Sepharose column, yielding three electrophoretically pure fractions, eluted from the column by 100, 125, and 150 mM NaCl, respectively. All three fractions showed a single band of the expected molecular mass (16 kDa) and were composed of >95% monomeric protein. Proper refolding was evidenced by comparing the circular dichroism spectrum of the analog with spectra of nonmutated chicken and ovine leptins. The biological activity of the C4S analog was evidenced by its ability to stimulate proliferation of leptin-sensitive BAF/3 cells transfected with a long form of human leptin receptor construct similar to its nonmutated counterpart, indicating that Cys4 plays no role in leptin activity. The in vitro activity of both wild-type and mutated chicken leptins was ∼10-fold lower than that of ovine leptin. After intravenous or intraperitoneal injections, C4S analog and the nonmutated chicken and ovine leptins all lowered the food intake of starved 9-day-old broiler or 5-wk-old layer male chickens by 11–34%. Monitoring food behavior revealed that the attenuated food intake resulted not from a decreased number of approaches to the feeders but from a decrease in the average time spent eating during each approach.

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Le, Xuan Mai Huong, To Dinh Le, Thao Thi Phuong Dang, and Thuoc Linh Tran. "Cloning and expression of recombinant human leptin in Escherichia coli." Science and Technology Development Journal 16, no. 1 (2013): 5–12. http://dx.doi.org/10.32508/stdj.v16i1.1391.

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Leptin, a peptide hormone, is produced by mature adipocytes and functions primarily in the hypothalamus to reduce food intake and body weight. Recombinant h-leptin has been shown to be effective in obesity treatment. To overexpression of recombinant human leptin in Escherichia coli, the human leptin gene (hob gene) was cloned into the vector pET-28a. When analysis expression of human leptin in E. coli BL21(DE3) strain, it was found that recombinant vector pET-hob expressed h-leptinproteins in cytoplasm, and mainly as insoluble inclusion bodies. This result will be the premise for researching to produce recombinant human leptin protein.

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Fruhbeck, G. "Chronobiology of Recombinant Leptin Therapy." JAMA: The Journal of the American Medical Association 283, no. 12 (2000): 1567–68. http://dx.doi.org/10.1001/jama.283.12.1567.

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Frühbeck, Gema, Alberto Díez-Caballero, Javier Salvador, and Javier Alvarez-Cienfuegos. "Chronobiology of Recombinant Leptin Therapy." JAMA 283, no. 12 (2000): 1567. http://dx.doi.org/10.1001/jama.283.12.1567-jlt0322-13-1.

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G. Correia, M., and W. Haynes. "Lessons from Leptins Molecular Biology: Potential Therapeutic Actions of Recombinant Leptin and Leptin-Related Compounds." Mini-Reviews in Medicinal Chemistry 7, no. 1 (2007): 31–38. http://dx.doi.org/10.2174/138955707779317858.

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Jeong, Ki Jun, and Sang Yup Lee. "High-Level Production of Human Leptin by Fed-Batch Cultivation of Recombinant Escherichia coli and Its Purification." Applied and Environmental Microbiology 65, no. 7 (1999): 3027–32. http://dx.doi.org/10.1128/aem.65.7.3027-3032.1999.

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ABSTRACT Human leptin is a 16-kDa (146-amino-acid) protein that is secreted from adipocytes and influences body weight homeostasis. In order to obtain high-level production of leptin, the human obesegene coding for leptin was expressed in Escherichia coliBL21(DE3) under the strong inducible T7 promoter. The recombinant leptin was produced as inclusion bodies in E. coli, and the recombinant leptin content was as high as 54% of the total protein content. For production of recombinant human leptin in large amounts, pH-stat fed-batch cultures were grown. Expression of leptin was induced at three different cell optical densities at 600 nm (OD600), 30, 90, and 140. When cells were induced at an OD600 of 90, the amount of leptin produced was 9.7 g/liter (37% of the total protein). After simple purification steps consisting of inclusion body isolation, denaturation and refolding, and anion-exchange chromatography, 144.9 mg of leptin that was more than 90% pure was obtained from a 50-ml culture, and the recovery yield was 41.1%.

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Zamorano, Pedro L., Liesl De Sevilla, Virendra B. Mahesh, and Darrell W. Brann. "Production and Refolding of Recombinant Leptin." BioTechniques 23, no. 5 (1997): 800–804. http://dx.doi.org/10.2144/97235bm07.

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Heymsfield, Steven B. "Chronobiology of Recombinant Leptin Therapy—Reply." JAMA 283, no. 12 (2000): 1567. http://dx.doi.org/10.1001/jama.283.12.1567-jlt0322-14-1.

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Hen, Gideon, Sera Yosefi, Ana Ronin, et al. "Monitoring leptin activity using the chicken leptin receptor." Journal of Endocrinology 197, no. 2 (2008): 325–33. http://dx.doi.org/10.1677/joe-08-0065.

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We report on the construction of a leptin bioassay based on the activation of chicken leptin receptor in cultured cells. A human embryonic kidney (HEK)-293 cell line, stably transfected with the full-length cDNA of chicken leptin receptor together with a STAT3-responsive reporter gene specifically responded to recombinant human and Xenopus leptins. The observed higher sensitivity of chicken leptin receptor to the former is in agreement with the degree of sequence similarity among these species (about 60 and 38% identical amino acids between humans and chickens, and between humans and Xenopus respectively). The specific activation of signal transduction through the chicken leptin receptor, shown here for the first time, suggests that the transition of Gln269 (implicated in the Gln-to-Pro Zucker fatty mutation in rats) to Glu in chickens does not impair its activity. Analysis of leptin-like activity in human serum samples of obese and lean subjects coincided well with leptin levels determined by RIA. Serum samples of pre- and post partum cows showed a tight correlation with the degree of adiposity. However, specific activation of the chicken leptin receptor in this assay was not observed with serum samples from broiler or layer chickens (representing fat and lean phenotypes respectively) or with those from turkey. Similar leptin receptor activation profiles were observed with cells transfected with human leptin receptor. Further work is needed to determine whether the lack of leptin-like activity in the chicken serum samples is due to a lack of leptin in this species or simply to a serum level of leptin that is below the detection threshold.

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Rock, F., D. Peterson, B. Weig, R. Kastelein, and J. Bazan. "Binding of Leptin to the Soluble Ectodomain of Recombinant Leptin Receptor." Hormone and Metabolic Research 28, no. 12 (1996): 748–50. http://dx.doi.org/10.1055/s-2007-979892.

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Fujioka, K. "CSF Leptin Levels After Exogenous Administration of Recombinant Methionyl Human Leptin." JAMA: The Journal of the American Medical Association 282, no. 16 (1999): 1517–18. http://dx.doi.org/10.1001/jama.282.16.1517.

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Harris, R. B., J. Zhou, D. S. Weigle, and J. L. Kuijper. "Recombinant leptin exchanges between parabiosed mice but does not reach equilibrium." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 6 (1997): R1800—R1808. http://dx.doi.org/10.1152/ajpregu.1997.272.6.r1800.

