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Table of Contents
Year : 2019  |  Volume : 62  |  Issue : 5  |  Page : 182-187

Effects of cannabinoid modulation on hypothalamic nesfatin-1 and insulin resistance

1 Department of Physiology, Faculty of Medicine, Trakya University, Edirne, Turkey
2 Department of Anesthesiology, Sultan 1. Murat State Hospital, Edirne, Turkey
3 Department of Histology and Embryology, Faculty of Medicine, Trakya University, Edirne, Turkey
4 Department of Pharmacology, Faculty of Medicine, Trakya University, Edirne, Turkey

Date of Submission01-Jul-2019
Date of Decision29-Aug-2019
Date of Acceptance25-Sep-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Dr. Oktay Kaya
Department of Physiology, Faculty of Medicine, Trakya University, Balkan Campus, D Block, 22030, Edirne
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CJP.CJP_50_19

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Both nesfatin-1 and cannabinoid systems involved in the regulation of sleep, metabolism, and food intake. The relationship between cannabinoid system and nesfatin-1 levels remains to be elucidated. This study investigated nesfatin-1 and insulin resistance in 72-h rapid eye movement (REM) sleep-deprived mice under the effects of cannabinoid, and cannabinoid receptors CB1R and CB2R blocking. Sixty mice were exposed to 72-h sleep deprivation. Groups and drug administrations were as follows: Group 1 (control) received injection of vehicle. Group 2 received WIN 55,212,2. Group 3 received AM251 (CB1R antagonist) followed by WIN 55,212,2 injection. Group 4 received SR144528 (CB2R antagonist) followed by WIN 55,212,2 injection. Group 5 received only AM251. Group 6 received only SR144528. Blood samples were collected 1 h after drug administration and prepared for biochemical measurements. Glucose levels were measured by glucometer, whereas insulin and nesfatin-1 levels were measured by ELISA. Central nesfatin-1 was also assessed using immunohistochemistry. One-way analysis of variance together with post hoc Tukey's test was used for inter-group comparisons. Serum nesfatin-1 levels were comparable in all study groups. Brain nesfatin-1 immune-positive cell count was lower in WIN group compared to controls. The administration of CB1R or CB2R antagonist prevented reduction in nesfatin-1-positive cell count. Insulin resistance was higher in WINCB2 and CB2 groups than in control and WINCB1 groups. Cannabinoid treatment reduced nesfatin-1 immunoreactivity in the central nervous system and this effect was prevented by either CB1R or CB2R antagonist pretreatment. Insulin resistance might be related to CB2 receptor activation which was independent from central nesfatin-1 immunoreactivity.

Keywords: Cannabinoid receptor CB2, cannabinoid receptors, insulin resistance, nesfatin-1, sleep deprivation

How to cite this article:
Kaya O, Yilmaz ME, Bayram S, Gunduz O, Kizilay G, Ozturk L. Effects of cannabinoid modulation on hypothalamic nesfatin-1 and insulin resistance. Chin J Physiol 2019;62:182-7

How to cite this URL:
Kaya O, Yilmaz ME, Bayram S, Gunduz O, Kizilay G, Ozturk L. Effects of cannabinoid modulation on hypothalamic nesfatin-1 and insulin resistance. Chin J Physiol [serial online] 2019 [cited 2022 Dec 9];62:182-7. Available from: https://www.cjphysiology.org/text.asp?2019/62/5/182/269837

