scholarly journals Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

2021 ◽  
Vol 22 (16) ◽  
pp. 8928
Author(s):  
Jaume Lillo ◽  
Alejandro Lillo ◽  
David A. Zafra ◽  
Cristina Miralpeix ◽  
Rafael Rivas-Santisteban ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Cb2 Receptor ◽  
Striatal Neurons ◽  
High Fat ◽  
Proximity Ligation ◽  
Receptor Complexes ◽  
Allosteric Interactions ◽  
Heterologous System ◽  
The Central Nervous System

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.

scholarly journals Ghrelin and Cannabinoid Functional Interactions Mediated by Ghrelin/CB1 Receptor Heteromers That Are Upregulated in the Striatum From Offspring of Mice Under a High-Fat Diet

2021 ◽  
Vol 15 ◽  
Author(s):  
Alejandro Lillo ◽  
Jaume Lillo ◽  
Iu Raïch ◽  
Cristina Miralpeix ◽  
Francesc Dosrius ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Striatal Neurons ◽  
High Fat ◽  
Receptor Complexes ◽  
Functional Interactions ◽  
Heterologous System ◽  
Receptor Heteromers ◽  
The One

There is evidence of ghrelinergic-cannabinoidergic interactions in the central nervous system (CNS) that may impact on the plasticity of reward circuits. The aim of this article was to look for molecular and/or functional interactions between cannabinoid CB1 and ghrelin GHS-R1a receptors. In a heterologous system and using the bioluminescence resonance energy transfer technique we show that human versions of cannabinoid CB1 and ghrelin GHS-R1a receptors may form macromolecular complexes. Such receptor heteromers have particular properties in terms of CB1/Gi-mediated signaling and in terms of GHS-R1a-Gq-mediated signaling. On the one hand, just co-expression of CB1R and GHS-R1a led to impairment of cannabinoid signaling. On the other hand, cannabinoids led to an increase in ghrelin-derived calcium mobilization that was stronger at low concentrations of the CB1 receptor agonist, arachidonyl-2’-chloroethylamide (ACEA). The expression of CB1-GHS-R1a receptor complexes in striatal neurons was confirmed by in situ proximity ligation imaging assays. Upregulation of CB1-GHS-R1a- receptor complexes was found in striatal neurons from siblings of pregnant female mice on a high-fat diet. Surprisingly, the expression was upregulated after treatment of neurons with ghrelin (200 nM) or with ACEA (100 nM). These results help to better understand the complexities underlying the functional interactions of neuromodulators in the reward areas of the brain.

scholarly journals Reversal of Diet-Induced Obesity Increases Insulin Transport into Cerebrospinal Fluid and Restores Sensitivity to the Anorexic Action of Central Insulin in Male Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1047-1054 ◽  
Author(s):  
Denovan P. Begg ◽  
Joram D. Mul ◽  
Min Liu ◽  
Brianne M. Reedy ◽  
David A. D'Alessio ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Food Intake ◽  
High Fat Diet ◽  
Male Rats ◽  
Control Group ◽  
Chow Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Insulin Transport ◽  
The Central Nervous System

Abstract Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.

Different Responses to a High-Fat Diet in IL-6 Conditional Knockout Mice Driven by Constitutive GFAP-Cre and Synapsin 1-Cre Expression

2019 ◽  
Vol 109 (2) ◽  
pp. 113-130 ◽  
Author(s):  
Olaya Fernández-Gayol ◽  
Paula Sanchis ◽  
Kevin Aguilar ◽  
Alicia Navarro-Sempere ◽  
Gemma Comes ◽  
...  
Keyword(s):  
Body Weight ◽  
High Fat Diet ◽  
Control Diet ◽  
Conditional Knockout ◽  
Mrna Levels ◽  
High Fat ◽  
Significant Difference ◽  
Cellular Source ◽  
The Central Nervous System ◽  
Synapsin 1