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Parabiosis experiments suggest that ob/ob mice are deficient in a circulating "lipostatic" signal but respond to such a signal when it is delivered in the cross circulation from their parabiotic partner. Identification of leptin as the mutation in ob/ob mice leads to the assumption that leptin is the lipostatic signal. The objective of these experiments was to determine the circulating half-life of leptin and to demonstrate whether it exchanged between parabiosed mice. Measurement of disappearance of recombinant leptin from serum in SWRJ mice indicated a circulating half-life of approximately 36 min. Single ob/ob mice or one member of a parabiosed pair of ob/ob mice received 50 micrograms recombinant murine leptin in two intraperitoneal injections a day for 10 days, starting 40 days after parabiosis surgery. Control mice and pairs received equivalent injections of vehicle. In single mice, leptin significantly reduced food intake, body weight, serum insulin, and pancreatic and liver weight. Leptin treatment of one member of a parabiosed pair of ob/ob mice reduced serum insulin, gut content (an index of food intake), and body fat in both partners. The injected parabiont lost more fat than its partner, and body temperature was increased only in the injected mouse, indicating that leptin did not reach equilibrium in the two animals. This was confirmed by Western blot analysis of serum leptin measured 2 h after injection. Therefore, although leptin can exchange between parabionts, its half-life is inadequate to allow equilibrium when a large concentration gradient exists between partners.

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Niv-Spector, L., N. Raver, M. Friedman-Einat, et al. "Mapping leptin-interacting sites in recombinant leptin-binding domain (LBD) subcloned from chicken leptin receptor." Biochemical Journal 390, no. 2 (2005): 475–84. http://dx.doi.org/10.1042/bj20050233.

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The binding domain of the chicken leptin receptor [chLBD (chicken leptin-binding domain)], subcloned from the full-size chicken leptin receptor and prepared in an Escherichia coli system, was subjected to site-directed mutagenesis to identify the amino acids involved in leptin binding. A total of 22 electrophoretically pure, >90% monomer-containing mutants were expressed, refolded and purified. The effects of the mutations were tested by the ability to form complexes with ovine leptin, and the kinetic parameters of interaction were determined by surface plasmon resonance. Six mutants were used to determine whether mutations of several amino acids that differ between chLBD and mammalian LBDs will affect affinity: none showed any such effect, except the mutant A105D (Ala105→Asp), which exhibited some decrease in affinity. Surface plasmon resonance analysis identified six mutants in which binding activity was totally abolished (F73A, Y14A/F73A, V76A/F77A, L78A/L79A, V76A/F77A/L78A/L79A and A105D/D106V) and six mutants (Y14A, R41A, R41A/S42A/K43A, V103A, V135A/F136A and F136A) in which affinity for the hormone was reduced, mainly by increased dissociation rates. Gel-filtration experiments indicated the formation of a 1:1 ovine or human leptin–chLBD complex with a molecular mass of approx. 41 kDa. Gel-filtration experiments yielded 1:1 complexes with those mutants in which affinity had decreased, but not with the six mutants, which had totally lost their binding capacity. Modelling the leptin–chLBD complex indicated that the binding domain of the latter is located mainly in the L3 loop, which contributes nine amino acid residues interacting with leptin. Contact-surface analysis identified the residues having the highest contribution to the recognition site to be Phe73, Phe77 and Leu79.

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Bermúdez-Humarán, Luis G., Sébastien Nouaille, Vladimir Zilberfarb, et al. "Effects of Intranasal Administration of a Leptin-Secreting Lactococcus lactis Recombinant on Food Intake, Body Weight, and Immune Response of Mice." Applied and Environmental Microbiology 73, no. 16 (2007): 5300–5307. http://dx.doi.org/10.1128/aem.00295-07.

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ABSTRACT Leptin is an adipocyte-derived pleiotropic hormone that modulates a large number of physiological functions, including control of body weight and regulation of the immune system. In this work, we show that a recombinant strain of the food-grade lactic acid bacterium Lactococcus lactis (LL-lep) can produce and efficiently secrete human leptin. The secreted leptin is a fully biologically active hormone, as demonstrated by its capacity to stimulate a STAT3 reporter gene in HEK293 cells transfected with the Ob-Rb leptin receptor. The immunomodulatory activity of leptin-secreting L. lactis was evaluated in vivo by coexpression with the human papillomavirus type 16 E7 protein. In C57BL/6 mice immunized intranasally with a recombinant L. lactis strain coproducing leptin and E7 antigen, the adaptive immune response was significantly higher than in mice immunized with recombinant L. lactis producing only E7 antigen, demonstrating adjuvanticity of leptin. We then analyzed the effects of intranasally administered LL-lep in obese ob/ob mice. We observed that daily administration of LL-lep to these mice significantly reduced body weight gain and food intake. These results demonstrate that leptin can be produced and secreted in an active form by L. lactis and that leptin-producing L. lactis regulates in vivo antigen-specific immune responses, as well as body weight and food consumption.

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Mineev, V. N., and T. M. Lalaeva. "Characteristics of the expression of the transcription factor pSTAT3 in asthma." Terapevticheskii arkhiv 89, no. 3 (2017): 48–53. http://dx.doi.org/10.17116/terarkh201789348-53.

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Aim. To investigate the transcription factor pSTAT3 in overweight asthmatics on a model of peripheral blood mononuclear cells at baseline and during recombinant leptin modulation. Materials and methods. A flow fluorometric assay was used according to the standard Bio-Plex protocol on a Bio-Plex immunoanalyzer (a flow fluorimeter) (Bio-Rad, USA) using xMAP technology at baseline and during modulation with recombinant leptin (Leptin, human, recombinant, expressed in a E. coli, Sigma, USA). Results. There was an obvious reduction in the level of the transcription factor pSTAT3 in patients with non-allergic asthma and an increase in that in patients with allergic asthma (AA). Recombinant leptin modulation of pSTAT3 levels caused their paradoxical decrease in both overweight women younger than 45 years of age with AA and in those with non-allergic asthma. Conclusion. The elevated level of the transcription factor pSTAT3 in AA is probably due to the overexpression of pSTAT3 in this group of patients. The paradoxical decrease in pSTAT3 levels in overweight women under 45 years of age with AA, which is similar in the non-allergic asthma group, can be explained by the enhanced expression of negative SOCS3 regulators and by leptin resistance.

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Vatier, Camille, Jean-François Gautier, and Corinne Vigouroux. "Therapeutic use of recombinant methionyl human leptin." Biochimie 94, no. 10 (2012): 2116–25. http://dx.doi.org/10.1016/j.biochi.2012.03.013.

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Barrachina, M. D., V. Martinez, J. Y. Wei, and Y. Tache. "Leptin-induced decrease in food intake is not associated with changes in gastric emptying in lean mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 3 (1997): R1007—R1011. http://dx.doi.org/10.1152/ajpregu.1997.272.3.r1007.