  Introduction Top

Nesfatin-1 is a potent anorexigenic peptide which was shown to reduce food intake in a dose-dependent manner.[1] Specific nesfatin-1 binding sites were identified both in parts of the central nervous system such as hypothalamus and peripheral tissues such as the pancreas.[2] Recent studies suggested that nesfatin-1 may be related to regulation of both blood glucose and sleep.[3] For instance, nesfatin-1 infusion led to improved glucose utilization by increased insulin secretion and the activation of intracellular insulin signaling in a mouse model.[4] Furthermore, nesfatin-1 modulated excitability of glucose-responsive neurons in the hypothalamus which may indicate a role for both central glucose sensing and hypothalamic sleep regulation.[5] On the other hand, tuberal hypothalamic area, a rapid eye movement (REM) sleep-regulating central nervous structure was shown to coexpress both nesfatin-1 and melanin-concentrating hormone.[6] Several studies investigated nesfatin-1 as a potential sleep-regulating peptide in hypothalamus.[7],[8]

Sleep loss is a common condition which may impair metabolic homeostasis besides its cognitive consequences. In a recent study, 40-h total sleep deprivation led to 3.5-fold increased circulating insulin levels in healthy volunteers independent of resistin and visfatin alterations.[9] Partial sleep deprivation or sleep curtailment up to 4 h per night reduced insulin sensitivity irrespective of its nocturnal timing in healthy men.[10] Furthermore, inadequate sleep is suggested as a modifiable risk factor for type 2 diabetes in children and adolescents.[11] However, the mechanisms linking sleep loss with impaired glucose homeostasis remain unresolved. Cannabinoids are lipid signaling molecules involved in numerous physiologic processes such as pain perception, inflammatory responses, and regulation of blood glucose through binding-specific receptors CB1R and CB2R.[12] Overactivity of CB1R system contributed to the development of insulin resistance, whereas its blockade led to beneficial effects in preventing its cardiometabolic complications.[13],[14],[15],[16],[17] Interestingly, nesfatin-1 and cannabinoid system may be interrelated and up-to-date only one study investigated this relationship. It has been demonstrated that peripheral cannabinoid system regulates food intake through a mechanism that implies gastric nesfatin-1 production and release.[18]

In this study, we aimed to investigate the possible relationship of cannabinoid system with both peripheral and central nesfatin-1 levels in the setting of total sleep deprivation. We hypothesized that cannabinoid receptor blockade alters blood glucose regulation and insulin resistance by changing peripheral and central nesfatin-1.

  Materials and Methods Top

A total of 60 male BALB/c mice in six groups (n = 10 for each) were used. Before experimental procedures, approval of the Local Ethics Committee of Animal Experiments of Trakya University was obtained (TÜHADYEK 2015/35). Animals were kept under laboratory conditions of 12/12 light/dark cycle, 22°C ± 2°C, 40% humidity. Mouse chow and tap water were obtained ad libitum. All animal groups underwent 72-h REM sleep deprivation by using modified flower pot technique.[19],[20] Sleep deprivation was followed by drug injections. And after completion of drug administrations, all animals were sacrificed under general anesthesia (10 mg/kg xylazine and 50 mg/kg ketamine). Following induction of general anesthesia, intracardiac blood samples were collected for biochemical assay. Then, all animals were decapitated, skulls were removed and whole brains were embedded into formaldehyde solution for immunohistochemical examination.

Animal groups

Six study groups were formed. All animals underwent 72-h REM sleep deprivation protocol and differed by intraperitoneal (i.p.) drug injections. Animals in the control group (CONT) were injected vehicle (78% saline, 1% ethanol, 1% tween 80, 20% DMSO), whereas WIN group was injected by cannabinoid agonist WIN 55,212,2 (5 mg/kg), WINCB1 group was injected by WIN 55,212,2 (5 mg/kg) and CB1R antagonist AM251 (1 mg/kg), WINCB2 group was injected by WIN 55,212,2 (5 mg/kg) and CB2R antagonist SR144528 (1 mg/kg). CB1 and CB2 groups were injected by CB1R antagonist AM251 (1 mg/kg) and CB2R antagonist SR144528 (1 mg/kg), respectively [Figure 1].
Figure 1: Study protocol

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Rapid eye movement sleep deprivation protocol

Modified multiple platform technique was used to establish REM sleep deprivation.[19],[20],[21] Mice were placed on round platforms of 3-cm diameter to induce REM sleep deprivation.[22] To prevent social isolation, seven platforms were put in each water tank (125 cm × 45 cm × 45 cm) with shallow water (2–3 cm depth). Thus, platforms were surrounded by water up to 1–2 cm. Only five animals (for seven platforms) were kept in each tank, thus animals were free to move and change platform which prevented immobility stress. All animals easily reached food (standardized mice pellets) and water ad libitum. We performed cleaning and water change of the tanks on a daily basis.

