scholarly journals CB1R Regulates Soluble Leptin Receptor Levels via CHOP, Contributing to Hepatic Leptin Resistance

2020 ◽  
Author(s):  
Adi Drori ◽  
Asaad Gammal ◽  
Shahar Azar ◽  
Liad Hinden ◽  
Rivka Hadar ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Dependent Manner ◽  
Molecular Aspect ◽  
Homologous Protein ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Soluble Leptin Receptor ◽  
Direct Regulation

AbstractThe soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contributes to hyperleptinemia and leptin resistance, effects that are known to be regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade as well as genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and consequently hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, fat mass, dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system involves in the development of hepatic leptin resistance by regulating sOb-R levels via CHOP.SummaryHere we describe a novel molecular aspect by which the hepatic endocannabinoid/CB1R system contributes to hepatic leptin resistance by regulating soluble leptin receptor levels via CHOP.

scholarly journals CB1R regulates soluble leptin receptor levels via CHOP, contributing to hepatic leptin resistance

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Adi Drori ◽  
Asaad Gammal ◽  
Shahar Azar ◽  
Liad Hinden ◽  
Rivka Hadar ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Leptin Resistance ◽  
Dependent Manner ◽  
Molecular Aspect ◽  
Wild Type ◽  
Homologous Protein ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Soluble Leptin Receptor ◽  
Direct Regulation

The soluble isoform of leptin receptor (sOb-R), secreted by the liver, regulates leptin bioavailability and bioactivity. Its reduced levels in diet-induced obesity (DIO) contribute to hyperleptinemia and leptin resistance, effects that are regulated by the endocannabinoid (eCB)/CB1R system. Here we show that pharmacological activation/blockade and genetic overexpression/deletion of hepatic CB1R modulates sOb-R levels and hepatic leptin resistance. Interestingly, peripheral CB1R blockade failed to reverse DIO-induced reduction of sOb-R levels, increased fat mass and dyslipidemia, and hepatic steatosis in mice lacking C/EBP homologous protein (CHOP), whereas direct activation of CB1R in wild-type hepatocytes reduced sOb-R levels in a CHOP-dependent manner. Moreover, CHOP stimulation increased sOb-R expression and release via a direct regulation of its promoter, while CHOP deletion reduced leptin sensitivity. Our findings highlight a novel molecular aspect by which the hepatic eCB/CB1R system is involved in the development of hepatic leptin resistance and in the regulation of sOb-R levels via CHOP.

scholarly journals Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity

2013 ◽  
Vol 114 (6) ◽  
pp. 734-741 ◽  
Author(s):  
Bhavaani Jayaram ◽  
Weihong Pan ◽  
Yuping Wang ◽  
Hung Hsuchou ◽  
Aurelien Mace ◽  
...  
Keyword(s):  
Heat Dissipation ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Leptin Resistance ◽  
Blood Concentrations ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Soluble Leptin Receptor ◽  
Similar Body

To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling.

scholarly journals HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms

2009 ◽  
Vol 296 (2) ◽  
pp. E291-E299 ◽  
Author(s):  
Christy L. White ◽  
Amy Whittington ◽  
Maria J. Barnes ◽  
Zhong Wang ◽  
George A. Bray ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Tyrosine Phosphatase ◽  
Leptin Resistance ◽  
Whole Body ◽  
Mrna Levels ◽  
Protein Levels ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Concomitant Reduction ◽  
Specific Deletion

Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus ( P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 μg/day icv) for 14 days ( P = 0.01) and in leptin-deficient ob/ ob mice infused with leptin (5 μg/day sc for 14 days; P = 0.003). When saline-infused ob/ ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected ( P = 0.001) despite the absence of circulating leptin. In addition, although ob/ ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance.

scholarly journals IL-6 ameliorates defective leptin sensitivity in DIO ventromedial hypothalamic nucleus neurons

2016 ◽  
Vol 311 (4) ◽  
pp. R764-R770 ◽  
Author(s):  
Louise Larsen ◽  
Christelle Le Foll ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Leptin Receptor ◽  
Cellular Level ◽  
Leptin Resistance ◽  
Hypothalamic Nucleus ◽  
Reduce Food Intake ◽  
Bardet Biedl Syndrome ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Ventromedial Hypothalamic Nucleus ◽  
Pancreatic Peptide