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Chronic treatment with leptin regulates body weight and energy balance and reduces food intake in obese and lean mice. In 18- to 20-h fasted lean mice (C57BL/6, +/+), we examined the acute effect of a single intraperitoneal injection of recombinant mouse leptin (0.12 mg/kg) on food intake and gastric emptying. Leptin reduced food intake, with a peak inhibition at the 5th h postinjection (69 +/- 12%/h), although there was no change in food consumption at the 1st h. Leptin did not alter the 4-h rate of gastric emptying of a solid nutrient meal (free access to Purina chow for either 1-, 2-, or 4-h period). In normal Sprague-Dawley rats fasted for 18-20 h, a single intraperitoneal injection of recombinant mouse leptin (0.2 or 1.2 mg/kg) did not modify the 7-h cumulative or hourly food intake. These results show that a single intraperitoneal injection of recombinant mouse leptin reduces food intake within 5 h while not influencing gastric emptying of ingested food in lean mice. Sprague-Dawley rats are unresponsive to the food intake-reducing effect of a single intraperitoneal injection of mouse leptin at a dose 10-fold higher than that shown to be effective in mice within the first 4-7 h postinjection.

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Farooqi, I. Sadaf, Susan A. Jebb, Gill Langmack, et al. "Effects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency." New England Journal of Medicine 341, no. 12 (1999): 879–84. http://dx.doi.org/10.1056/nejm199909163411204.

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Janssen, YJ, M. Frolich, P. Deurenberg, and F. Roelfsema. "Serum leptin levels during recombinant human GH therapy in adults with GH deficiency." European Journal of Endocrinology 137, no. 6 (1997): 650–54. http://dx.doi.org/10.1530/eje.0.1370650.

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OBJECTIVE: Recent studies suggest an involvement of the obese (OB) gene and its product leptin in the regulation of body fat. Since adults with growth hormone deficiency (GHD) have a high body fat mass which can be normalized with recombinant human (rh) GH therapy, we investigated whether GH influences serum leptin directly or indirectly via its lipolytic effect. DESIGN: Fourteen adults with GHD were treated with subcutaneous injections of rhGH given every evening for 52 weeks. Serum leptin, fat mass and body fat percentage were measured at baseline and after 4 and 52 weeks of treatment. METHODS: Serum leptin was measured with a commercially available RIA. Total body water was determined by dilution of deuterium. Fat free mass was estimated by assuming a hydration of 73%. Fat mass was estimated by subtracting fat free mass from weight. RESULTS: At baseline, serum leptin levels were exponentially related to body fat percentage (r = 0.88; P < 0.0005). rhGH treatment for 4 weeks did not significantly influence serum leptin levels, whereas treatment for 52 weeks significantly decreased serum leptin levels (15.6 +/- 2.9 to 10.8 +/- 2.1 micrograms/l; P = 0.020). Fat percentage was significantly decreased after 52 weeks of treatment (37.6 +/- 2.1 to 33.8 +/- 2.5%; P < 0.0005). The decrease in serum leptin could largely be explained by the decrease in body fat percentage, whereas the relation between leptin and body fat percentage did not change. CONCLUSIONS: The influence of GH on serum leptin in indirect, via its effect on body fat percentage.

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Liapakis, Ioannis, Stavros Anagnostoulis, Anastasios Karayiannakis, et al. "Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats." Acta Cirurgica Brasileira 23, no. 2 (2008): 118–24. http://dx.doi.org/10.1590/s0102-86502008000200002.

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BACKGROUND: Leptin is a potent direct angiogenic factor that stimulates endothelial cell migration and activation in vitro and angiogenesis in vivo. In addition, leptin has been discussed to play an important role in angiogenesis, as it promotes the formation of new blood vessels. PURPOSE: The effect of exogenously administered leptin on the healing process of a full tissue burn wound model. METHODS: Sixty-three Sprague-Dawley male rats were used. Full tissue burn wound was created by electrocautery. The width of the pin was 0.3 cm; its length was 2 cm and was used at the "cut" modulation. Rats were divided into seven groups of nine animals each. Burn wounds were injected with murine recombinant leptin and the rats were sacrificed 3, 7 and 9 days after surgery. Every group had obtained three animals for the three different days of sacrifice. Three different leptin doses of 250 pg/ml, 500 pg/ml and 1000 pg/ml were used in different animal groups (A, B and C). For every one of the three leptin doses used, another animal group was evaluated by using the combined injection of leptin and antileptin (A1, B1, and C1), in order to study the inhibitory effect to the leptin factor. Nine rats were served as controls. These were injected with 0.3 ml water for injection solution and sacrificed at the same time intervals. After sacrifice of the animals, the skin was grossly determined by its appearance, colour and texture. Full thickness burn wounds were dissected for histological examination. A qualitative analysis of angiogenesis in the burn wound was conducted following a standard hematoxylin and eosin stain. The wound tissue samples from each experimental group underwent immunohistochemical evaluation of microvessel density by endothelial cell staining with mouse anti-rat CD 34 monoclonal antibody. RESULTS: The most impressive growth of new blood vessels appeared seven and nine days after treatment with the highest leptin doses. There were no significant differences in microvessel density between the seventh and the ninth postoperative day among different groups treated with leptin. All wounds from the control group, as well as those from animal groups treated with the combined injection of leptin and antileptin did not develop any new vessels. CONCLUSION: Exogenous administration of recombinant leptin increases early tissue angiogenesis in the burn wound level of an experimental animal model.

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Zeng, Qingxiang, Xi Luo, Yiquan Tang, Wenlong Liu, and Renzhong Luo. "Leptin Regulated ILC2 Cell through the PI3K/AKT Pathway in Allergic Rhinitis." Mediators of Inflammation 2020 (March 7, 2020): 1–9. http://dx.doi.org/10.1155/2020/4176082.

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Background. Recent studies suggest that leptin is involved in Th2 response in allergic rhinitis (AR). However, the effect of leptin on type II innate lymphoid cells (ILC2s) in AR is not well characterized. Methods. Twenty-six AR patients and 20 healthy controls were enrolled. Serum leptin levels were measured, and their correlation with ILC2 and type II cytokines were analyzed using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. ILC2 differentiation and cytokine production stimulated by human recombinant leptin were analyzed by real-time polymerase chain reaction (PCR) and ELISA. AR mouse models were also established to verify the effect of leptin on ILC2 cell regulation. Results. Our results showed that elevated serum leptin in AR patients was correlated with the percentage of ILC2 and the expression of type II cytokines. The recombinant leptin enhanced the expression of ILC2 cell transcription factors and type II cytokine through the PI3K/AKT pathway. The AR mice treated with leptin showed as stronger ILC2 inflammation and symptoms compared with control mice. Conclusions. Our data provide evidence that upregulation of leptin promotes ILC2 responses in AR and this process was achieved through the PI3K/AKT pathway.

