Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats
Katsuro HimenoMasataka SeikeSatoshi FukuchiTakayuki MasakiTetsuya KakumaToshiie SakataHironobu Yoshimatsu
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Leptin receptor
One of the five possible mechanisms of leptin resistance in human obesity is the defect in the leptin receptor (Ob-R). Evidence has accumulated that leptin-binding activity in human serum is related to a soluble form of the leptin receptor, and restriction of energy intake resulted a decrease in circulating leptin levels. Aim of this study is to examine the difference of serum soluble leptin receptor level and leptin receptor density in rat adipose tissue of adventitial aorta after four weeks treated with different restricted diets. Soluble leptin receptor level was measured by ELISA and leptin receptor density by using immuno-histochemistry. The soluble leptin receptor in group treated with 40% of normal daily calori diet was found significantly lower than control (p = 0.02). There were no any significant differences among group treated with 40 % of normal daily calori diet, â1 day fast-1day eatâ, and â1day fast-2 days eatâ groups, and among 1 day fast-1 day eatâ, âday fast - 2 days eatâ and control groups as well. On the other hand, leptin receptor density in adipose tissues was higher in restricted diet group than control. Diet of 40 % normal daily calorie for 4 weeks decreased soluble leptin receptor level, but increased adipocyte leptin receptor density of the adipose tissue of rat adventitial aorta. These changes may be resulted from an up regulation mechanism in relation with homeostatic maintenance. (Med J Indones 2006; 15:145-50) Keywords: restricted diet, leptin receptor, soluble leptin receptor, adipocyte, obesity
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Introduction: Leptin (LEP) is a multifunctional hormone which plays an important role in angiogenesis, cell proliferation induction, cell survival and anchorage-independent growth. These activities are mediated via leptin receptor (LEPR) that binds leptin molecule and stimulates Jak/STAT 3, ERK, cyclin D1 expression and other signal pathways. According to the recent data, targeting leptin signaling may reduce mammary carcinogenesis and breast cancer (BC) progression. However, the link between obesity and leptin expression in serum/breast tumor as well as its role in modulation of estrogen receptor (EsR) and HER2/neu expression is not clear.Materials and methods: We studied LEP, LEPR, EsR, HER2/neu expression in patients with sporadic, familial and pregnancy-associated BC by means of RT PCR using BC fresh tissue and primers for genes encoding LEP, LEPR, EsR-α, β. Leptin level in the patient sera was estimated also by ELISA (Leptin Sandwich DRG, Germany). The data on immunohistochemical staining of LEP, HER2/neu, EsR and PrR were also obtained. The control group consisted of the patients with benign fibroadenoma (BFA) and healthy women of similar age.Results: RT PCR results and immunohistochemistry/ELISA values are mainly concordant. Leptin overexpression in triple-negative tumors was observed. Leptin sera level in postmenopause patients with obesity was significantly higher than in premenopause counterparts and in BC patients with normal body mass. Blood sera leptin level correlated positively with LEPR expression. Leptin expression in tumor tissue also correlated with HER2/neu overexpression in all BC groups involved into the study, except triple-negative ones: EsR (-), PrR(-), HER2/neu(-). Leptin serum level in BFA patients was significantly higher than the level in healthy women and mean leptin level in the serum of BC patients (96.7±10.2; 17.8±8.3; 24.6±8.4, correspondingly, p<0.05)Conclusions: The obtained data indicate that LEP/LEPR expression is involved in mammary tumor progression. It indicates that LEPR suppression is a possible way of targeted BC therapy, especially for triple-negative tumors, HER2/neu (-), when common hormone therapy is not effective. Introduction: Leptin (LEP) is a multifunctional hormone which plays an important role in angiogenesis, cell proliferation induction, cell survival and anchorage-independent growth. These activities are mediated via leptin receptor (LEPR) that binds leptin molecule and stimulates Jak/STAT 3, ERK, cyclin D1 expression and other signal pathways. According to the recent data, targeting leptin signaling may reduce mammary carcinogenesis and breast cancer (BC) progression. However, the link between obesity and leptin expression in serum/breast tumor as well as its role in modulation of estrogen receptor (EsR) and HER2/neu expression is not clear. Materials and methods: We studied LEP, LEPR, EsR, HER2/neu expression in patients with sporadic, familial and pregnancy-associated BC by means of RT PCR using BC fresh tissue and primers for genes encoding LEP, LEPR, EsR-α, β. Leptin level in the patient sera was estimated also by ELISA (Leptin Sandwich DRG, Germany). The data on immunohistochemical staining of LEP, HER2/neu, EsR and PrR were also obtained. The control group consisted of the patients with benign fibroadenoma (BFA) and healthy women of similar age. Results: RT PCR results and immunohistochemistry/ELISA values are mainly concordant. Leptin overexpression in triple-negative tumors was observed. Leptin sera level in postmenopause patients with obesity was significantly higher than in premenopause counterparts and in BC patients with normal body mass. Blood sera leptin level correlated positively with LEPR expression. Leptin expression in tumor tissue also correlated with HER2/neu overexpression in all BC groups involved into the study, except triple-negative ones: EsR (-), PrR(-), HER2/neu(-). Leptin serum level in BFA patients was significantly higher than the level in healthy women and mean leptin level in the serum of BC patients (96.7±10.2; 17.8±8.3; 24.6±8.4, correspondingly, p<0.05) Conclusions: The obtained data indicate that LEP/LEPR expression is involved in mammary tumor progression. It indicates that LEPR suppression is a possible way of targeted BC therapy, especially for triple-negative tumors, HER2/neu (-), when common hormone therapy is not effective.
