scholarly journals The Importance of Leptin to Reproduction

Endocrinology ◽  
2020 ◽  
Vol 162 (2) ◽  
Author(s):  
Gwen V Childs ◽  
Angela K Odle ◽  
Melanie C MacNicol ◽  
Angus M MacNicol
Keyword(s):  
Regulatory Protein ◽  
Leptin Resistance ◽  
Testicular Development ◽  
Signal Timing ◽  
Adult Males ◽  
Serum Leptin ◽  
Obesity Epidemic ◽  
Messenger Ribonucleic Acid ◽  
Cell Functions ◽  
Hormone Pulses

Abstract A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.

POSTOPERATIVE COMPLIANCE OF BARIATRIC SURGERY PATIENTS REGARDING THE ASSESSMENT OF SERUM LEPTIN LEVELS AND INSULIN RESISTANCE

2019 ◽  
Vol 49 (1/2019) ◽  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Serum Levels ◽  
Medical Laboratory ◽  
Leptin Resistance ◽  
Obese Patients ◽  
Laboratory Assessment ◽  
Serum Leptin ◽  
Before And After ◽  
Bariatric Patients

Background and aims: Overweight and obese patients who undergo bariatric surgery require a rigorous clinical and paraclinical assessment both before and after the surgery at 3, 6, and 12 months.The present study aims the assessment of serum leptin levels and insulin resistance status in compliant bariatric patients to scheduled medical laboratory assessment at 6 months after surgery. Material and Method: The study included 109 eligible patients selected for bariatric surgery, 48 of whom attended the scheduled visit at 6 months after the surgery. Laboratory assessing regarded the insulin resistance by determining before meal the serum levels of leptin, glucose and insulin, as well as HOMA 1 and HOMA 2 indexes. Results: Patients who underwent bariatric treatment experienced a significant decrease in insulin resistance status. A higher percentage in the preoperative group was recorded in women, feature which was also recorded in the postoperative group that attended the scheduled visit at 6 months after surgery. Age is also an important factor that significantly influences the behavioral adherence to postoperative visits. Conclusions: Insulin resistance status improved significantly in 6 months after bariatric surgery among the fully compliant patients. The percentage of attendance at scheduled visits is higher among women, and decreases with age. Keywords: obesity surgery, leptin resistance, insulin resistance, HOMA index, compliance

188 Novel Anti-SIRpalpha antibodies with differentiated characteristics as promising cancer therapeutics

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A202-A202
Author(s):  
Swati Jalgaonkar ◽  
George Huang ◽  
Erin Filbert ◽  
Christine Tan ◽  
Ryan Alvarado ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Immunity ◽  
Cell Activation ◽  
Regulatory Protein ◽  
Cancer Therapeutics ◽  
Myeloid Cell ◽  
Therapeutic Window ◽  
Close Relative ◽  
Cell Functions ◽  
Tumor Clearance

BackgroundTherapeutically targeting tumor myeloid cells has emerged as a novel and complementary strategy to existing cancer immunotherapy approaches. The interaction of tumor expressed CD47 with SIRP alpha (signal regulatory protein-alphaa, SIRPA) on macrophages, dendritic cells and neutrophils inhibits key immune effector mechanisms. Targeting SIRPa-CD47 represents a novel approach to enhance anti-tumor immunity by augmenting or reactivating critical tumor clearance mechanisms.H5F9, an antibody against CD47, has shown promising therapeutic activities in patients with MSD, AML and NHL. However, agents targeting CD47 present hematological toxicities and present a huge antigen sink leading to not achieving an optimum therapeutic window. Our approach is to target SIRP alpha, the receptor of CD47 and focus therapeutic targeting to relevant mechanisms related to phagocytosis and myeloid cell activation and at the same time avoid undesired effects of blocking CD47. SIRP gamma, a very close relative of SIRP alpha is expressed on T cells and also binds to CD47. It has been shown that blockade of SIRP gamma-CD47 interaction inhibits T cell proliferation and blocks trans-endothelial T cell migration. Hence, our aim is to generate SIRP alpha selective antibodies that do not cross-react with SIRP gamma and have minimal impact on T cell functions.MethodsUsing Apexigen’s APXiMAB™ proprietary antibody discovery platform, we have generated two novel anti-SIRP alpha antibodies (APX701 & APX702) with differentiated properties as compared to other approaches targeting the CD47/SIRP alpha axis. We have used ELISA, FACS based cell binding and blocking assays, and functional assays including in vitro phagocytosis and antibody-dependent cell phagocytosis (ADCP) in combination with tumor-opsonizing antibody to select APX701 & APX702.ResultsOur novel preclinical-stage APX701 & APX702 antibodies have demonstrated the following attributes: high binding affinity to human SIRP alpha (APX701 Kd = 0.95nM, APX702 Kd = 0.88nM), no binding to SIRP gamma, efficient blockade of SIRP alpha binding to CD47(APX701 IC50 = 1.04nM, APX702 IC50 = 0.80nM), potent macrophage mediated phagocytosis, enhancement of ADCP mediated by tumor-opsonizing antibody and favorable developability CMC profiles. In comparison with the benchmark antibody OSE-172, APX701 & APX702 showed potent phagocytosis activity and ADCP enhancement in all donors tested while OSE-172 induced phagocytosis in only 50% of the donors. This may result from the fact that APX701 and APX702 bind to all major SIRP alpha variants (V1, V2 & V8; covering ~92% population) while OSE 172 only binds to SIRPalpha V1 (~50% population).ConclusionsAPX701 and APX702 demonstrate differentiated anti-SIRPalpha activities by enhancing myeloid cell-mediated anti-tumor immunity and reactivating critical tumor clearance mechanisms within the tumor microenvironment.