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Robinson, CJ, R. Gaines Das, and D. Woollacott. "The first international standard for human leptin and the first international standard for mouse leptin: comparison of candidate preparations by in vitro bioassays and immunoassays." Journal of Molecular Endocrinology 27, no. 1 (2001): 69–76. http://dx.doi.org/10.1677/jme.0.0270069.

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In an international collaborative study, two preparations of human sequence recombinant leptin and two preparations of mouse sequence recombinant leptin were evaluated, using in vitro bioassays and immunoassays, by eight laboratories, in three countries, for their suitability to serve as the international standard (IS) for human and mouse leptin respectively. The bioassays detected the human and mouse leptin with similar potency, while the immunoassays showed a greater response to the leptin of the species against which the antibody preparation had been raised. Comparison of the candidate standards with the various preparations of leptin of the same species currently assayed in the participating laboratories showed that immunoassay measurements cannot be used to predict the biological potency. On the basis of the results reported here, in October 1999 the Expert Committee on Biological Standardization of the World Health Organization established the preparation coded 97/594 as the first IS for human leptin, with an assigned unitage of 4000 IU/ampoule, and the preparation coded 97/626 as the first IS for mouse leptin, with an assigned unitage of 4000 IU/ampoule. The ISs for leptin are distributed by the National Institute for Biological Standards and Control, UK, http://www.nibsc.ac.uk.

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Zhang, Y., JT Wilsey, CD Frase, et al. "Peripheral but not central leptin prevents the immunosuppression associated with hypoleptinemia in rats." Journal of Endocrinology 174, no. 3 (2002): 455–61. http://dx.doi.org/10.1677/joe.0.1740455.

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Leptin is a peripheral immunoenhancing reagent that directly activates splenic lymphocytes in mice. We found that a 48 h fast in rats resulted in a decrease in serum leptin that was accompanied by a lower delayed-type hypersensitivity (DTH) response. Peripheral leptin replacement completely restored this response in fasted animals. We employed a recombinant adeno-associated virus (rAAV) system to deliver leptin gene directly into rat brain to assess the effect of sustained long-term central expression of leptin on immune responses. The rAAV-leptin rats had elevated central leptin over the 60 day duration of the experiment, whereas body fat and circulating leptin fell to near zero levels. The DTH response was significantly reduced by 10-20% in rats receiving rAAV-leptin compared with the control rats, and the difference was maintained for over 50 h. When the rats undergoing rAAV-leptin gene therapy were given either murine recombinant leptin or PBS s.c., rats receiving leptin had a 17% higher DTH response than rats receiving PBS. The isolated splenocytes from the former group also proliferated 34% more in vitro in response to the mitogen concanavalin A as compared with the latter group. These results suggest that peripheral leptin has a dominant role in maintaining T-cell-mediated immune responses in rats, and central leptin is unable to compensate for the immunosuppression associated with peripheral hypoleptinemia. Furthermore, preservation of normal cell-mediated immune responses does not require fat tissue as along as serum leptin levels are maintained.

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Cammisotto, Philippe G., Diane Gingras, and Moïse Bendayan. "Transcytosis of gastric leptin through the rat duodenal mucosa." American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 4 (2007): G773—G779. http://dx.doi.org/10.1152/ajpgi.00260.2007.

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Leptin is secreted into the gastric juice by epithelial Chief cells and reaches the duodenum in a biologically intact active form. We assessed the possibility that this gastric leptin crosses the intestinal mucosa by transcytosis through enterocytes to reach blood circulation. Endogenous gastric leptin secretion was triggered by cholinergic stimulation. In another set of experiments, recombinant leptin was inserted in vivo into the duodenal lumen. Plasma levels of leptin were assessed by enzyme immunoassay and Western blot, and duodenal tissue was processed for immunocytochemistry. We first observed that leptin was found inside duodenal enterocytes from fed rats but not inside those from fasted ones. Stimulation of gastric secretion by a cholinergic agent led to rapid increases in plasma leptin levels (202 ± 39%) except when the pylorus was clamped. Insertion of recombinant leptin into the duodenal lumen raised plasma leptin concentrations (558 ± 34%) quite rapidly, whereas carrier solution without leptin had no effect. The use of FITC-tagged leptin reinforced these results. Light and electron microscopy revealed the cellular compartments involved in its transcytosis, namely, the enterocyte microvilli, the endocytotic vesicles, the Golgi complex, and the basolateral interdigitations. Leptin was also present in the lamina propria, in capillary endothelial cell plasmalemmal vesicles, and in capillary lumina. These results demonstrate that gastric exocrine leptin is internalized by duodenal enterocytes and delivered to the lamina propria and blood circulation. It may thus be able to play important paracrine and endocrine functions for the control of gastric emptying and nutrient absorption.

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Farooqi, I. Sadaf, and Stephen O'Rahilly. "20 YEARS OF LEPTIN: Human disorders of leptin action." Journal of Endocrinology 223, no. 1 (2014): T63—T70. http://dx.doi.org/10.1530/joe-14-0480.

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The discovery of leptin has provided a robust framework upon which our current understanding of the mechanisms involved in energy homeostasis has been built. In this review, we describe how the identification of humans with mutations in the genes encoding leptin and the leptin receptor and the characterisation of the associated clinical phenotypes have provided insights into the role of leptin-responsive pathways in the regulation of eating behaviour, intermediary metabolism and the onset of puberty. Importantly, administration of recombinant human leptin in leptin deficiency represents the first mechanistically based targeted therapy for obesity and has provided immense clinical benefits for the patients concerned. In subsequent years, we and others have shown that human obesity can result from a multiplicity of defects in the pathways downstream of leptin signalling within the brain.

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Procopio, Cristina, Francesco Andreozzi, Emanuela Laratta, et al. "Leptin-Stimulated Endothelial Nitric-Oxide Synthase via an Adenosine 5′-Monophosphate-Activated Protein Kinase/Akt Signaling Pathway Is Attenuated by Interaction with C-Reactive Protein." Endocrinology 150, no. 8 (2009): 3584–93. http://dx.doi.org/10.1210/en.2008-0921.

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The AMP-activated protein kinase (AMPK) lies upstream of Akt in the pathway leading to endothelial NO synthase (eNOS) activation. Whether leptin promotes eNOS activation via AMPK-dependent activation of Akt, and which of the two AMPKα catalytic subunits is involved, remains unknown. Leptin resistance may be partly attributed to interaction between leptin and C-reactive protein (CRP). We hypothesized that leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human recombinant CRP. Small interfering RNAs (siRNAs) were used to knock down expression of α1- or α2-AMPK in transient transfection assay to evaluate which is involved in this pathway and whether leptin effect on eNOS activation in human aortic endothelial cells might be blunted by direct interaction with human CRP. siRNA-mediated down-regulation of AMPKα1, but not AMPKα2, abolished leptin-induced Akt-Ser473 phosphorylation, eNOS-Ser1177 phosphorylation, eNOS activation, and cGMP accumulation. By contrast, siRNA-mediated knockdown of Akt1 did not affect AMPKα1 phosphorylation, but it abolished leptin-induced phosphorylation of Akt-Ser473 and eNOS-Ser1177, suggesting that Akt functions downstream of AMPKα1. Preincubation of leptin with human recombinant CRP impaired leptin-induced AMPK activation, eNOS-Ser1177 phosphorylation, eNOS activity, and intracellular cGMP accumulation. The data are consistent with a model implicating an AMPKα1→Akt→eNOS pathway leading to NO production in response to leptin supporting the idea that interaction between leptin and CRP may have a role in impairing leptin effect on eNOS activation, suggesting a link between leptin resistance, low-grade inflammation, and endothelial dysfunction.

