| 1. |
- Schéle, Erik, 1980, et al.
(författare)
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Regulation of body fat mass by the gut microbiota: Possible mediation by the brain.
- 2016
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Ingår i: Peptides. - : Elsevier BV. - 1873-5169 .- 0196-9781. ; 77, s. 54-59
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Forskningsöversikt (refereegranskat)abstract
- New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further.
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| 2. |
- Schéle, Erik, 1980, et al.
(författare)
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The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system.
- 2013
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 154:10, s. 3643-51
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood. To investigate whether the gut microbiota affects hypothalamic and brainstem body fat-regulating circuits, we compared gene expression of food intake-regulating neuropeptides between germ-free and conventionally raised (CONV-R) mice. We found that CONV-R mice had decreased expression of the antiobesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in the brainstem. Moreover, in both the hypothalamus and the brainstem, CONV-R mice had decreased expression of the antiobesity neuropeptide brain-derived neurotrophic factor (Bdnf). CONV-R mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the antiobesity peptides proopiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart) in the hypothalamus. The latter changes in neuropeptide expression could be secondary to elevated fat mass in CONV-R mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in CONV-R mice compared with germ-free mice. The hypothalamic expression of leptin resistance-associated suppressor of cytokine signaling 3 (Socs-3) was increased in CONV-R mice. In conclusion, the gut microbiota reduces the expression of 2 genes coding for body fat-suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat-inducing gut microbiota is associated with hypothalamic signs of Socs-3-mediated leptin resistance, which may be linked to failed compensatory body fat reduction.
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| 3. |
- Anesten, Fredrik, et al.
(författare)
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Functional interleukin-6 receptor- is located in tanycytes at the base of the third ventricle
- 2017
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Ingår i: Journal of Neuroendocrinology. - : Wiley. - 0953-8194 .- 1365-2826. ; 29:12
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-6(-)/(-) mice develop mature onset obesity, whereas i.c.v. injection of IL-6 decreases obesity in rodents. Moreover, levels of IL-6 in cerebrospinal fluid (CSF) were reported to be inversely correlated with obesity in humans. Tanycytes lining the base of the third ventricle (3V) in the hypothalamus have recently been reported to be of importance for metabolism. In the present study, we investigated whether tanycytes could respond to IL-6 in the CSF. With immunohistochemistry using a well characterised antibody directed against the ligand binding receptor for IL-6, IL-6 receptor (IL-6R), it was found that tanycytes, identified by the two markers, vimentin and dopamine- and cAMP-regulated phosphoprotein of 32 kDa, contained IL-6R. There were fewer IL-6R on another type of ventricle-lining cells, ependymal cells, as identified by the marker glucose transporter-1. To demonstrate that the immunoreactive IL-6R were responsive to IL-6, we injected IL-6 i.c.v. This treatment increased immunoreactive phosphorylated signal transducer and activator of transcription-3 (pSTAT3) in tanycytes after 5minutes and in cells in the medial part of the arcuate nucleus after 5 and 15 minutes. Intracerebroventricular injection of leptin exerted similar effects. As expected, i.p. injection of leptin also induced pSTAT3 staining in the hypothalamus, whereas i.p. IL-6 injection had little effect on this parameter. Intracerebroventricular or i.p. injection of vehicle only had no effect on pSTAT3-immunoreactivity. In summary, there are functional IL-6R on tanycytes at the bottom of the 3V, in agreement with the possibility that ventricular administration of IL-6 decreases obesity in mice via an effect on this cell type.
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| 4. |
- Anesten, Fredrik, et al.