scholarly journals The Pattern of Inhibin/Activin α- andβB-Subunit Messenger Ribonucleic Acid Expression in Rat Testis after Selective Leydig Cell Destruction by Ethylene Dimethane Sulfonate1

Endocrinology ◽  
1999 ◽  
Vol 140 (12) ◽  
pp. 5761-5770 ◽  
Author(s):  
Manuel Tena-Sempere ◽  
Jukka Kero ◽  
Antti Rannikko ◽  
Wei Yan ◽  
Ilpo Huhtaniemi
Keyword(s):  
Messenger Rna ◽  
Leydig Cells ◽  
Fold Increase ◽  
Northern Hybridization ◽  
Testicular Development ◽  
Mrna Levels ◽  
Adult Type ◽  
Mature Adult ◽  
Messenger Ribonucleic Acid ◽  
High Doses

Abstract To further investigate the regulatory mechanisms responsible for the control of testicular inhibin/activin subunit gene expression, inhibin-α, -βA, and -βB messenger RNA (mRNA) levels were assessed after ethylene dimethane sulfonate (EDS)-induced destruction of Leydig cells (LC) in different animal models: the intact rat, the rat treated with high doses of testosterone, and the unilaterally cryptorchid rat. In intact rats, EDS selectively eliminates the mature adult-type LCs, activating the proliferation and differentiation of preexisting LC precursors into a new population of functionally active LCs. In this model, a single dose of EDS (75 mg/kg BW, ip) induced a significant increase in testicular inhibin-α and -βB mRNA levels 5 days after treatment (5.0- and 5.5-fold increases, respectively), whereas inhibin-βA mRNA remained undetectable upon Northern hybridization in control and EDS-treated testes. Moreover, in situ hybridization analysis demonstrated that the increased expression of inhibin-α and -βB mRNAs observed 5 days after EDS takes place mainly in Sertoli cells. Along with LC repopulation, the expression level of inhibin-α and -βB messages declined, and inhibin-α mRNA returned to control values on day 40 after EDS. This treatment, however, failed to alter the pattern of testicular expression of FSH receptor and androgen-binding protein mRNAs, thus suggesting selectivity for the above effects. In EDS-treated rats supplemented with high doses of testosterone, the preexisting mature LCs are destroyed, but, due to elevated testosterone concentrations, disruption of spermatogenesis is attenuated, and the post-EDS rise in serum gonadotropins is blocked; the latter prevents LC regeneration. In this model, a 5.0-fold increase in inhibin-α mRNA levels, similar to that found in intact animals, was detected 5 days after EDS administration, but the rise in inhibin-βB levels was partially delayed. In addition, the blockade of LC repopulation resulted in permanent elevation of inhibin-α and -βB messages throughout the study period. In unilaterally cryptorchid rats, the abdominal testis shows disrupted spermatogenesis and altered paracrine environment that expedites LC repopulation after EDS treatment. In this model, the abdominal testes showed a significant 2.5-fold increase in inhibin-α mRNA levels 5 days after EDS, but no effect was found in those of inhibin-βB. Further, the faster rate of LC repopulation resulted in precocious decline of inhibin-α mRNA levels. Finally, the expression of inhibin/activin subunit mRNAs was monitored during postnatal testicular development, specifically at the time of regression of fetal-type LCs and appearance of those of the adult type. High levels of expression of inhibin-α and -βB mRNAs were detected in neonatal and infantile testes. A sharp decline in both messages took place between days 15–20, i.e. at the time when fetal-type Leydig cells are replaced by adult-type cells. From this time point onward, inhibin-α and -βB mRNA levels remained low, ranging between 15–30% of the maximum. In conclusion, our results suggest that the adult-type LCs differentially modulate the expression of inhibin/activin subunit genes and point to a major inhibitory role in this cell type on expression of the inhibin-α gene.