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Alexander, L. "Human Recombinant Leptin for Treatment of Hypothalamic Amenorrhea." MD Conference Express 11, no. 5 (2011): 9. http://dx.doi.org/10.1177/155989771105003.

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Welt, Corrine K., Jean L. Chan, John Bullen, et al. "Recombinant Human Leptin in Women with Hypothalamic Amenorrhea." New England Journal of Medicine 351, no. 10 (2004): 987–97. http://dx.doi.org/10.1056/nejmoa040388.

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Welt, Corrine K., Jean L. Chan, John Bullen, et al. "Recombinant Human Leptin in Women With Hypothalamic Amenorrhea." Obstetrical & Gynecological Survey 60, no. 2 (2005): 104–5. http://dx.doi.org/10.1097/01.ogx.0000151645.22134.0b.

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De Blasio, Miles J., Stuart A. Lanham, Dominique Blache, Richard O. C. Oreffo, Abigail L. Fowden, and Alison J. Forhead. "Sex- and bone-specific responses in bone structure to exogenous leptin and leptin receptor antagonism in the ovine fetus." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 314, no. 6 (2018): R781—R790. http://dx.doi.org/10.1152/ajpregu.00351.2017.

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Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.9% saline, n = 13), recombinant ovine leptin at two doses (0.6 mg·kg−1·day−1 LEP1, n = 10 or 1.4 mg·kg−1·day−1 LEP2, n = 7), or recombinant superactive ovine leptin receptor antagonist (4.6 mg·kg−1·day−1 SOLA, n = 6). No significant differences in plasma insulin-like growth factor-I, osteocalcin, calcium, inorganic phosphate, or alkaline phosphatase were observed between treatment groups. Total femur midshaft diameter and metatarsal lumen diameter were narrower in male fetuses treated with exogenous leptin. In a fixed length of femur midshaft, total and bone volumes were reduced by the higher dose of leptin; nonbone space volume was lower in both groups of leptin-treated fetuses. Leptin infusion caused increments in femur porosity and connectivity density, and vertebral trabecular thickness. Leptin receptor antagonism decreased trabecular spacing and increased trabecular number, degree of anisotrophy, and connectivity density in the lumbar vertebrae. The increase in vertebral porosity observed following leptin receptor antagonism was greater in the malecompared with female, fetuses. Therefore, leptin may have a role in the growth and development of the fetal skeleton, dependent on the concentration of leptin, sex of the fetus, and bone type examined.

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Kaibara, Atsushi, Armin Moshyedi, Troy Auffenberg, et al. "Leptin produces anorexia and weight loss without inducing an acute phase response or protein wasting." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 274, no. 6 (1998): R1518—R1525. http://dx.doi.org/10.1152/ajpregu.1998.274.6.r1518.

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The ob gene product leptin is known to produce anorexia and loss of body fat when chronically administered to both lean and genetically obese mice. The current study was undertaken to examine whether administration of recombinant leptin in quantities sufficient to produce decreases in food intake and body weight and alterations in body composition would elicit either an hepatic acute phase protein response or preferential loss of carcass lean tissue. Mice were administered increasing quantities of recombinant human leptin or human tumor necrosis factor-α as a positive control. Although leptin (at 10 mg/kg body wt) produced significant anorexia and weight loss (both P < 0.05), human leptin administration did not appear to induce an hepatic acute phase protein response in either lean or genetically obese mice, as determined by protein synthetic rates in the liver or changes in the plasma concentration of the murine acute phase protein reactants, amyloid A, amyloid P, or seromucoid (α1-acid glycoprotein). In addition, human leptin administration did not induce a loss of fat-free dry mass (protein) in lean or obese animals. The findings suggest that at doses adequate to alter food intake and body weight leptin is not a significant inducer of the hepatic acute phase response nor does leptin promote the preferential loss of somatic protein characteristic of a chronic inflammatory process.

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Delavaud, C., F. Bocquier, Y. Chilliard, DH Keisler, A. Gertler, and G. Kann. "Plasma leptin determination in ruminants: effect of nutritional status and body fatness on plasma leptin concentration assessed by a specific RIA in sheep." Journal of Endocrinology 165, no. 2 (2000): 519–26. http://dx.doi.org/10.1677/joe.0.1650519.

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A specific leptin RIA was developed to assess concentrations of leptin in ovine plasma, and was shown to be efficient with bovine and caprine plasma. A specific, high-affinity antibody was generated against recombinant ovine leptin which, when used in a competitive leptin RIA, provided valid estimates of linearity (r=+0.989-0.998), recovery (102%), repeatability (13%) and limit of sensitivity (0.83 ng/ml for 100 microl sample size). Serial dilutions of five ovine, bovine or caprine plasma samples showed good linearity and parallelism with the recombinant ovine leptin standard curve. A comparison of this RIA was made with a commercial 'multi-species' RIA kit using 56 ovine plasma samples. Major differences were found in assay sensitivity. Non-lactating, non-pregnant, ovariectomized ewes were fed a ration for 65 days which provided 90+/-9% (control; n=12) or 39+/-2% of maintenance energy requirements (underfed; n=16) in order to analyse the respective effects of body fatness (estimated by either an in vivo dilution technique or body condition scoring) and of nutritional status on plasma leptin concentration. There was a significant positive correlation between body fatness or body condition score and plasma leptin levels (r=+0.68, P<0.001 or r=+0.72, P<0.001 respectively). When concentrations of leptin were assessed over time, underfed ewes exhibited a dramatic reduction in plasma leptin values (-56%, P<0.001). These data provide strong evidence that, in sheep, the variations in plasma concentrations of leptin are related to variations in body fatness (35%) and, to a lesser extent, in nutritional status (17%).

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Paczoska-Eliasiewicz, H., M. Proszkowiec, A. Hrabia, et al. "Leptin is involved in the regulation of ovarian activity in fasted hens (Gallus domesticus)." Proceedings of the British Society of Animal Science 2002 (2002): 3. http://dx.doi.org/10.1017/s1752756200006591.