Rats selectively bred to develop diet-induced obesity (DIO) have an early onset reduction in the sensitivity of their ventromedial hypothalamic nucleus (VMN) neurons to leptin compared with diet-resistant (DR) rats. This reduced sensitivity includes decreased leptin receptor (Lepr-b) mRNA expression, leptin receptor binding, leptin-induced phosphorylation of STAT3 (pSTAT3), and impaired leptin excitation (LepE) of VMN neurons. When administered exogenously, the pancreatic peptide, amylin, acts synergistically to reduce food intake and body weight in obese, leptin-resistant DIO rats by increasing VMN leptin signaling, likely by stimulation of microglia IL-6, which acts on its receptor to increase leptin-induced pSTAT3. Here, we demonstrate that incubation of cultured VMN neurons of outbred rats with IL-6 increases their leptin sensitivity. Control, dissociated DIO VMN neurons express 66% less Lepr-b and 75% less Bardet Biedl Syndrome-6 (BBS6) mRNA and have reduced leptin-induced activation of LepE neurons compared with DR neurons. Incubation for 4 days with IL-6 increased DIO neuron Lepr-b expression by 77% and BBS6 by 290% and corrected their defective leptin activation of LepE neurons to DR levels. Since BBS6 enhances trafficking of Lepr-b to the cell membrane, the increases in Lepr-b and BBS6 expression appear to account for correction of the reduced leptin excitation of DIO LepE neurons to that of control DR rats. These data support prior findings suggesting that IL-6 mediates the leptin-sensitizing effects of amylin on VMN neurons and that the inherent leptin resistance of DIO rats can be effectively reversed at a cellular level by IL-6.

scholarly journals Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

2018 ◽  
Vol 108 (2) ◽  
pp. 132-141
Author(s):  
Clara Roujeau ◽  
Ralf Jockers ◽  
Julie Dam
Keyword(s):  
Signaling Pathways ◽  
Intracellular Trafficking ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Human Obesity ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Important Regulator ◽  
Neuronal Plasma Membrane ◽  
Underlying Mechanisms

Endospanin 1 (Endo1), a protein encoded in humans by the same gene than the leptin receptor (ObR), and increased by diet-induced obesity, is an important regulator of ObR trafficking and cell surface exposure, determining leptin signaling strength. Defective intracellular trafficking of the leptin receptor to the neuronal plasma membrane has been proposed as a mechanism underlying the development of leptin resistance observed in human obesity. More recently, Endo1 has emerged as a mediator of “selective leptin resistance.” The underlying mechanisms of the latter are not completely understood, but the possibility of differential activation of leptin signaling pathways was suggested among others. In this respect, the expression level of Endo1 is crucial for the appropriate balance between different leptin signaling pathways and leptin functions in the hypothalamus and is likely participating in selective leptin resistance for the control of energy and glucose homeostasis.

scholarly journals Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling

2009 ◽  
Vol 296 (3) ◽  
pp. R537-R548 ◽  
Author(s):  
Christa M. Patterson ◽  
Sebastien G. Bouret ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Food Intake ◽  
Receptor Binding ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
High Energy ◽  
Decrease Food Intake ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity

In rats selectively bred to develop diet-induced obesity (DIO) 3 wk of postweaning exercise reduces weight and adipose regain for 10 wk after exercise cessation, despite intake of 31% fat high-energy (HE) diet. To test the hypothesis that this effect is due to increased central leptin sensitivity, 4-wk-old DIO rats were fed the HE diet and left sedentary (Sed), exercised for 3 wk, and then remained sedentary for 10 additional weeks (Ex/Sed) or continued exercise for a full 13 wk (Ex). After 3 wk, leptin (5 mg/kg ip) induced a 36% decrease in 24-h food intake in Ex rats, while Sed rats had no change in 24-h intake. Ex rats also had 23% more leptin-induced phospho-STAT3 (pSTAT3)-expressing neurons in the arcuate nucleus (ARC) and 95% and 68% higher 125I-labeled leptin receptor binding in the ventromedial and dorsomedial nuclei than did Sed rats, respectively. At 7 wk after onset, leptin decreased 24-h intake by 20% in Ex and 24% in Ex/Sed rats without altering Sed intake. After a total of 13 wk, compared with Sed rats, Ex and Ex/Sed rats had 58% and 38% less fat, respectively, but leptin failed to decrease food intake in any group. Nevertheless, Ex, but not Ex/Sed rats, still had 32% more ARC leptin-induced pSTAT3-expressing neurons than Sed rats. These data suggest that brief postweaning exercise in DIO rats that are inherently leptin resistant causes a sustained resistance to obesity on HE diet, which is, in part, due to increased central leptin sensitivity.

