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.

Cloning and characterization of a human leptin receptor using a biologically active leptin immunoadhesin

1997 ◽  
Vol 18 (1) ◽  
pp. 77-85 ◽  
Author(s):  
S-M Luoh ◽  
F Di Marco ◽  
N Levin ◽  
M Armanini ◽  
M-H Xie ◽  
...  
Keyword(s):  
Body Weight ◽  
Binding Sites ◽  
Leptin Receptor ◽  
Short Form ◽  
Biologically Active ◽  
Expression Cloning ◽  
Kidney Cells ◽  
Long Form

ABSTRACT Leptin, the product of the ob gene, is a hormone secreted by fat cells which is primarily involved in the regulation of body weight. We have generated a leptin immunoadhesin (leptin-IgG) which was more potent than leptin alone at reducing body weight and food intake when injected into ob/ob mice. This molecule was used to identify high affinity binding sites on human embryonic 293 kidney cells and subsequently to isolate a cDNA encoding the leptin receptor from this cell line by expression cloning. This receptor corresponds to the short form of the recently isolated leptin receptor. Analysis of the expression pattern of the two forms of receptor by Northern blot, in situ hybridization and quantitative PCR showed that the receptor is expressed in most tissues but that the long form is prevalent in the hypothalamus.

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 action is modified by an interaction between dietary fat content and ambient temperature

2004 ◽  
Vol 287 (5) ◽  
pp. R1250-R1255 ◽  
Author(s):  
Andrea L. Haltiner ◽  
Tiffany D. Mitchell ◽  
Ruth B. S. Harris
Keyword(s):  
Energy Intake ◽  
Body Fat ◽  
Dietary Fat ◽  
Leptin Receptor ◽  
Environmental Temperature ◽  
Short Form ◽  
Uncoupling Protein ◽  
Fat Content ◽  
High Fat ◽  
Leptin Receptors

Mice adapted to a high-fat diet are reported to be leptin resistant; however, we previously reported that mice fed a high-fat (HF) diet and housed at 23°C remained sensitive to peripheral leptin and specifically lost body fat. This study tested whether leptin action was impaired by a combination of elevated environmental temperature and a HF diet. Male C57BL/6 mice were adapted to low-fat (LF) or HF diet from 10 days of age and were housed at 27°C from 28 days of age. From 35 days of age, baseline food intake and body weight were recorded for 1 wk and then mice on each diet were infused with 10 μg leptin/day or PBS from an intraperitoneal miniosmotic pump for 13 days. HF-fed mice had a higher energy intake than LF-fed mice and were heavier but not fatter. Serum leptin was lower in PBS-infused HF- than LF-fed mice. Leptin significantly inhibited energy intake of both LF-fed and HF-fed mice, and this was associated with a significant increase in hypothalamic long-form leptin receptors with no change in short-form leptin receptor or brown fat uncoupling protein-1 mRNA expression. Leptin significantly inhibited weight gain in both LF- and HF-fed mice but reduced the percentage of body fat mass only in LF-fed mice. The percentage of lean and fat tissue in HF-fed mice did not change, implying that overall growth had been inhibited. These results suggest that dietary fat modifies the mechanisms responsible for leptin-induced changes in body fat content and that those in HF-fed mice are sensitive to environmental temperature.

Cellular, molecular and physiological aspects of leptin: Potential application in animal production

1998 ◽  
Vol 78 (4) ◽  
pp. 463-472 ◽  
Author(s):  
Kim L. Hossner
Keyword(s):  
Leptin Receptor ◽  
Short Form ◽  
Signal Transduction Pathway ◽  
Leptin Receptors ◽  
Specific Effects ◽  
Key Words Leptin ◽  
Fat Stores ◽  
Regulate Food Intake ◽  
Specific Receptors