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The objectives of this study were to determine if reduced long-form leptin receptor (ObRb) expression in diet-induced obese (DIO) animals is associated with deficits in maximal leptin signaling and, secondly, to establish the effects of short-term caloric restriction (CR) on ObRb expression and function. Groups of DIO and life-long chow-fed (CHOW) F344xBN male rats, aged 6 months, were given an i.c.v. injection containing 2 micro g leptin or artificial cerebrospinal fluid (ACSF) vehicle. Leptin induced a >6-fold increase in STAT3 phosphorylation in CHOW rats, but less than 2-fold increase in DIO. Reduced maximal leptin-stimulated STAT3 phosphorylation in DIO rats was coupled with a decline in both ObRb expression and protein. At this point, subgroups of DIO and CHOW animals underwent CR for 30 days and were then tested for acute leptin responsiveness. CR resulted in a 45 and 85% increase respectively in leptin-stimulated STAT3 phosphorylation in CHOW and DIO animals. Similarly, CR increased ObRb expression and protein in both CHOW and DIO animals. To explore the role of leptin in regulating ObRb expression, we reversibly overexpressed leptin in the hypothalamus and found that ObRb mRNA inversely follows central leptin expression. By enhancing both ObRb expression and signaling capacity, CR may enhance leptin responsiveness in leptin-resistant DIO animals.
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Abstract Serum leptin concentrations are an important afferent signal in energy balance homeostasis. It has been speculated that the leptin responsiveness to energy restriction is affected by the functionality of the leptin receptor. The purpose of this analysis was to explore the effect of polymorphisms in the LEPR gene on the acute decline in leptin after 4 days of 65% energy restriction. Leptin concentrations of the study group ( n = 44; all men) declined by 2.3 ± 1.5 μg/L [–39.4% (95% confidence interval: −43.6 to −34.9)]. Leptin responses did not statistically differ between noncarriers and carriers of three mutant variants of the polymorphisms: Lys109/Lys109 (−41.4%) vs. Arg109/+ (−37.0%) ( p = 0.33); Gln223/Gln223 (−41.5%) vs. Arg223/+ (−37.8%) ( p = 0.40); Lys656/Lys656 (−39.5%) vs. Asn656/+ (−39.3%) ( p = 0.96). No effect of the assessed polymorphisms in the LEPR gene on the acute decline in leptin after energy restriction was observed. Power calculations are provided for future studies on the leptin responsiveness to energy restriction.