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In mammals leptin plays a key role in regulating the whole-body energy homeostasis and is important for for normal reproduction Much evidence indicates that leptin mediates the undernutrition-induced alterations of the reproductive axis (Ahima and Flier, 2000). In birds leptin gene was cloned in chickens (Taouis et al., 1998) and recombinant chicken leptin (chLep) was prepared in our laboratory (Raver et al., 1998). Unlike mammals, leptin is expressed not only in the adipose tissue but also in liver and leptin plasma level is lower in fasted than in fed hens (Dridi et al., 2000). However, the importance of leptin in avian reproduction is not known. Therefore, the aim of the present study was to examine whether in chickens leptin affects events occuring in the ovary during fasting.

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Pelleymounter, Mary Ann, Mary Jane Cullen, Denis Healy, Randy Hecht, Dwight Winters, and Michael McCaleb. "Efficacy of exogenous recombinant murine leptin in lean and obese 10- to 12-mo-old female CD-1 mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275, no. 4 (1998): R950—R959. http://dx.doi.org/10.1152/ajpregu.1998.275.4.r950.

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Leptin efficacy was compared in obese and lean female CD-1 mice. Body weights in these 10- to 12-mo-old mice ranged from 29.7 to 62.0 g, and leptin levels correlated with body weight. Mice from the lean and obese ends of the weight distribution were treated with daily peripheral leptin injections (1–100 mg/kg) for a 33-day period. The half-maximal effective doses for weight loss and fat reduction were shifted 0.5–0.7 log to the right for obese mice. Leptin was less efficacious at low doses (1–3 mg/kg) in obese mice but equal to or more efficacious in obese than lean mice at high doses (30–100 mg/kg). Leptin’s initial effects on weight loss could be explained by appetite suppression in both groups, but its effects on fat reduction were greater in leptin-treated than pair-fed mice, particularly in the lean group. Leptin also prevented the elevations in serum corticosterone and ketones found in pair-fed lean mice. These data allow a quantitative comparison of leptin sensitivity in obese vs. lean CD-1 mice and suggest that in mice where obesity is a function of outbreeding and age, leptin sensitivity is moderately reduced. Furthermore, although appetite suppression has a clear role in leptin’s effects on body weight, leptin may also have specific effects on lipid metabolism and mobilization that are different from the metabolic compensations that normally occur with food deprivation.

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Nilsson, C., D. Swolin-Eide, C. Ohlsson, et al. "Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure." Journal of Endocrinology 176, no. 1 (2003): 13–21. http://dx.doi.org/10.1677/joe.0.1760013.

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Leptin is involved in regulating food intake, energy balance and bone formation. Increasing evidence suggests that leptin is also involved in fetal growth and development. The aim of this study was to determine if increased maternal leptin is followed by changes in body composition, skeletal growth or hormonal regulation in the adult rat offspring. Pregnant rats were given injections of either human recombinant leptin (3.5 mg/kg, i.p.) or vehicle on days 8, 10 and 12 of gestation. Both genders of leptin-exposed offspring showed significantly reduced adipose tIssue weight at adult age. Skeletal growth and cortical bone dimensions were significantly reduced. Circulating testosterone levels were significantly increased in female leptin-exposed offspring, and male leptin-exposed offspring had significant testicular enlargement. No significant effects were seen on circulating leptin levels or hypothalamic protein levels of the leptin receptor. The results demonstrate that maternally administered leptin is involved in fetal growth and development, leading to lean offspring with reduced skeletal growth.

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Benomar, Y., M. Taouis, and N. Rideau. "Leptin fully suppresses insulin secretion induced by acetylcholine and its effect is reversed by tolbutamide in in vitro perfused chicken pancreas." Proceedings of the British Society of Animal Science 2002 (2002): 98. http://dx.doi.org/10.1017/s1752756200007547.

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The chicken leptin cDNA has been cloned and sequenced (AF012727, AF082500) (Taouis et al., 2001) and in this species, the leptin messenger has been found to be expressed not only in adipose tissue but also in the liver. In mammals, circulating leptin acts through specific receptors (Ob-Rb) located in the region of hypothalamus that regulates feeding behavior and energy expenditure; Ob-Rb have also been identified in the pancreatic ß-cells that produce insulin supporting evidence that leptin directly regulates insulin release (Kieffer et al. 2000). A direct effect of leptin on peripheral target tissues has not yet been demonstrated in chicken. The work was designed to study the effect of recombinant chicken leptin on acetylcholine-induced insulin secretion by isolated perfused chicken pancreas.

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Masuo, Kazuko. "Human Recombinant Leptin Administration as a Potential Obesity Therapy." Immunology‚ Endocrine & Metabolic Agents in Medicinal Chemistry 10, no. 2 (2010): 50–54. http://dx.doi.org/10.2174/187152210793177018.

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Yacobovitz, M., G. Solomon, E. E. Gusakovsky, B. Levavi-Sivan, and A. Gertler. "Purification and characterization of recombinant pufferfish (Takifugu rubripes) leptin." General and Comparative Endocrinology 156, no. 1 (2008): 83–90. http://dx.doi.org/10.1016/j.ygcen.2007.11.013.

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Bertile, Fabrice, Hugues Oudart, Yvon Le Maho, and Thierry Raclot. "Recombinant leptin in the hypothalamic response to late fasting." Biochemical and Biophysical Research Communications 310, no. 3 (2003): 949–55. http://dx.doi.org/10.1016/j.bbrc.2003.09.117.

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Ormseth, O. A., M. Nicolson, M. A. Pelleymounter, and B. B. Boyer. "Leptin inhibits prehibernation hyperphagia and reduces body weight in arctic ground squirrels." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 271, no. 6 (1996): R1775—R1779. http://dx.doi.org/10.1152/ajpregu.1996.271.6.r1775.

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The ob gene product leptin is thought to play a physiological role in the fine tuning of a homeostatic mechanism regulating satiety and adiposity. Mouse recombinant leptin was administered to seasonally hyperphagic arctic ground squirrels as a first step in demonstrating the evolutionary conservation of leptin function and the potential involvement of leptin in the seasonal regulation of adiposity in hibernators. Continuous infusion of leptin for 3 wk via miniosmotic pumps resulted in a reduction in food intake and body weight in a manner consistent with its proposed role as a satiety hormone. During the recovery period after leptin administration, squirrels that had received leptin became hyperphagic relative to controls. Percent body fat was estimated at weekly intervals by measuring total body electrical conductivity and decreased after 3 wk of leptin administration. Our observations support the role of leptin as a regulatory hormone involved in the control of satiety, adiposity, and possibly energy expenditure in hibernating mammals.

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Conroy, Rushika, Gerardo Febres, Donald J. McMahon, et al. "Recombinant Human Leptin Does Not Alter Gut Hormone Levels after Gastric Bypass but May Attenuate Sweet Cravings." International Journal of Endocrinology 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/120286.