Drug injections and blood/tissue sampling

After completion of 72-h sleep deprivation, drug injections were performed. All groups received two injections by a 20-min interval as follows [Figure 1]: CONT group, vehicle and vehicle; WIN group, vehicle and agonist; WINCB1 group, antagonist-1 and agonist; WINCB2 group, antagonist-2 and agonist; CB1 group, antagonist-1 and vehicle; CB2 group, antagonist-2 and vehicle. Sixty minutes after the last injection, blood samples were collected through cardiac puncture under general anesthesia. Following blood sampling, all animals were decapitated and the crania were surgically removed, and brain tissues were taken and embedded into formaldehyde solution and then paraffin block.

Nesfatin-1, insulin, blood glucose measurements, and calculation of insulin resistance

Nesfatin-1 and insulin levels were measured by commercial ELISA kits (Raybiotech; EIA-NES-1 and Millipore; EZRMI-13K, respectively). Glucose was used by glucometer (GlucoDr blood glucose monitoring system, allmedicus, Korea). Insulin resistance was calculated using the homeostatic model of insulin resistance (HOMA-IR = [fasting glucose, mg/dL × fasting insulin IU/mL]/405).

Immunohistochemistry for nesfatin-1

Formaldehyde-fixed, paraffin-embedded hypothalamic tissues were cut into 5 μm sections. Slides were deparaffinized, rehydrated in a graded series of ethanol, and then boiled in citrate buffer (10 mM; pH 6.0, Invitrogen, Carlsbad, USA) for 20 min for antigen retrieval. Following washing in phosphate-buffered saline (Invitrogen), the sections were immersed in hydrogen peroxide blocking reagent (Abcam, Cambridge, USA) for 5 min. Slides were incubated with blocking solution (Histostain-Plus IHC kit, Invitrogen) for 10 min at room temperature in a humidified chamber. Excess serum was drained and incubated in rabbit polyclonal nesfatin-1 antibody (NBP1-87383; Novus Biologicals) diluted 1:1000 in antibody diluent reagent solution (Life Technologies) for 1 h at room temperature. For negative controls, primary antibodies were replaced by their nonimmune isotypes. The sections were incubated for 10 min in biotinylated secondary antibody (Life Technologies) that had been produced against the primary antibody and then incubated for 10 min HRP-streptavidin solution (Life Technologies). Staining reactions were visualized using Diaminobenzidine (DAB) (Life Technologies), then counterstained with hematoxylin (Merck). Sections were examined using a X400 objective on a BX-51 Olympus microscope. The nesfatin-1 immunoreactivity score was calculated by counting immunopositive cells in a 0.1 mm 2 area in hypothalamic paraventricular nucleus.

Statistical analysis

Means and standard deviations were used for descriptive analysis. Normal distribution was tested using Kolmogorov–Smirnov test. Nesfatin-1-positive cell counts, peripheral nesfatin, insulin and glucose levels, and HOMA-IR were compared among the six groups by one-way analysis of variance. Post hoc pairwise comparisons were performed by Tukey's test using GraphPad Prism software (GraphPad Inc., La Jolla, CA, USA). Statistical significance was adjusted to a value of P < 0.05.