This review encompasses the biochemistry and physiology of the newly discovered adipose hormone, leptin. Leptin appears to fulfill the role of the long sought after "lipostat", which functions to regulate energy intake in relation to body stores in the form of fat. Leptin is a 16 000 Dalton polypeptide which interacts with specific receptors in the hypothalamus to regulate food intake and body fat stores. Leptin receptors exist in several forms, which can be divided into those with small cytoplasmic domains and one with a single long cytoplasmic tail. The latter is thought to mediate most of leptin's effects, acting through the JAK-STAT signal transduction pathway. Several reports have shown direct effects of leptin on tissues with the short form of the leptin receptor. Specific effects of leptin on appetite, energy metabolism and reproduction are reviewed. Leptin may prove to be most useful to animal producers as a stimulant of the reproductive system or as a molecular marker to genetically select livestock for improved reproductive capacities or carcass characteristics, while leptin antagonists may improve metabolic rate and body composition. Key words: Leptin, obese protein, leptin receptor, review, livestock production

scholarly journals Rescue of cardiac leptin receptors in db/db mice prevents myocardial triglyceride accumulation

2014 ◽  
Vol 307 (3) ◽  
pp. E316-E325 ◽  
Author(s):  
Michael E. Hall ◽  
Matthew W. Maready ◽  
John E. Hall ◽  
David E. Stec
Keyword(s):  
Body Weight ◽  
Lipid Accumulation ◽  
Leptin Receptor ◽  
Systolic Function ◽  
Left Ventricular ◽  
Diastolic Filling ◽  
Cardiac Lipid ◽  
Leptin Receptors ◽  
Triglyceride Accumulation ◽  
Long Form

Increased leptin levels have been suggested to contribute to cardiac hypertrophy and attenuate cardiac lipid accumulation in obesity, although it has been difficult to separate leptin's direct effects from those caused by changes in body weight and adiposity. To determine whether leptin attenuates cardiac lipid accumulation in obesity or directly causes left ventricular hypertrophy (LVH), we generated a novel mouse model in which the long form of the leptin receptor (LepR) was “rescued” only in cardiomyocytes of obese db/db mice. Reexpression of cardiomyocyte leptin receptors in db/db mice did not cause LVH but reduced cardiac triglycerides and improved cardiac function. Compared with lean wild-type (WT) or db/db-cardiac LepR rescue mice, db/db mice exhibited significantly lower E/A ratio, a measurement of early to late diastolic filling, which averaged 1.5 ± 0.07 in db/db vs. 1.9 ± 0.08 and 1.8 ± 0.11 in WT and db/db-cardiac LepR rescue mice, respectively. No differences in systolic function were observed. Although db/db and db/db-cardiac LepR rescue mice exhibited similar increases in plasma triglycerides, insulin, glucose, and body weight, cardiac triglycerides were significantly higher in db/db compared with WT and db/db cardiac LepR rescue mice, averaging 13.4 ± 4.2 vs. 3.8 ± 1.6 vs. 3.8 ± 0.7 mg/g, respectively. These results demonstrate that despite significant obesity and increases in plasma glucose and triglycerides, db/db cardiac LepR rescue mice are protected against myocardial lipid accumulation. However, we found no evidence that leptin directly causes LVH.

scholarly journals Expression of Leptin Receptor in Human Endometrium and Fluctuation during the Menstrual Cycle

2000 ◽  
Vol 85 (5) ◽  
pp. 1946-1950 ◽  
Author(s):  
Jo Kitawaki ◽  
Hisato Koshiba ◽  
Hiroaki Ishihara ◽  
Izumi Kusuki ◽  
Katsumi Tsukamoto ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Splice Variants ◽  
Human Endometrium ◽  
Messenger Ribonucleic Acid ◽  
Leptin Receptors ◽  
Decidual Tissue ◽  
Long Form ◽  
Uterine Diseases ◽  
Disease Free

Abstract Leptin is secreted by adipocytes and regulates appetite through interaction with hypothalamic leptin receptors (OB-R). Accumulated evidence shows that leptin is involved in the stimulation of reproductive functions and that local expression of leptin and OB-R in the ovary, oocyte, embryo, and placenta plays a role in early development. To investigate the role of leptin in implantation, we examined the expression of OB-R and leptin in the human endometrium. Northern and Western blot analyses and RT-PCR showed that the long form of OB-R (OB-RL) messenger ribonucleic acid (mRNA) and protein were expressed. In contrast, leptin mRNA or protein was not detected. All of the splice variants of OB-R (OB-RT) and OB-RL transcripts were expressed in 90% and 84% of the cases, respectively. OB-R mRNA expression peaked in the early secretory phase. Decidual tissue of early gestation also expressed OB-RT and OB-RL. Their incidence and abundance were comparable among endometria with benign uterine diseases and disease-free endometria and were not related to a body mass index within the normal range. The present results indicate that OB-R, but not leptin, is expressed in the human endometrium.