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Bariatric surgery improves glucose homeostasis and alters gut hormones partly independent of weight loss. Leptin plays a role in these processes; levels are decreased following bariatric surgery, creating a relative leptin insufficiency. We previously showed that leptin administration in a weight-reduced state after Roux-en-Y gastric bypass (RYGB) caused no further weight loss. Here, we discuss the impact of leptin administration on gut hormones, glucostasis, and appetite. Weight stable women after RYGB were randomized to receive placebo or recombinant human metreleptin (0.05 mg/kg twice daily). At weeks 0 and 16, a liquid meal challenge was performed. Glucose, insulin, C-peptide, GLP-1, PYY, glucagon, and ghrelin (total, acyl, and desacyl) were measured fasting and postprandially. Appetite was assessed using a visual analog scale. Mean post-op period was53±2.3months; mean BMI was34.6±0.2 kg/m2. At 16 weeks, there was no significant change in weight within or between groups. Fasting PYY was significantly different between groups and the leptin group had lower sweets craving at week 16 than the placebo group (P<0.05). No other differences were observed. Leptin replacement does not alter gut hormones or glucostasis but may diminish sweet cravings compared to placebo in this population of post-RYGB women.

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Blache, Dominique, Pietro Celi, Margaret A. Blackberry, Robyn A. Dynes, and Graeme B. Martin. "Decrease in voluntary feed intake and pulsatile luteinizing hormone secretion after intracerebroventricular infusion of recombinant bovine leptin in mature male sheep." Reproduction, Fertility and Development 12, no. 8 (2000): 373. http://dx.doi.org/10.1071/rd00102.

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The aim of the present study was to determine whether leptin might play a role in the gonadotrophic response of mature merino rams to changes in the level of nutrition in rams fed ad libitum. Recombinant bovine leptin was infused intracerebroventricularly and voluntary food intake (VFI) and luteinizing hormone (LH) pulse frequency were measured. In Experiment 1, rams (n = 5) were infused for 24 h per day for 5 days with vehicle or with leptin (0.04, 0.4 and 4.0g h –1 ). All doses decreased both VFI and LH pulse frequency. In Experiment 2, rams were infused for 24 h per day for 5 days with vehicle (n = 10) or leptin (4 g h –1; n= 5); a sub-group of 5 controls was pair-fed to the leptin-infused group to control for effects of changes in feed intake. LH pulse frequency was reduced equally in both the leptin-infused and pair-fed groups. Leptin did not affect other systems controlled by the hypothalamic–pituitary axis. Thus, rather than stimulate LH secretion, intracerebral leptin specifically inhibits it by reducing food intake, so it is unlikely that effects of nutrition on the reproductive axis in mature rams involves leptin as a single blood-borne signal. A range of nutritional or metabolic inputs may be needed, and perhaps interconnections between neural centres that control appetite and reproduction.

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Esteve, M., P. Savall, J. Virgilli, J. A. Fernández-López, X. Remesar, and M. Alemany. "Modulation by Leptin, Insulin and Corticosterone of Oleoyl-estrone Synthesis in Cultured 3T3 L1 Cells." Bioscience Reports 21, no. 6 (2001): 755–63. http://dx.doi.org/10.1023/a:1015580623325.

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Preadipocytes (3T3 L1) were used between 7 and 14 days after differentiation; they were incubated with 44 nM 3H-esterone. The medium was supplemented with 1 μM recombinant murine leptin, 10 nM recombinant human insulin, or 1 μM corticosterone for up to 72 hr. In a second series of experiments, cells were incubated for 48 hr with different concentrations of leptin, insulin or corticosterone, and compared with controls (plain medium). Cells were harvested, washed in buffer and homogenized, and protein was measured. Lipid extracts of cell homogenates were used for HPLC; the label distribution in free and acyl-estrone peaks was measured. Overall uptake of estrone (i.e., the sum of free and acyl-estrone) by cells was not affected by leptin or corticosterone, but strongly reduced by insulin. Leptin and corticosterone increased the synthesis of acyl-esterone in a dose- and time-dependent way. Insulin decreased acyl-estrone synthesis at low concentrations and with little change over time. The results suggest that control of oleoyl-estrone deposition in adipocytes is modulated in at least two distinct steps: (a) estrone uptake, affected by insulin in the physiological range; and (b) synthesis of oleoyl-estrone from cell estrone. The latter may be affected by insulin, but leptin and corticosterone enhance the process.

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Janik, John E., Brendan D. Curti, Robert V. Considine та ін. "Interleukin 1α Increases Serum Leptin Concentrations in Humans". Journal of Clinical Endocrinology & Metabolism 82, № 9 (1997): 3084–86. http://dx.doi.org/10.1210/jcem.82.9.4214.

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Abstract Leptin, the protein product of the ob gene, regulates appetite and body weight in animals. Endotoxin and cytokines, induced by endotoxin, interleukin (IL) 1 and tumor necrosis factor, increase expression of leptin in mice and hamsters. We measured serum leptin concentrations in patients with cancer before and after administration of recombinant human IL-1α. Fourteen patients received IL-1α at one of three dose levels (0.03, 0.1, or 0.3 μg/kg·day) for 5 days. Serum leptin concentrations increased in all but two patients within 24 h after the first dose. The increase in leptin was correlated directly with IL-1α dose (P = 0.0030). Despite continued administration of IL-1α, serum leptin concentrations returned to pretreatment levels by day 5 of therapy. An increase in serum leptin concentrations may be one mechanism by which anorexia is induced by IL-1α. However, tachyphylaxis of the leptin response suggests that other mechanisms also are involved.

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Tena-Sempere, M., L. Pinilla, LC Gonzalez, C. Dieguez, FF Casanueva, and E. Aguilar. "Leptin inhibits testosterone secretion from adult rat testis in vitro." Journal of Endocrinology 161, no. 2 (1999): 211–18. http://dx.doi.org/10.1677/joe.0.1610211.

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Leptin, the product of the ob gene, has emerged recently as a pivotal signal in the regulation of fertility. Although the actions of leptin in the control of reproductive function are thought to be exerted mainly at the hypothalamic level, the potential direct effects of leptin at the pituitary and gonadal level have been poorly characterised. In the present study, we first assessed the ability of leptin to regulate testicular testosterone secretion in vitro. Secondly, we aimed to evaluate whether leptin can modulate basal gonadotrophin and prolactin (PRL) release by incubated hemi-pituitaries from fasted male rats. To attain the first goal, testicular slices from prepubertal and adult rats were incubated with increasing concentrations (10(-9)-10(-7) M) of recombinant leptin. Assuming that in vitro testicular responsiveness to leptin may be dependent on the background leptin levels, testicular tissue from both food-deprived and normally-fed animals was used. Furthermore, leptin modulation of stimulated testosterone secretion was evaluated by incubation of testicular samples with different doses of leptin in the presence of 10 IU human chorionic gonadotrophin (hCG). In addition, analysis of leptin actions on pituitary function was carried out using hemi-pituitaries from fasted adult male rats incubated in the presence of increasing concentrations (10(-9)-10(-7) M) of recombinant leptin. Serum testosterone levels, and basal and hCG-stimulated testosterone secretion by incubated testicular tissue were significantly decreased by fasting in prepubertal and adult male rats. However, a significant reduction in circulating LH levels was only evident in adult fasted rats. Doses of 10(-9)-10(-7) M leptin had no effect on basal or hCG-stimulated testosterone secretion by testes from prepubertal rats, regardless of the nutritional state of the donor animal. In contrast, leptin significantly decreased basal and hCG-induced testosterone secretion by testes from fasted and fed adult rats. In addition, 10(-9) M leptin inhibited LH and FSH secretion by incubated hemi-pituitaries from fasted adult males, whereas, at all doses tested, it was ineffective in modulating PRL release. Our results show that leptin, depending on the state of sexual maturation, is able to inhibit testosterone secretion acting at the testicular level. Furthermore, the present data suggest that the actions of leptin on the reproductive system are complex and are probably carried out at different levels of the hypothalamic-pituitary-gonadal axis.