scholarly journals Excessive Weight Gain Followed by Catch-Down in Exclusively Breastfed Infants: An Exploratory Study

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1290 ◽  
Author(s):  
Melanie Larsson ◽  
Mads Lind ◽  
Anni Larnkjær ◽  
Anette Due ◽  
Irina Blom ◽  
...  
Keyword(s):  
Weight Gain ◽  
Fat Mass ◽  
High Serum ◽  
Normal Weight ◽  
Milk Intake ◽  
Leptin Resistance ◽  
Serum Leptin ◽  
Excessive Weight Gain ◽  
Breastfed Infants ◽  
Excessive Weight

Some infants experience excessive weight gain (EWG) during exclusive breastfeeding, but causes and consequences are unknown. The objective was to identify factors associated with early EWG. Infants with EWG (HW-group) were examined at 5, 9 and 18 mo and compared to a breastfed group with normal weight gain (NW-group). Anthropometry, body composition, milk and blood samples, and milk intake were measured. Mean body-mass-index-for-age z-scores (BAZ) increased 1.93 from birth to 5 mo in the HW-group (n = 13) while the NW-group (n = 17) was unchanged (−0.01). The HW-group had 70% more fat mass at 5 mo, and then showed marked catch-down in BAZ from 5 to 18 mo (−0.84). Milk intake at 5–6 mo did not differ between the groups. In the HW-group milk-leptin was lower at 5 mo and serum-leptin was considerably higher at 5 and 9 mo compared to the NW-group. Serum-leptin at 5 mo was positively associated with weight-for-age z-score (WAZ) and fat mass and negatively with WAZ change from 5 to 9 mo. In conclusion, breastfed infants with EWG had catch-down growth when other foods were introduced. Low milk-leptin in the HW-group may have stimulated appetite and milk intake when weight gain was high. High serum-leptin in the HW-group suggests early leptin resistance, which could impact cerebral regulation of energy intake. Larger studies are needed to confirm these results.

scholarly journals Collectin-11 Is an Important Modulator of Retinal Pigment Epithelial Cell Phagocytosis and Cytokine Production

2017 ◽  
Vol 9 (6) ◽  
pp. 529-545 ◽  
Author(s):  
Xia Dong ◽  
Weiju Wu ◽  
Liang Ma ◽  
Chengfei Liu ◽  
Mohajeet B. Bhuckory ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Retinal Pigment Epithelial ◽  
Cytokine Production ◽  
Retinal Pigment Epithelial Cell ◽  
Retinal Pigment ◽  
Regulatory Protein ◽  
Phagocytic Cells ◽  
Rpe Cells ◽  
Cell Functions ◽  
Pigment Epithelial

In this paper, we report previously unknown roles for collectin-11 (CL-11, a soluble C-type lectin) in modulating the retinal pigment epithelial (RPE) cell functions of phagocytosis and cytokine production. We found that CL-11 and its carbohydrate ligand are expressed in both the murine and human neural retina; these resemble each other in terms of RPE and photoreceptor cells. Functional analysis of murine RPE cells showed that CL-11 facilitates the opsonophagocytosis of photoreceptor outer segments and apoptotic cells, and also upregulates IL-10 production. Mechanistic analysis revealed that calreticulin on the RPE cells is required for CL-11-mediated opsonophagocytosis whereas signal-regulatory protein α and mannosyl residues on the cells are involved in the CL-11-mediated upregulation of IL-10 production. This study is the first to demonstrate the role of CL-11 and the molecular mechanisms involved in modulating RPE cell phagocytosis and cytokine production. It provides a new insight into retinal health and disease and has implications for other phagocytic cells.

Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance

The Lancet ◽  
1996 ◽  
Vol 348 (9021) ◽  
pp. 159-161 ◽  
Author(s):  
José F Caro ◽  
Jerzy W Kolaczynski ◽  
Mark R Nyce ◽  
Joanna P Ohannesian ◽  
Irina Opentanova ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Leptin Resistance ◽  
Serum Leptin

scholarly journals Suppression of Leptin Receptor Messenger Ribonucleic Acid and Leptin Responsiveness in the Ventromedial Nucleus of the Hypothalamus during Pregnancy in the Rat

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3868-3874 ◽  
Author(s):  
S. R. Ladyman ◽  
D. R. Grattan
Keyword(s):  
Choroid Plexus ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Ventromedial Nucleus ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Messenger Ribonucleic Acid ◽  
Leptin Receptors ◽  
Receptor Isoforms

