Upregulation of the leptin receptor as a mechanism to overcome leptin deficiency in apoptotic processes and miscarriages

2014 ◽  
Vol 101-102 ◽  
pp. 54
Author(s):  
Aurelia Pestka ◽  
B. Toth ◽  
C. Kuhn ◽  
I. Wiest ◽  
C. Hoffmann ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Leptin Deficiency

Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin

2003 ◽  
Vol 284 (3) ◽  
pp. R763-R770 ◽  
Author(s):  
Abram M. Madiehe ◽  
Tiffany D. Mitchell ◽  
Ruth B. S. Harris
Keyword(s):  
Rectal Temperature ◽  
Leptin Receptor ◽  
Short Form ◽  
Endotoxic Shock ◽  
Cytokine Receptors ◽  
Leptin Receptors ◽  
Leptin Deficiency ◽  
Tnf Α ◽  
Long Form

Leptin deficiency in ob/ob mice increases susceptibility to endotoxic shock, whereas leptin pretreatment protects them against LPS-induced lethality. Lack of the long-form leptin receptor (Ob-Rb) in db/db mice causes resistance. We tested the effects of LPS in C57BL/6J db3J/db3J (BL/3J) mice, which express only the circulating leptin receptors, compared with C57BL/6J db/db (BL/6J) mice, which express all short-form and circulating isoforms of the leptin receptor. Intraperitoneal injections of LPS significantly decreased rectal temperature and increased leptin, corticosterone, and free TNF-α in fed and fasted BL/3J and BL/6J mice. TNF-α was increased three- and fourfold in BL/3J and BL/6J, respectively. LPS (100 μg) caused 50% mortality of fasted BL/6J mice but caused no mortality in fasted BL/3J mice. Pretreatment of fasted BL/3J mice with 30 μg leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNF-α induced by 100 μg LPS. Taken together, these data provide evidence that fasted BL/3J mice are more resistant than BL/6J mice to LPS toxicity, presumably due to the absence of leptin receptors in BL/3J mice. This resistance may be due to high levels of free leptin cross-reacting with other cytokine receptors.

scholarly journals Leptin Deficiency and Its Effects on Tibial and Vertebral Bone Mechanical Properties in Mature Genetically Lean and Obese JCR:LA-Corpulent Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Raylene A. Reimer ◽  
Jeremy M. LaMothe ◽  
Ronald F. Zernicke
Keyword(s):  
Mechanical Properties ◽  
Leptin Receptor ◽  
Lumbar Vertebrae ◽  
Insulin Resistance Syndrome ◽  
Proportional Limit ◽  
Leptin Signaling ◽  
Bone Mechanical Properties ◽  
Geometrical Properties ◽  
Leptin Deficiency ◽  
Obese Rats

Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp;n=8) and lean (+/?;n=7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae(L6)were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading(L6). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely,L6in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently.

Relative leptin deficiency in children with severe early-onset obesity (SEOO) – results of the Early-onset Obesity and Leptin – German-Polish Study (EOL-GPS)

2020 ◽  
Vol 33 (2) ◽  
pp. 255-263 ◽  
Author(s):  
Agnieszka Zachurzok ◽  
Michael B. Ranke ◽  
Bertram Flehmig ◽  
Katarzyna Jakubek-Kipa ◽  
Katarzyna Marcinkiewicz ◽  
...  
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Standard Deviation Score ◽  
Tanner Stage ◽  
Serum Levels ◽  
The Body ◽  
Biologically Active ◽  
World Health ◽  
Strong Negative Correlation ◽  
Leptin Deficiency

AbstractBackgroundSevere early-onset obesity (SEOO) in children is a common feature of monogenic obesity. Gene defects of the leptin-melanocortin pathway can be analysed biochemically and genetically. The aim of this study was to search for children with leptin deficiency or biologically inactive leptin in a cohort of children with SEOO and to study associations between leptin parameters and anthropometric data.MethodsThe cohort included n = 50 children with SEOO (22 boys) who were recruited at one of four study centres (Germany: Ulm; Poland: Katowice, Szczecin, Rzeszow) between October 2015 and October 2017. Weight (kg) and height (m) were measured, Tanner stage was obtained and a fasting serum blood sample was taken. Serum levels of total leptin (LEP, ng/mL), biologically active leptin (bioLEP, ng/mL) and soluble leptin receptor (sLEPR, ng/mL) were measured. The body mass index (BMI [kg/m2]), BMI z-score (World Health Organization [WHO]), quotient of bioLEP/LEP and leptin-standard deviation score (LEP-SDS) (Tanner stage, BMI and sex-adjusted) were calculated.ResultsWe did not find any child with leptin deficiency or biologically inactive leptin in our cohort. The serum LEP and bioLEP levels were strongly correlated with age (r = 0.50, p < 0.05) and BMI (r = 0.70; p < 0.0001). Girls had higher LEP and bioLEP levels (49.7 ± 35.9 vs. 37.1 ± 25.5 ng/mL, p > 0.05) as well as lower LEP-SDS than boys (−1.77 ± 2.61 vs. −1.40 ± 2.60, p > 0.05). sLEPR levels were negatively correlated with BMI values (r = −0.44; p < 0.05), LEP (r = −0.39; p < 0.05) and bioLEP levels (r = −0.37; p < 0.05). Interestingly, there was a strong inverse relationship between LEP-SDS and BMI (r = −0.72, p < 0.001).ConclusionsIn this cohort with SEOO, we identified no new cases of children with leptin deficiency or bioinactive leptin. A strong negative correlation between the LEP-SDS and BMI values could be interpreted as relative leptin deficiency in children with SEOO. In case this hypothesis can be confirmed, these children would benefit from a substitution therapy with methionyl human leptin (metreleptin™).