(författare)
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Glucagon-Like Peptide-1-, but not Growth and Differentiation Factor 15-, Receptor Activation Increases the Number of Interleukin-6-Expressing Cells in the External Lateral Parabrachial Nucleus
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 109:4, s. 310-321
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin (IL)-6 in the hypothalamus and hindbrain is an important downstream mediator of suppression of body weight and food intake by glucagon-like peptide-1 (GLP-1) receptor stimulation. CNS GLP-1 is produced almost exclusively in prepro-glucagon neurons in the nucleus of the solitary tract. These neurons innervate energy balance-regulating areas, such as the external lateral parabrachial nucleus (PBNel); essential for induction of anorexia. Using a validated novel IL-6-reporter mouse strain, we investigated the interactions in PBNel between GLP-1, IL-6, and calcitonin gene-related peptide (CGRP, a well-known mediator of anorexia). We show that PBNel GLP-1R-containing cells highly (to about 80%) overlap with IL-6-containing cells on both protein and mRNA level. Intraperitoneal administration of a GLP-1 analogue exendin-4 to mice increased the proportion of IL-6-containing cells in PBNel 3-fold, while there was no effect in the rest of the lateral parabrachial nucleus. In contrast, injections of an anorexigenic peptide growth and differentiation factor 15 (GDF15) markedly increased the proportion of CGRP-containing cells, while IL-6-containing cells were not affected. In summary, GLP-1R are found on IL-6-producing cells in PBNel, and GLP-1R stimulation leads to an increase in the proportion of cells with IL-6-reporter fluorescence, supporting IL-6 mediation of GLP-1 effects on energy balance.
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| 5. |
- Anesten, Fredrik
(författare)
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IL-6 and GLP-1 in body fat regulating parts of the CNS in healthy mice
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It has previously been shown that mice lacking interleukin-6 (IL-6) develop mature onset obesity. The weight-suppressing effects of IL-6 have been assumed to be exerted at a central level, as supported by the fact that ICV- injections, but not peripheral injections of IL-6, increases energy expenditure and decreases body fat in rodents. Glucagon-like peptide-1 (GLP-1) is an incretin derived from the transcription product of the pro-glucagon gene. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (dpp-4) and has a very short half-life in serum. Consequently, to study the effects of GLP-1 on obesity and other metabolic parameters, GLP-1 analogues that are less easily degraded by dpp-4 with have been useful. One such analogue is Exendin-4 (Ex-4), first found in the saliva of the gila monster, a lizard. Ex4 has been used clinically as a treatment for diabetes type 2. In some patients Ex-4 and other long-acting GLP-1 analogues also promotes moderate weight loss, but the mechanisms for this action has been essentially unknown. Tanycytes are specialized glial cells located mainly at the bottom of the third ventricle wall. They have processes that reach deep into the parenchyma of the hypothalamus, reaching into the ARN and the median eminence. These cells have been proposed to act as gatekeepers, regulating which substances that passes into the brain parenchyma and which that do not. It has recently been shown that tanycytes regulate the transport of leptin into the brain. The aim of this thesis has been to investigate possible interactions between IL-6 and GLP-1 in the CNS. Using immunohistochemistry, we aimed to map the location of the IL-6 receptor-α (IL-6R α) in the brainstem as well as investigate its possible co-localization with GLP-1. Furthermore, we aimed to elucidate whether the weight-suppressing effects of Ex4 are dependent on IL-6. We also aimed to find out whether GLP-1 can act as an anti-obesity agent in the parabrachial nucleus (PBN). Finally, we sought to determine whether tanycytes express IL-6Rα, making them candidate cells for transport of IL-6 from cerebrospinal fluid further into the brain. We found that IL-6 as well as interleukin-1 (IL-1) appears to act as downstream mediators of GLP-1 in the hypothalamus and brainstem. Aministration of blocking antibodies against the receptors of these cytokines lead to an attenuation of the effect of Ex4 on food intake and body weight. To expand upon these findings, we also show that the GLP-1 neurons present in the nucleus of the solitary tract (NTS) of the brainstem contain IL-6Rα. By using electrophysiology, we were able to show that this population of cells responds to IL-6 by and influx of Ca2+. Our studies of the PBN showed that direct GLP-1 receptor stimulation with Ex4 led to a decrease in food intake and body weight of rats. We also found that projections from GLP-1 neurons in the NTS reach cells in the PBN. A sizeable portion of these cells in the lateral PBN (lPBN) stain positively for calcitonin gene-related peptide (CGRP). In mice, studies have shown that stimulation of the CGRP neurons leads to a reduction in food intake. It is thus possible that GLP-1 and CGRP influence each other. Finally, using immunohistochemistry we found that IL-6Rα is indeed present on tanycytes. This leads to a possible way for CSF-IL-6 to influence appetite-regulating centers in the brain, such as the arcuate nucleus. Taken together, our findings show that IL-6 and GLP-1 influence each other in some of the important appetite-regulating centers of the brain.