Background/Aims: Interleukin-6 (IL-6) is a major cytokine controlling body weight and metabolism, at least in part through actions in the central nervous system (CNS) from local sources. Methods: We herewith report results obtained in conditional IL-6 KO mice for brain cells (Il6ΔGfap and Il6ΔSyn). Results: The reporter RiboTag mouse line demonstrated specific astrocytic expression of GFAP-dependent Cre in the hypothalamus but not in other brain areas, whereas that of synapsin 1-dependent Cre was specific for neurons. Feeding a high-fat diet (HFD) or a control diet showed that Il6ΔGfap and Il6ΔSyn mice were more prone and resistant, respectively, to HFD-induced obesity. Energy intake was not altered in HFD experiments, but it was reduced in Il6ΔSyn male mice following a 24-h fast. HFD increased circulating insulin, leptin, and cholesterol levels, decreased triglycerides, and caused impaired responses to the insulin and glucose tolerance tests. In Il6ΔGfap mice, the only significant difference observed was an increase in insulin levels of females, whereas in Il6ΔSyn mice the effects of HFD were decreased. Hypothalamic Agrp expression was significantly decreased by HFD, further decreased in Il6ΔGfap, and increased in Il6ΔSyn female mice. Hypothalamic Il-6 mRNA levels were not decreased in Il6ΔSyn mice and even increased in Il6ΔGfapmale mice. Microarray analysis of hypothalamic RNA showed that female Il6ΔGfap mice had increased interferon-related pathways and affected processes in behavior, modulation of chemical synaptic transmission, learning, and memory. Conclusion: The present results demonstrate that brain production of IL-6 regulates body weight in the context of caloric excess and that the cellular source is critical.

scholarly journals Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

2016 ◽  
Vol 310 (7) ◽  
pp. R640-R658 ◽  
Author(s):  
James E. Blevins ◽  
Benjamin W. Thompson ◽  
Vishwanath T. Anekonda ◽  
Jacqueline M. Ho ◽  
James L. Graham ◽  
...  
Keyword(s):  
High Fat Diet ◽  
High Fat ◽  
Short Term ◽  
Satiety Response ◽  
Diet Induced Obesity ◽  
Sustained Reduction ◽  
Oxytocin Infusion ◽  
Term Administration ◽  
The Central Nervous System

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity.

scholarly journals Central Administration of 1-Deoxynojirimycin Attenuates Hypothalamic Endoplasmic Reticulum Stress and Regulates Food Intake and Body Weight in Mice with High-Fat Diet-Induced Obesity

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Jongwan Kim ◽  
Eun-Young Yun ◽  
Fu-Shi Quan ◽  
Seung-Won Park ◽  
Tae-Won Goo
Keyword(s):  
Body Weight ◽  
Er Stress ◽  
High Fat Diet ◽  
Central Administration ◽  
High Fat ◽  
Signal Transducers ◽  
Diet Induced Obesity ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
The Central Nervous System

Theα-glucosidase inhibitor, 1-deoxynojirimycin (DNJ), is widely used for its antiobesity and antidiabetic effects. Researchers have demonstrated that DNJ regulates body weight by increasing adiponectin levels, which affects energy intake and prevents diet-induced obesity. However, the mechanism by which centrally administered DNJ exerts anorexigenic effects has not been studied until now. We investigated the effect of DNJ in the hypothalamus of mice with high-fat diet-induced obesity. Results showed that intracerebroventricular (ICV) administration of DNJ reduced hypothalamic ER stress, which activated the leptin-induced Janus-activated kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) signaling pathway to cause appetite suppression. We conclude that DNJ may reduce obesity by moderating feeding behavior and ER stress in the hypothalamic portion of the central nervous system (CNS).

scholarly journals High-fat diet feeding differentially affects the development of inflammation in the central nervous system

2016 ◽  
Vol 13 (1) ◽  
Author(s):  
Owein Guillemot-Legris ◽  
Julien Masquelier ◽  
Amandine Everard ◽  
Patrice D. Cani ◽  
Mireille Alhouayek ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Fat Diet ◽  
High Fat ◽  
The Central Nervous System

Expression of the cannabinoid system in muscle: effects of a high-fat diet and CB1 receptor blockade

2010 ◽  
Vol 433 (1) ◽  
pp. 175-185 ◽  
Author(s):  
Ana Crespillo ◽  
Juan Suárez ◽  
Francisco J. Bermúdez-Silva ◽  
Patricia Rivera ◽  
Margarita Vida ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Weight Gain ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
Caloric Intake ◽  
Cb1 Receptor ◽  
Cb2 Receptor ◽  
High Fat