scholarly journals Complex Regulation of Mammalian Target of Rapamycin Complex 1 in the Basomedial Hypothalamus by Leptin and Nutritional Status

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4541-4551 ◽  
Author(s):  
Eneida C. Villanueva ◽  
Heike Münzberg ◽  
Daniela Cota ◽  
Rebecca L. Leshan ◽  
Keely Kopp ◽  
...  
Keyword(s):  
Energy Balance ◽  
Neuronal Activity ◽  
Leptin Receptor ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Hypothalamic Nucleus ◽  
Related Protein ◽  
Leptin Deficiency ◽  
Mtorc1 Signaling ◽  
Agouti Related Protein

Abstract The medial basal hypothalamus, including the arcuate nucleus (ARC) and the ventromedial hypothalamic nucleus (VMH), integrates signals of energy status to modulate metabolism and energy balance. Leptin and feeding regulate the mammalian target of rapamycin complex 1 (mTORC1) in the hypothalamus, and hypothalamic mTORC1 contributes to the control of feeding and energy balance. To determine the mechanisms by which leptin modulates mTORC1 in specific hypothalamic neurons, we immunohistochemically assessed the mTORC1-dependent phosphorylation of ribosomal protein S6 (pS6). In addition to confirming the modulation of ARC mTORC1 activity by acute leptin treatment, this analysis revealed the robust activation of mTORC1-dependent ARC pS6 in response to fasting and leptin deficiency in leptin receptor-expressing Agouti-related protein neurons. In contrast, fasting and leptin deficiency suppress VMH mTORC1 signaling. The appropriate regulation of ARC mTORC1 by mutant leptin receptor isoforms correlated with their ability to suppress the activity of Agouti-related protein neurons, suggesting the potential stimulation of mTORC1 by the neuronal activity. Indeed, fasting- and leptin deficiency-induced pS6-immunoreactivity (IR) extensively colocalized with c-Fos-IR in ARC and VMH neurons. Furthermore, ghrelin, which activates orexigenic ARC neurons, increased ARC mTORC1 activity and induced colocalized pS6- and c-Fos-IR. Thus, neuronal activity promotes mTORC1/pS6 in response to signals of energy deficit. In contrast, insulin, which activates mTORC1 via the phosphatidylinositol 3-kinase pathway, increased ARC and VMH pS6-IR in the absence of neuronal activation. The regulation of mTORC1 in the basomedial hypothalamus thus varies by cell and stimulus type, as opposed to responding in a uniform manner to nutritional and hormonal perturbations.

scholarly journals Leptin deficiency suppresses MMTV-Wnt-1 mammary tumor growth in obese mice and abrogates tumor initiating cell survival

2011 ◽  
Vol 18 (4) ◽  
pp. 491-503 ◽  
Author(s):  
Qiao Zheng ◽  
Sarah M Dunlap ◽  
Jinling Zhu ◽  
Erinn Downs-Kelly ◽  
Jeremy Rich ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cells ◽  
Mammary Tumor ◽  
Leptin Receptor ◽  
Tumor Burden ◽  
Obese Mice ◽  
Leptin Deficiency ◽  
Phosphorylated Akt