scholarly journals Attenuation of Inflammation and Leptin Resistance by Pyrogallol-Phloroglucinol-6,6-Bieckol on in the Brain of Obese Animal Models

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2773 ◽  
Author(s):  
Myeongjoo Son ◽  
Seyeon Oh ◽  
Junwon Choi ◽  
Ji Tae Jang ◽  
Chang Hu Choi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Cytokines ◽  
Brain Inflammation ◽  
Leptin Resistance ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
M1 Polarization ◽  
Activated Macrophage ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Obesity induces inflammation both in the adipose tissue and the brain. Activated macrophage infiltration, polarization of macrophages to a more inflammatory type (M1), and increased levels of pro-inflammatory cytokines are related to brain inflammation, which induces leptin resistance in the brain. Pyrogallol-phloroglucinol-6,6-bieckol (PPB), a compound from Ecklonia cava, has anti-inflammatory effects. In this study, we evaluated the effects of PPB effect M1 polarization and inflammation and its ability to restore the effects of leptin, such as a decrease in appetite and body weight. We administered PPB to diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice, evaluated macrophage activation, polarization, and changes of inflammatory cytokine level in adipose tissue and brain, and determined the effect of PPB on leptin resistance or leptin sensitivity in the brain. The levels of activated macrophage marker, M1/M2, and pro-inflammatory cytokines were increased in the adipose tissue and brain of DIO and ob/ob mice than control. TLR4 expression, endoplasmic reticulum (ER) stress, and NF-κB expression in the brain of DIO and ob/ob mice were also increased; this increase was related to the upregulation of SOCS3 and decreased phosphorylated STAT3, which decreased leptin sensitivity in the brain. PPB decreased inflammation in the brain, restored leptin sensitivity, and decreased food intake and weight gain in both DIO and ob/ob mice.

Ontogeny of diet-induced obesity in selectively bred Sprague-Dawley rats

2003 ◽  
Vol 285 (3) ◽  
pp. R610-R618 ◽  
Author(s):  
Matthew R. Ricci ◽  
Barry E. Levin
Keyword(s):  
Leptin Receptor ◽  
Splice Variants ◽  
Caloric Intake ◽  
High Energy ◽  
Sprague Dawley ◽  
Low Fat Diet ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Sprague Dawley Rats ◽  
Plasma Leptin

Outbred Sprague-Dawley rats selectively bred for their propensity to develop diet-induced obesity (DIO) become heavier on low-fat diet than those bred to be diet resistant (DR) beginning at ∼5 wk of age. Here we assessed the development of metabolic and neural functions for insights into the origins of their greater weight gain. From week 5 to week 10, chow-fed DIO rats gained 15% more body weight and ate ∼14% more calories but had only slightly greater adiposity and plasma leptin than DR rats. From day 3 through week 10, DIO and DR rats had similar mRNA expression of arcuate nucleus neuropeptide Y, proopiomelanocortin, agouti-related peptide, and all splice variants of the leptin receptor (OB-R). When fed a high-energy (HE; 31% fat) diet, 7-wk-old DIO rats had a 240% increase in plasma leptin levels after only 3 days. Despite this early leptin rise, they maintained a persistent hyperphagia and became more obese than chow-fed DIO rats and DR rats fed chow or HE diet. Their failure to reduce caloric intake, despite high levels of leptin, suggests that selectively bred DIO rats might have reduced leptin sensitivity similar to that seen in the outbred DIO parent strain.

scholarly journals Leptin resistance: a prediposing factor for diet-induced obesity