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Abstract Background Leptin is primarily secreted by the adipose tissue. It binds not only to hypothalamic structures involved in energy regulation but also to many peripheral tissues including the liver. Leptin circulates in free and receptor‐bound forms. Both components are differentially regulated under various pathophysiological conditions and serve different physiological functions. They are released from adipose tissue but previous data suggest an additional formation outside the fat compartment. Here we tested the contribution of the liver in binding and modulating leptin in the circulation. Materials and methods In vivo experiments were performed with radioactive labelled leptin with and without pretreatment with unlabelled leptin in freely moving, chronic intravenously cannulated male rats. Livers were investigated by immunohistochemistry and in situ hybridization and immunoblotting was performed, followed by ex vivo liver perfusion studies with human recombinant leptin. Results In in vivo experiments radioactively labelled leptin (at low concentrations) is avidly bound to rat liver (greater than 80% of basal serum values 90 min following i.v. infusion). Pre‐treatment with excess of unlabelled leptin in vivo revealed a rapid hepatic down‐regulation of leptin receptor isoforms when tested by in situ hybridization, immunoblotting or immunohistochemistry. Ex vivo perfusion of rat liver with human recombinant leptin induced a dose‐ and time‐dependent formation of receptor‐bound leptin in the perfusate. Conclusions The present data support an active role of the liver in the modulation of the leptin signal through different regulation of the soluble leptin receptor, the bound and free forms of the hormone, which may have important implications for leptin's central efficacy and the development of ‘leptin resistance’.
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In the present study, the effects of electroacupuncture (EA) on body weight and sensitivity of leptin in diet-induced obese rats were examined and the underlying mechanisms were explored. After feeding with high-fat (HIF) diet for 12 weeks, the diet-induced obese rats received electroacupuncture stimulation three times per week for four weeks. The expression of the leptin receptor in the hypothalamus was measured using immunohistochemistry. The plasma leptin was detected with ELISA. The leptin and leptin receptor mRNA was examined with real-time PCR. Results showed that electroacupuncture treatment led to a reduction of body weight, decrease in the plasma leptin levels, and an increase in leptin receptor expression in the hypothalamus. Our results suggested that regulating the expression of leptin and the leptin receptor might be one of the molecular mechanisms underlying the reduction of body weight in diet-induced obese rats by electroacupuncture treatment.
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Leptin has been suggested to play a role in the etiology of Adolescent Idiopathic Scoliosis (AIS), however, the leptin levels in AIS girls are still a discrepancy, and no in vitro study of leptin in AIS is reported. We took a series of case-control studies, trying to understand whether Leptin gene polymorphisms are involved in the etiology of the AIS or the change in leptin level is a secondary event, to assess the level of leptin receptor, and to evaluate the differences of response to leptin between AIS cases and controls. We screened all exons of Leptin gene in 45 cases and 45 controls and selected six tag SNPs to cover all the observed variations. Association analysis in 446 AIS patients and 550 healthy controls showed no association between the polymorphisms of Leptin gene and susceptibility/severity to AIS. Moreover, adipogenesis assay of bone mesenchymal stem cells (MSCs) suggested that the adipogenic ability of MSCs from AIS girls was lower than controls. After adjusting the differentiation rate, expressions of leptin and leptin receptor were similar between two groups. Meanwhile, osteogenesis assay of MSC showed the leptin level was similar after adjusting the differentiation rate, but the leptin receptor level was decreased in induced AIS osteoblasts. Immunocytochemistry and western blot analysis showed less leptin receptors expressed in AIS group. Furthermore, factorial designed studies with adipogenesis and osteogenesis revealed that the MSCs from patients have no response to leptin treatment. Our results suggested that Leptin gene variations are not associated with AIS and low serum leptin probably is a secondary outcome which may be related to the low capability of adipogenesis in AIS. The decreased leptin receptor levels may lead to the hyposensitivity to leptin. These findings implied that abnormal peripheral leptin signaling plays an important role in the pathological mechanism of AIS.
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A part of serum Ob leptin, an adipocyte-secreted peptide, is bound to a soluble Ob receptor (sObR). Immunoreactive sObR was measured in 125 lean or obese control subjects (group 1), 18 individuals with a mutation in the leptin gene impairing leptin secretion (group 2), and 10 individuals with a mutation in the ObR gene, leading to production of a truncated ObR not anchored to cell membranes (group 3). In group 1, sObR levels were negatively correlated with age and BMI in children and with BMI in adults. sObR levels were also negatively correlated with leptin levels. Leptin binding activity and sObR levels coeluted in gel-filtration chromatography. In group 2, sObR levels did not differ from those in lean control subjects and were not correlated with BMI. A single peak was detected in chromatographic fractions. In group 3, sObR levels were high and positively correlated with BMI. Immunoreactive sObR coeluted with leptin binding activity. These data demonstrate that leptin is not needed for ObR gene expression, and they suggest that leptin plays a role in receptor downregulation because sObR levels are negatively correlated with leptin levels and BMI in control subjects, whereas sObR levels are not depressed in obese leptin-deficient or leptin receptor–deficient individuals.
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