The ECS (endocannabinoid system) plays an important role in the onset of obesity and metabolic disorders, implicating central and peripheral mechanisms predominantly via CB1 (cannabinoid type 1) receptors. CB1 receptor antagonist/inverse agonist treatment improves cardiometabolic risk factors and insulin resistance. However, the relative contribution of peripheral organs to the net beneficial metabolic effects remains unclear. In the present study, we have identified the presence of the endocannabinoid signalling machinery in skeletal muscle and also investigated the impact of an HFD (high-fat diet) on lipid-metabolism-related genes and endocannabinoid-related proteins. Finally, we tested whether administration of the CB1 inverse agonist AM251 restored the alterations induced by the HFD. Rats were fed on either an STD (standard/low-fat diet) or an HFD for 10 weeks and then treated with AM251 (3 mg/kg of body weight per day) for 14 days. The accumulated caloric intake was progressively higher in rats fed on the HFD than the STD, resulting in a divergence in body weight gain. AM251 treatment reduced accumulated food/caloric intake and body weight gain, being more marked in rats fed on the HFD. CB2 (cannabinoid type 2) receptor and PPARα (peroxisome-proliferator-activated receptor α) gene expression was decreased in HFD-fed rats, whereas MAGL (monoglyceride lipase) gene expression was up-regulated. These data suggest an altered endocannabinoid signalling as a result of the HFD. AM251 treatment reduced CB2 receptor, PPARγ and AdipoR1 (adiponectin receptor 1) gene expression in STD-fed rats, but only partially normalized the CB2 receptor in HFD-fed rats. Protein levels corroborated gene expression results, but also showed a decrease in DAGL (diacylglycerol) β and DAGLα after AM251 treatment in STD- and HFD-fed rats respectively. In conclusion, the results of the present study indicate a diet-sensitive ECS in skeletal muscle, suggesting that blockade of CB1 receptors could work towards restoration of the metabolic adaption imposed by diet.

scholarly journals The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Susana S. Correia ◽  
Guang Liu ◽  
Sarah Jacobson ◽  
Sylvie G. Bernier ◽  
Jenny V. Tobin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
High Fat Diet ◽  
Soluble Guanylate Cyclase ◽  
Primary Neurons ◽  
Target Engagement ◽  
High Fat ◽  
Markers Of Inflammation ◽  
Cgmp Signaling ◽  
The Central Nervous System

Abstract Background Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO–sGC–cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO–sGC–cGMP signaling. We evaluated target engagement and the effects of CYR119 on markers of neuroinflammation in vitro in mouse microglial cells and in vivo in quinolinic acid (QA)-induced and high-fat diet-induced rodent neuroinflammation models. Methods Target engagement was verified in human embryonic kidney (HEK) cells, rat primary neurons, mouse SIM-A9 cells, and in rats by measuring changes in cGMP and downstream targets of sGC signaling [phosphorylated vasodilator-stimulated phosphoprotein (pVASP), phosphorylated cAMP-response element binding (pCREB)]. In SIM-A9 cells stimulated with lipopolysaccharides (LPS), markers of inflammation were measured when cells were treated with or without CYR119. In rats, microinjections of QA and vehicle were administered into the right and left hemispheres of striatum, respectively, and then rats were dosed daily with either CYR119 (10 mg/kg) or vehicle for 7 days. The activation of microglia [ionized calcium binding adaptor molecule 1 (Iba1)] and astrocytes [glial fibrillary acidic protein (GFAP)] was measured by immunohistochemistry. Diet-induced obese (DIO) mice were treated daily with CYR119 (10 mg/kg) for 6 weeks, after which inflammatory genetic markers were analyzed in the prefrontal cortex. Results In vitro, CYR119 synergized with exogenous NO to increase the production of cGMP in HEK cells and in primary rat neuronal cell cultures. In primary neurons, CYR119 stimulated sGC, resulting in accumulation of cGMP and phosphorylation of CREB, likely through the activation of protein kinase G (PKG). CYR119 attenuated LPS-induced elevation of interleukin 6 (IL-6) and tumor necrosis factor (TNF) in mouse microglial cells. Following oral dosing in rats, CYR119 crossed the blood–brain barrier (BBB) and stimulated an increase in cGMP levels in the cerebral spinal fluid (CSF). In addition, levels of proinflammatory markers associated with QA administration or high-fat diet feeding were lower in rodents treated with CYR119 than in those treated with vehicle. Conclusions These data suggest that sGC stimulation could provide neuroprotective effects by attenuating inflammatory responses in nonclinical models of neuroinflammation.

Sign in / Sign up

Export Citation Format

Share Document