Abstract Pregnancy in the rat is a state of leptin resistance associated with impaired leptin signal transduction in the hypothalamus. The aim of this study was to determine whether this leptin-resistant state is mediated by a change in the level of leptin receptors in the hypothalamus. Real-time RT-PCR was used to determine levels of mRNA for the various leptin receptor isoforms in a number of microdissected hypothalamic nuclei and the choroid plexus. To investigate the functional activation of the leptin receptor, immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3) was examined in the arcuate nucleus and the ventromedial nucleus of the hypothalamus (VMH) of fasted diestrous and d-14 pregnant rats after an intracerebroventricular (i.c.v.) injection of either leptin (4 μg) or vehicle. A significant reduction of Ob-Rb mRNA levels was observed in the VMH during pregnancy compared with the nonpregnant controls. Furthermore, in pregnant rats the number of cells positive for leptin-induced pSTAT3 in the VMH was greatly reduced during pregnancy compared with nonpregnant rats. There were no differences in the level of Ob-Rb mRNA or in the number of leptin-induced pSTAT3-positive cells in the arcuate nucleus of nonpregnant and pregnant rats. These data implicate the VMH as a key hypothalamic site involved in pregnancy-induced leptin resistance. There were also reduced levels of mRNA for Ob-Ra, a proposed leptin transporter molecule, in the choroid plexus on d 7 and 21 of pregnancy. Hence, diminished transport of leptin into the brain may also contribute to pregnancy-induced leptin resistance.

The annual testicular cycle in an equatorial colony of lesser rock hyrax, Heterohyrax brucei

1979 ◽  
Vol 206 (1163) ◽  
pp. 183-189 ◽  
Keyword(s):  
Annual Cycle ◽  
Leydig Cells ◽  
Seminal Vesicles ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Adult Males ◽  
Sperm Production ◽  
Rock Hyrax ◽  
Germinal Cells ◽  
Caput Epididymidis

Adult males from a colony of lesser rock hyrax found near the equator in Kenya exhibited an annual cycle of testicular activity characterized by intense spermatogenesis and elevated androgen status from May to July. Average masses of testes and seminal vesicles taken in these months were almost fourfold greater than those from September to January. During the months of peak testicular activity average diameters of Leydig cells and seminiferous tubules were increased by approximately one half and total tubule length was doubled, compared with values for the quiescent months. Variable testicular development occurred during transitional intervals preceding and following peak testicular activity. From February to April thickening of the seminiferous epithelium and appearance of spermatozoa in the caput epididymidis signalled re-establishment of sperm production. In August shedding of germinal cells from the epithelium heralded impending failure of spermatogenesis. Evidence of an annual testicular cycle contradicted the prevalent belief that equatorial hyrax breed all year and suggested that the testicular cycle is a conservative element of hyracoid reproductive strategy.

scholarly journals Rictor Regulates Spermatogenesis by Controlling Sertoli Cell Cytoskeletal Organization and Cell Polarity in the Mouse Testis

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4244-4256 ◽  
Author(s):  
Heling Dong ◽  
Zhenguo Chen ◽  
Caixia Wang ◽  
Zhi Xiong ◽  
Wanlu Zhao ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Cell Function ◽  
Regulatory Protein ◽  
Small Gtpase ◽  
Mutant Mice ◽  
Actin Dynamics ◽  
Testicular Development ◽  
Developmental Defects

Maintenance of cell polarity is essential for Sertoli cell and blood-testis barrier (BTB) function and spermatogenesis; however, the signaling mechanisms that regulate the integrity of the cytoskeleton and polarity of Sertoli cells are not fully understood. Here, we demonstrate that rapamycin-insensitive component of target of rapamycin (TOR) (Rictor), a core component of mechanistic TOR complex 2 (mTORC2), was expressed in the seminiferous epithelium during testicular development, and was down-regulated in a cadmium chloride-induced BTB damage model. We then conditionally deleted the Rictor gene in Sertoli cells and mutant mice exhibited azoospermia and were sterile as early as 3 months old. Further study revealed that Rictor may regulate actin organization via both mTORC2-dependent and mTORC2-independent mechanisms, in which the small GTPase, ras-related C3 botulinum toxin substrate 1, and phosphorylation of the actin filament regulatory protein, Paxillin, are involved, respectively. Loss of Rictor in Sertoli cells perturbed actin dynamics and caused microtubule disarrangement, both of which accumulatively disrupted Sertoli cell polarity and BTB integrity, accompanied by testicular developmental defects, spermiogenic arrest and excessive germ cell loss in mutant mice. Together, these findings establish the importance of Rictor/mTORC2 signaling in Sertoli cell function and spermatogenesis through the maintenance of Sertoli cell cytoskeletal dynamics, BTB integrity, and cell polarity.

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