  Results Top

Serum glucose, insulin, and homeostatic model of insulin resistance

Serum glucose and insulin levels of the study groups are given in [Figure 2]a and [Figure 2]b. Serum glucose level was significantly higher in WINCB2 than in WINCB1 group (124.6 ± 30.14 vs. 79.30 ± 11.33 mg/dL, respectively, P < 0.05, [Figure 2]a), whereas serum insulin level was significantly higher in CB2 than in CONT group (0.55 ± 0.15 vs. 0.29 ± 0.09 ng/mL, respectively, P < 0.05, [Figure 2]b). Calculated HOMA-IR values were compared among the study groups. Insulin resistance was higher in WINCB2 and CB2 groups than in the control and WINCB1 groups [Figure 2]c.
Figure 2: Serum glucose (a) and insulin (b) levels of study groups. Insulin resistance (c) was calculated according to homeostatic model. *P < 0.05 compared to control group, #P < 0.05 compared to WINCB1 group

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Hypothalamic nesfatin-1 immunohistochemistry and serum nesfatin-1 levels

Immunohistochemistry study of hypothalamic paraventricular nucleus sections [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, [Figure 3]e, [Figure 3]f showed that nesfatin-1 immune-positive cell count was lower in WIN group compared to CONT (54.75 ± 7.67 vs. 78.33 ± 6.50, respectively, P < 0.05, [Figure 3]a and [Figure 3]b). When compared to WIN group, nesfatin-1 immune-positive cell counts were higher in WINCB1 and WINCB2 groups [Figure 3]b, [Figure 3]c, [Figure 3]d. CB1 and CB2 groups showed similar nesfatin-1 immunoreactivity [Figure 3]e and [Figure 3]f. Immune-positive cells counts are given in [Figure 3]g. As shown, the administration of CB1 or CB2 receptor antagonists together with WIN 55,212,2 prevented reduction in nesfatin-1-positive cell count [Figure 3]g. Serum nesfatin-1 levels were comparable in all study groups [Figure 3]h.
Figure 3: Hypothalamic nesfatin-1 immunohistochemical staining. (a) Control group. The small square below depicts negative control, (b) WIN group, (c) WINCB1 group, (d) WINCB2 group, (e) CB1 group, (f) CB2 group, (g) İmmunohistochemistry score in groups, (h) Nesfatin-1 serum concentration, ×400. *P < 0.05 is significant compared to control group, ¥P < 0.05 is significant compared to WIN group

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  Discussion Top

The main and novel finding of this study is that cannabinoid treatment reduced nesfatin-1 immunoreactivity in the hypothalamus of the central nervous system, and this effect was prevented by pretreatment of either CB1R or CB2R antagonist. In addition, serum nesfatin-1 levels were comparable in all study groups independent of cannabinoid agonist or antagonist treatments. To our knowledge, this is the first study that investigated the relationship of cannabinoid receptor blocking and central nesfatin-1 in REM-sleep deprived animals. Although nesfatin-1 was originally detected in brain areas involved in food intake regulation such as arcuate nucleus, paraventricular nucleus, and nucleus of the solitary tract,[23] the largest nesfatin-1 neuron population is found in the dorsolateral hypothalamus and zona incerta which are closely associated with sleep-wake regulation.[8] These findings may suggest a putative modulating role for nesfatin-1 in the regulation of both sleep and metabolism. REM sleep deprivation downregulated the expression of hypothalamic nesfatin-1 which returned baseline levels after recovery sleep.[8] Thus, nesfatin-1 was recognized as a vigilance factor in the above-mentioned study. Cannabinoid WIN55-212 treatment further reduced hypothalamic nesfatin-1 immunoreactivity when compared to REM sleep-deprived animals in our study. Taken together, this may indicate that the somnogenic effect of cannabinoids may be due to nesfatin-1 reduction. In addition, this effect is not receptor-specific as both CB1R and CB2R blockade reversed nesfatin-1 reduction.