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Niv-Spector, Leonora, Dana Gonen-Berger, Isabelle Gourdou, et al. "Identification of the hydrophobic strand in the A–B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists." Biochemical Journal 391, no. 2 (2005): 221–30. http://dx.doi.org/10.1042/bj20050457.

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Interaction of leptin with its receptors resembles that of interleukin-6 and granulocyte colony-stimulating factor, which interact with their receptors through binding sites I–III. Site III plays a pivotal role in receptors' dimerization or tetramerization and subsequent activation. Leptin's site III also mediates the formation of an active multimeric complex through its interaction with the IGD (immunoglobulin-like domain) of LEPRs (leptin receptors). Using a sensitive hydrophobic cluster analysis of leptin's and LEPR's sequences, we identified hydrophobic stretches in leptin's A–B loop (amino acids 39–42) and in the N-terminal end of LEPR's IGD (amino acids 325–328) that are predicted to participate in site III and to interact with each other in a β-sheet-like configuration. To verify this hypothesis, we prepared and purified to homogeneity (as verified by SDS/PAGE, gel filtration and reverse-phase chromatography) several alanine muteins of amino acids 39–42 in human and ovine leptins. CD analyses revealed that those mutations hardly affect the secondary structure. All muteins acted as true antagonists, i.e. they bound LEPR with an affinity similar to the wild-type hormone, had no agonistic activity and specifically inhibited leptin action in several leptin-responsive in vitro bioassays. Alanine mutagenesis of LEPR's IGD (amino acids 325–328) drastically reduced its biological but not binding activity, indicating the importance of this region for interaction with leptin's site III. FRET (fluorescence resonance energy transfer) microscopy experiments have documented that the transient FRET signalling occurring upon exposure to leptin results not from binding of the ligand, but from ligand-induced oligomerization of LEPRs mediated by leptin's site III.

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Isozaki, O., T. Tsushima, M. Miyakawa, Y. Nozoe, H. Demura, and H. Seki. "Growth hormone directly inhibits leptin gene expression in visceral fat tissue in fatty Zucker rats." Journal of Endocrinology 161, no. 3 (1999): 511–16. http://dx.doi.org/10.1677/joe.0.1610511.

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Growth hormone (GH) is known to interact with adipose tissue and to induce lipolysis. Adipocytes produce leptin which regulates appetite and energy expenditure. In order to elucidate the role of GH in leptin production, we studied the effect of GH on leptin gene expression and body fat in fatty Zucker rats, a model of obesity with resistance to both leptin and insulin. Recombinant human GH administered subcutaneously at 0.5 mg/kg per day (low dose) as well as at 1.65 mg/kg per day (high dose) reduced leptin mRNA levels in epididymal fat tissue but not in subcutaneous fat tissue after 7 days. GH administration only at the high dose reduced percentage body fat. Insulin-like growth factor-I infusion (200 microg/kg per day) did not change percentage body fat or leptin mRNA levels in epididymal fat. These observations suggest that GH directly interacts with adipose tissue and reduces leptin gene expression in visceral fat tissue.

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Allman, Monique, Mathew Wallace, Latausha Gaskin, and Chantal A. Rivera. "Leptin Induces an Inflammatory Phenotype in Lean Wistar Rats." Mediators of Inflammation 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/738620.

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The present study addressed the hypothesis that leptin promotes leukocyte trafficking into adipose tissue. Accordingly, male Wistar rats were treated with saline or recombinant rat leptin (1 mg/kg) via the tail vein. Leukocyte trafficking in mesenteric venules was quantified by intravital microscopy. Treatment with leptin resulted in a 3- and 5-fold increases in rolling and firm adhesion, respectively. Compared to vehicle controls, leptin enhanced mRNA levels of IL-6 (8-fold) and MCP-1 (5-fold) in mesenteric adipose tissue (MAT). Similar increases in these markers were observed in mesenteric venules and in liver. Finally, the direct effect of leptin was assessed in C3A hepatocytes treated with leptin for 24 hours (7.8 ng/mL–125 ng/mL). Consistent with observations in vivo, production of ICAM-1, MCP-1, and IL-6 by hepatocytes was increased significantly. These findings support the hypothesis that leptin directly initiates inflammation in the local environment of mesenteric adipose tissue as well as systemically.

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Marques, Durval Santos, Flávia Meireles Gombar, Jorge Luiz Alves Pereira, Francisco José Barcellos Sampaio, and Cristiane da Fonte Ramos. "Metabolic programming of lipid profile and reproductive organs weight by leptin treatment on early life." Acta Cirurgica Brasileira 25, no. 1 (2010): 55–58. http://dx.doi.org/10.1590/s0102-86502010000100013.

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PURPOSE: To evaluate whether the neonatal leptin treatment during the first days of life can program the male reproductive organs weight and the lipid profile. METHODS: At birth 6 dams were divided into 2 groups: Leptin - each pup was injected with 50μL of recombinant rat leptin (80ng/g BW, sc), for the first 10 d of lactation; Control - each pup received the same volume of saline. After weaning, all pups received unlimited access to food until 190 days of age when they were killed. Values are given as mean ± SEM of 6 animals and Test t Student was used to analyze the results. RESULTS: The leptin treatment resulted in a significant increase in body weight (Control= 411.8±16.31; Leptin= 481.8±11.29, p=0.005) and food consumption (Control= 25.32±0.09; Leptin= 32.42±0.15, p=0.0001) and a significant reduction in triglycerides levels (Control= 540.0±117.9; Leptin= 93.25±15.21, p=0.006) and in the weight of hypothalamus (Control= 0.234±0.016; Leptin= 0.154±0.015, p=0.007), pituitary (Control= 0.104±0.0120; Leptin= 0.033±0.012, p=0.003), testis (Control= 3.75±0.055; Leptin= 3.19±0.10, p=0.002) and prostate (Control=1.641±0.1389; Leptin= 0.91±0.07, p=0.001). CONCLUSION: Leptin treatment on the first days of life can program the reproductive organs weight and the lipid profile of the progeny.

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