scholarly journals Increased pulmonary responses to acute ozone exposure in obese db/db mice

2006 ◽  
Vol 290 (5) ◽  
pp. L856-L865 ◽  
Author(s):  
Frank L. Lu ◽  
Richard A. Johnston ◽  
Lesley Flynt ◽  
Todd A. Theman ◽  
Raya D. Terry ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Leptin Receptor ◽  
Short Form ◽  
Epidemiological Studies ◽  
Airway Responsiveness ◽  
Ozone Exposure ◽  
Forced Oscillation Technique ◽  
Air Exposure ◽  
Tnf Α ◽  
Satiety Hormone

Epidemiological studies indicate the incidence of asthma is increased in obese and overweight humans. Responses to ozone (O3), an asthma trigger, are increased in obese ( ob/ob) mice lacking the satiety hormone leptin. The long form of leptin receptor (Ob-Rb) is required for satiety; mice lacking this receptor ( db/db mice) are also substantially obese. Here, wild-type (WT) and db/ db mice were exposed to air or O3 (2 ppm) for 3 h. Airway responsiveness, measured by the forced oscillation technique, was greater in db/db than WT mice after air exposure. O3-induced increases in pulmonary resistance and airway responsiveness were also greater in db/ db mice. BALF eotaxin, IL-6, KC, and MIP-2 increased 4 h after O3 exposure and subsided by 24 h, whereas protein and neutrophils continued to increase through 24 h. For each outcome, the effect of O3 was significantly greater in db/ db than WT mice. Previously published results obtained in ob/ob mice were similar except for O3-induced neutrophils and MIP-2, which were not different from WT mice. O3 also induced pulmonary IL-1β and TNF-α mRNA expression in db/db but not ob/ob mice. Leptin was increased in serum of db/db mice, and pulmonary mRNA expression of short form of leptin receptor (Ob-Ra) was similar in db/db and WT mice. These data confirm obese mice have innate airway hyperresponsiveness and increased pulmonary responses to O3. Differences between ob/ob mice, which lack leptin, and db/db mice, which lack Ob-Rb but not Ob-Ra, suggest leptin, acting through Ob-Ra, can modify some pulmonary responses to O3.

scholarly journals Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ilandarage Menu Neelaka Molagoda ◽  
Jayasingha Arachchige Chathuranga C Jayasingha ◽  
Yung Hyun Choi ◽  
Rajapaksha Gedara Prasad Tharanga Jayasooriya ◽  
Chang-Hee Kang ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Endotoxic Shock ◽  
Inflammatory Activity ◽  
Prostaglandin E ◽  
Necrosis Factor Alpha ◽  
Zebrafish Larvae ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Gsk 3Β

AbstractFisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Additionally, fisetin attenuated LPS-induced mortality and abnormalities in zebrafish larvae and normalized the heart rate. Fisetin decreased the recruitment of macrophages and neutrophils to the LPS-microinjected inflammatory site in zebrafish larvae, concomitant with a significant downregulation of proinflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase-2a (COX-2a), IL-6, and TNF-α. Fisetin inhibited the nuclear localization of nuclear factor-kappa B (NF-κB), which reduced the expression of pro-inflammatory genes. Further, fisetin inactivated glycogen synthase kinase 3β (GSK-3β) via phosphorylation at Ser9, and inhibited the degradation of β-catenin, which consequently promoted the localization of β-catenin into the nucleus. The pharmacological inhibition of β-catenin with FH535 reversed the fisetin-induced anti-inflammatory activity and restored NF-κB activity, which indicated that fisetin-mediated activation of β-catenin results in the inhibition of LPS-induced NF-κB activity. In LPS-microinjected zebrafish larvae, FH535 promoted the migration of macrophages to the yolk sac and decreased resident neutrophil counts in the posterior blood island and induced high expression of iNOS and COX-2a, which was accompanied by the inhibition of fisetin-induced anti-inflammatory activity. Altogether, the current study confirmed that the dietary flavonoid, fisetin, inhibited LPS-induced inflammation and endotoxic shock through crosstalk between GSK-3β/β-catenin and the NF-κB signaling pathways.

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
Sign in / Sign up

Export Citation Format

Share Document