Another important finding of our study is that blocking CB2Rs by an antagonist led to increased insulin resistance independent from exogenous agonist cannabinoid (WIN55) administration. Several studies investigated the relationship of blood glucose homeostasis and CB2R activation.[24],[25] Activation of CB2R improved glucose tolerance after i.p. glucose injection which was reversed by CB2R blockade in rats.[24] In another study, CB2R agonist SER601 improved systemic sensitivity to insulin in high-fat diet/streptozotocin induced diabetic mice.[24] Collectively, these findings suggest that CB2R agonism reduces blood glucose whereas antagonism impairs glucose homeostasis. Conversely, specific CB1R antagonist rimonabant decreased glucose-stimulated pancreatic insulin secretion.[26] Studies with selective antagonism or agonism of each cannabinoid receptor subtype revealed that glucose homeostasis could be controlled by actions of cannabinoids on both CB1R and CB2R by a coordinated fashion. However, this regulation may be species dependent. Immunohistochemistry studies revealed that CB2Rs are expressed on mouse pancreatic beta-cell membrane whereas CB1Rs are absent.[24] The study extended those previous findings and showed that circulating nesfatin-1 was not involved in CB2R activity-related glucose homeostasis.

Insulin resistance may result both from impaired intracellular signaling downstream the insulin receptor and from the altered secretion of apetite regulatory peptides such as leptin, ghrelin, and neuropeptide Y. It is well known that suppression of ghrelin is associated with insulin resistance and compensatory increased insulin secretion. Of late, several studies suggested a role for nesfatin-1 in insulin resistance.[27],[28],[29] Guo et al. demonstrated that the activation of central nesfatin-1 was sufficient to induce hepatic and peripheral insulin sensitivity.[27] Conversely, Anwar et al. reported positive correlation between serum insulin, HOMA-IR, and nesfatin-1 levels.[28] Furthermore, Ravussin et al. showed nesfatin-1 did not impact on hypothalamic satiety mechanisms; rather it controlled macrophage-mediated metabolic inflammation to control insulin resistance.[29] In other words, obesity-induced upregulation of nesfatin-1 in macrophages may sense energy excess which links inflammation and insulin resistance. In the present study, we further investigated the role of cannabinoid receptors in the mechanism that links nesfatin-1 to insulin resistance. Interestingly, selective CB2R blockade resulted in higher insulin resistance independent of exogenous cannabinoid administration in this model. This finding suggested that insulin sensitivity might be related to CB2R activation or insulin resistance might be related to CB1R activation. On the other hand, increased central nesfatin-1 immune reactivity in CB1R and CB2R blockade showed that nesfatin-1 down-regulation under the effect of cannabinoids was not receptor specific. Taken together, these data suggested that there is no interaction between nesfatin-1 and cannabinoids in central regulation of insulin sensitivity.

There are several limitations that deserve comment. First, we performed acute drug treatment and collected blood samples only 1 h following the last injections. Thus, these results may not be extrapolated to chronic administration. On the other hand, it may be argued whether 1 h was sufficient to provide any change in nesfatin-1 levels. A recent study showed that the duration was sufficient for a cannabinoid-related nesfatin-1 change even in the periphery.[18] Second, we calculated nesfatin-1 immunoreactivity score by counting immunopositive cells in two-dimensional sections of hypothalamic paraventricular nucleus. It would be better to use a volume-based method.

  Conclusions Top

Cannabinoid treatment reduced nesfatin-1 immunoreactivity in the hypothalamus and this effect was prevented by either CB1R or CB2R antagonist pretreatment. To our knowledge, this is the first study that investigated the relationship of cannabinoid receptor blocking and hypothalamic nesfatin-1. We further found that insulin sensitivity might be related to CB2R activation which was independent from central nesfatin-1 immunoreactivity.

Financial support and sponsorship

This study was supported by the Scientific Research Fund of Trakya University (TUBAP 2015/230).

Conflicts of interest

There are no conflicts of interest.

  References Top

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