Obesity increases both the risk and mortality associated with many types of cancer including that of the breast. In mice, obesity increases both incidence of spontaneous tumors and burden of transplanted tumors. Our findings identify leptin, an adipose secreted cytokine, in promoting increased mammary tumor burden in obese mice and provide a link between this adipokine and cancer. Using a transplantable tumor that develops spontaneously in the murine mammary tumor virus-Wnt-1 transgenic mice, we show that tumors transplanted into obese leptin receptor (LepRb)-deficient (db/db) mice grow to eight times the volume of tumors transplanted into lean wild-type (WT) mice. However, tumor outgrowth and overall tumor burden is reduced in obese, leptin-deficient (ob/ob) mice. The residual tumors in ob/ob mice contain fewer undifferentiated tumor cells (keratin 6 immunopositive) compared with WT or db/db mice. Furthermore, tumors in ob/ob mice contain fewer cells expressing phosphorylated Akt, a growth promoting kinase activated by the LepRb, compared with WT and db/db mice.In vivolimiting dilution analysis of residual tumors from ob/ob mice indicated reduced tumor initiating activity suggesting fewer cancer stem cells (CSCs). The tumor cell populations reduced by leptin deficiency were identified by fluorescence-activated cell sorting and found to express LepRb. Finally, LepRb expressing tumor cells exhibit stem cell characteristics based on the ability to form tumorspheresin vitroand leptin promotes their survival. These studies provide critical new insight on the role of leptin in tumor growth and implicate LepRb as a CSC target.

scholarly journals Ablation of the leptin receptor in myeloid cells impairs pulmonary clearance ofStreptococcus pneumoniaeand alveolar macrophage bactericidal function

2018 ◽  
Vol 315 (1) ◽  
pp. L78-L86 ◽  
Author(s):  
Peter Mancuso ◽  
Jeffrey L. Curtis ◽  
Christine M. Freeman ◽  
Marc Peters-Golden ◽  
Jason B. Weinberg ◽  
...  
Keyword(s):  
Pneumococcal Pneumonia ◽  
Respiratory Tract Infections ◽  
Bronchoalveolar Lavage Fluid ◽  
Leptin Receptor ◽  
Lavage Fluid ◽  
Bacterial Killing ◽  
Leptin Deficiency ◽  
Tract Infections ◽  
Bactericidal Function

Leptin is a pleiotropic hormone produced by white adipose tissue that regulates appetite and many physiological functions, including the immune response to infection. Genetic leptin deficiency in humans and mice impairs host defenses against respiratory tract infections. Since leptin deficiency is associated with obesity and other metabolic abnormalities, we generated mice that lack the leptin receptor (LepRb) in cells of the myeloid linage (LysM-LepRb-KO) to evaluate its impact in lean metabolically normal mice in a murine model of pneumococcal pneumonia. We observed higher lung and spleen bacterial burdens in LysM-LepRb-KO mice following an intratracheal challenge with Streptococcus pneumoniae. Although numbers of leukocytes recovered from bronchoalveolar lavage fluid did not differ between groups, we did observe higher levels of pulmonary IL-13 and TNFα in LysM-LepRb-KO mice 48 h post infection. Phagocytosis and killing of ingested S. pneumoniae were also impaired in alveolar macrophages (AMs) from LysM-LepRb-KO mice in vitro and were associated with reduced LTB4and enhanced PGE2synthesis in vitro. Pretreatment of AMs with LTB4and the cyclooxygenase inhibitor, indomethacin, restored phagocytosis but not bacterial killing in vitro. These results confirm our previous observations in leptin-deficient ( ob/ob) and fasted mice and demonstrate that decreased leptin action, as opposed to metabolic irregularities associated with obesity or starvation, is responsible for the defective host defense against pneumococcal pneumonia. They also provide novel targets for therapeutic intervention in humans with bacterial pneumonia.

scholarly journals Impact of leptin deficiency compared with neuronal-specific leptin receptor deletion on cardiometabolic regulation

2019 ◽  
Vol 317 (4) ◽  
pp. R552-R562 ◽  
Author(s):  
Jussara M. do Carmo ◽  
Alexandre A. da Silva ◽  
Fabio N. Gava ◽  
Sydney P. Moak ◽  
Xuemei Dai ◽  
...  
Keyword(s):  
Nervous System ◽  
Leptin Receptor ◽  
Liver Fat ◽  
Wild Type ◽  
Liver Fat Content ◽  
Protein Levels ◽  
Leptin Deficiency ◽  
Total Body ◽  
Plasma Leptin ◽  
The Impact