2009 ◽  
Vol 296 (3) ◽  
pp. R493-R500 ◽  
Author(s):  
Philip J. Scarpace ◽  
Yi Zhang
Keyword(s):  
Weight Gain ◽  
Leptin Receptor ◽  
Causative Factor ◽  
Leptin Resistance ◽  
Chow Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Dietary Fructose ◽  
Complex Chronic Disease ◽  
Obesity Syndrome

Obesity is a resilient and complex chronic disease. One potential causative factor in the obesity syndrome is leptin resistance. Leptin behaves as a potent anorexic and energy-enhancing hormone in most young or lean animals, but its effects are diminished or lacking in the obese state associated with a normal genetic background. Emerging evidence suggests that leptin resistance predisposes the animal to exacerbated diet-induced obesity (DIO). Elevation of central leptin in young, lean rats induces a leptin resistance that precludes obesity on a chow diet but accelerates high-fat (HF)-induced obesity. Similarly, chronic dietary fructose consumption evokes a leptin resistance that causes obesity only upon HF exposure. Inherent central leptin insensitivity also contributes to dietary weight gain in certain obesity-prone rats. Conversely, aged, leptin-resistant animals are obese with continuous chow feeding and demonstrate aggravated obesity when challenged with an HF diet. Additionally, a submaximal central blockade with a leptin antagonist leads to obesity on both chow and HF diets, as is the case in rodents with leptin receptor deficiency of genetic origin. Despite the differences in the incidence of obesity on a chow diet, all of these forms of leptin resistance predispose rodents to aggravated HF-mediated obesity. Moreover, once leptin resistance takes hold, it aggravates DIO, and the leptin resistance and obesity compound one another, promoting a vicious cycle of escalating weight gain.

scholarly journals Leptin, soluble leptin receptor, and free leptin index in patients with metabolic syndrome

2017 ◽  
Vol 14 (1) ◽  
pp. 30-34 ◽  
Author(s):  
Elena N. Smirnova ◽  
Sofia G. Shulkina
Keyword(s):  
Metabolic Syndrome ◽  
Leptin Receptor ◽  
Therapy Group ◽  
Objective Evaluation ◽  
Leptin Resistance ◽  
Obesity And Overweight ◽  
Soluble Leptin Receptor ◽  
Average Body Mass ◽  
Group 2 ◽  
Healthy Persons

Aim. To assess the levels of leptin, its soluble receptor, and index of the formation of free leptin in metabolic syndrome (MS). Materials and methods. The study included 110 individuals with obesity and overweight. The group 1 consisted of 70 patients with MS (IDF, 2005), the average body mass index (BMI) 38.4 4.4 kg/m2, aged 48.2 2.4 years, with arterial hypertension (AH) 12 degree, without regular antihypertensive therapy. Group 2 "healthy" obesity accounted for 40 patients aged 38.4 6.2 years, BMI 36.0 5.5 kg/m2 without hypertension and metabolic disorders. Group 3 consisted of 30 healthy persons, BMI 27.1 1.3 kg/m2. All patients were evaluated for insulin, HOMA index, leptin, leptin receptor, leptin free index (calculated as the ratio of leptin (ng/ml) to the leptin receptor (ng/ml), multiplied by 100). Results: In patients with MS as compared to other two groups there were higher levels of HOMA IR index, leptin and free leptin index. Values of leptin receptor in groups 1 and 2 did not differ significantly and were lower than in healthy persons. The free leptin index was significantly higher in MS group relative to the group 2 and 15 times higher than in the healthy individuals. Free leptin index correlated with values of BMI (R = 0.32; p = 0.02), blood pressure (R = 0.3; p = 0.04), uric acid (R = 0.27; p = 0.04), triglycerides (R = 0.42; p = 0.02), index HOMA-IR (R = 0.45; p = 0.02). Conclusions: Reduction of soluble leptin receptor, depending on the degree of abdominal obesity, may cause progression of leptin resistance in patients with MS. The levels of leptin and soluble leptin receptor appears to have dramatical gender differences. Calculation of free leptin index should be used for the objective evaluation of leptin resistance, regardless of gender, degree of obesity, and other metabolic parameters.

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