The main goal of this study was to compare the impact of total body leptin deficiency with neuronal-specific leptin receptor (LR) deletion on metabolic and cardiovascular regulation. Liver fat, diacylglycerol acyltransferase-2 (DGTA2), and CD36 protein content were measured in wild-type (WT), nervous system LR-deficient (LR/Nestin-Cre), and leptin deficient ( ob/ob) mice. Blood pressure (BP) and heart rate (HR) were recorded by telemetry, and motor activity (MA) and oxygen consumption (V̇o2) were monitored at 24 wk of age. Female and male LR/Nestin-Cre and ob/ob mice were heavier than WT mice (62 ± 5 and 61 ± 3 vs. 31 ± 1 g) and hyperphagic (6.2 ± 0.5 and 6.1 ± 0.7 vs. 3.5 ± 1.0 g/day), with reduced V̇o2 (27 ± 1 and 33 ± 1 vs 49 ± 3 ml·kg−1·min−1) and decreased MA (3 ± 1 and 7 ± 2 vs 676 ± 105 cm/h). They were also hyperinsulinemic and hyperglycemic compared with WT mice. LR/Nestin-Cre mice had high levels of plasma leptin, while ob/ob mice had undetectable leptin levels. Despite comparable obesity, LR/Nestin-Cre mice had lower liver fat content, DGTA2, and CD36 protein levels than ob/ob mice. Male WT, LR/Nestin-Cre, and ob/ob mice exhibited similar BP (111 ± 3, 110 ± 1 and 109 ± 2 mmHg). Female LR/Nestin-Cre and ob/ob mice, however, had higher BP than WT females despite similar metabolic phenotypes compared with male LR/Nestin-Cre and ob/ob mice. These results indicate that although nervous system LRs play a crucial role in regulating body weight and glucose homeostasis, peripheral LRs regulate liver fat deposition. In addition, our results suggest potential sex differences in the impact of obesity on BP regulation.

scholarly journals Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice

2006 ◽  
Vol 188 (1) ◽  
pp. 25-36 ◽  
Author(s):  
F Dong ◽  
X Zhang ◽  
X Yang ◽  
L B Esberg ◽  
H Yang ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Ventricular Myocytes ◽  
Contractile Function ◽  
Contractile Dysfunction ◽  
Maximal Velocity ◽  
Obese Mice ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Leptin Deficiency ◽  
Intracellular Ca

The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesity-associated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca2 + transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca2 + release upon electrical stimulus associated with a slowed intracellular Ca2 + decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age- and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca2 + hemostasis and ultrastructural derangement in ventricular myocytes.

scholarly journals Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy

2021 ◽  
Vol 22 (19) ◽  
pp. 10596
Author(s):  
Thiago Bruder-Nascimento ◽  
Taylor C. Kress ◽  
Matthew Pearson ◽  
Weiqin Chen ◽  
Simone Kennard ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Wild Type ◽  
Direct Role ◽  
Congenital Generalized Lipodystrophy ◽  
Vascular Contractility ◽  
Leptin Receptors ◽  
Leptin Deficiency ◽  
Deficient Mice ◽  
Mediated Reduction ◽  
Wild Type Control

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.

Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein

2004 ◽  
Vol 287 (5) ◽  
pp. G1078-G1085 ◽  
Author(s):  
Kengo Tomita ◽  
Toshifumi Azuma ◽  
Naoto Kitamura ◽  
Gen Tamiya ◽  
Satoshi Ando ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Leptin Receptor ◽  
Specific Interaction ◽  
Chronic Ethanol ◽  
Leptin Resistance ◽  
Mrna Levels ◽  
Hepatocellular Injury ◽  
Leptin Deficiency ◽  
Ethanol Feeding

Oxidative stress is stated to be a central mechanism of hepatocellular injury in alcohol-induced liver injury. Recent reports have shown that Kupffer cell dysfunction in the leptin-deficient state contributes partly to the increased sensitivity to endotoxin liver injury. Here we report that leptin also plays a key role in the development of alcoholic liver injury and that leptin signaling in hepatocytes is involved in cellular mechanisms that mediate ethanol-induced oxidative stress. We found that chronic ethanol feeding in leptin receptor-deficient Zucker (fa/fa) rats for 6 wk resulted in a much more severe liver injury and augmented accumulation of hepatic lipid peroxidation compared with control littermates. The hepatic induction of stress-response and antioxidant proteins, such as metallothionein (MT)-1 and -2, was significantly suppressed in fa/fa rats after chronic ethanol feeding. Zinc concentration in liver was also decreased in fa/fa rats, compared with control littermates. In primary cultured hepatocytes from fa/fa rats, incubation with ethanol significantly suppressed MT-1 and -2 expressions. Addition of leptin to leptin-deficient ob/ob mouse primary hepatocytes led to an increase in MT-1 and -2 mRNA levels and a decrease in oxidative stress after incubation with ethanol. In conclusion, leptin deficiency enhances sensitivity of rats to alcohol-induced steatohepatitis through hepatocyte-specific interaction of MT-1 and -2 and resultant exaggeration of oxidative stress in hepatocytes. These findings suggest that leptin resistance in hepatocytes is an important mechanism of alcohol-induced liver injury.

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