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| 6. |
- Anesten, Fredrik, et al.
(författare)
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Interleukin-6 in the central amygdala is bioactive and co-localised with glucagon-like peptide-1 receptor
- 2019
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Ingår i: Journal of Neuroendocrinology. - : Wiley. - 0953-8194 .- 1365-2826. ; 31:6
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal circuits involving the central amygdala (CeA) are gaining prominence as important centres for regulation of metabolic functions. As a part of the subcortical food motivation circuitry, CeA is associated with food motivation and hunger. We have previously shown that interleukin (IL)-6 can act as a downstream mediator of the metabolic effects of glucagon-like peptide-1 (GLP-1) receptor (R) stimulation in the brain, although the sites of these effects are largely unknown. In the present study, we used the newly generated and validated RedIL6 reporter mouse strain to investigate the presence of IL-6 in the CeA, as well as possible interactions between IL-6 and GLP-1 in this nucleus. IL-6 was present in the CeA, mostly in cells in the medial and lateral parts of this structure, and a majority of IL-6-containing cells also co-expressed GLP-1R. Triple staining showed GLP-1 containing fibres co-staining with synaptophysin close to or overlapping with IL-6 containing cells. GLP-1R stimulation enhanced IL-6 mRNA levels. IL-6 receptor-alpha (IL-6Rα) was found to a large part in neuronal CeA cells. Using electrophysiology, we determined that cells with neuronal properties in the CeA could be rapidly stimulated by IL-6 administration in vitro. Moreover, microinjections of IL-6 into the CeA could slightly reduce food intake in vivo in overnight fasted rats. In conclusion, IL-6 containing cells in the CeA express GLP-1R, are close to GLP-1-containing synapses, and demonstrate increased IL-6 mRNA in response to GLP-1R agonist treatment. IL-6, in turn, exerts biological effects in the CeA, possibly via IL-6Rα present in this nucleus. 2019 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology
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| 7. |
- Anesten, Fredrik, et al.
(författare)
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Preproglucagon neurons in the hindbrain have IL-6 receptor-α and show Ca2+ influx in response to IL-6
- 2016
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 311:1
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal circuits in the hypothalamus and hindbrain are of importance for control of food intake, energy expenditure, and fat mass. We have recently shown that treatment with exendin-4 (Ex-4), an analog of the proglucagonderived molecule glucagon-like peptide 1 (GLP-1), markedly increases mRNA expression of the cytokine interleukin-6 (IL-6) in the hypothalamus and hindbrain and that this increase partly mediates the suppression of food intake and body weight by Ex-4. Endogenous GLP-1 in the central nervous system (CNS) is produced by preproglucagon (PPG) neurons of the nucleus of the solitary tract (NTS) in the hindbrain. These neurons project to various parts of the brain, including the hypothalamus. Outside the brain, IL-6 stimulates GLP-1 secretion from the gut and pancreas. In this study, we aim to investigate whether IL-6 can affect GLP-1-producing PPG neurons in the nucleus of the solitary tract (NTS) in mouse hindbrain via the ligand binding part of the IL-6 receptor, IL-6 receptor-α (IL-6Rα). Using immunohistochemistry, we found that IL-6Rα was localized on PPG neurons of the NTS. Recordings of these neurons in GCaMP3/GLP-1 reporter mice showed that IL-6 enhances cytosolic Ca2+ concentration in neurons capable of expressing PPG. We also show that the Ca2+ increase originates from the extracellular space. Furthermore, we found that IL-6Rα was localized on cells in the caudal hindbrain expressing immunoreactive NeuN (a neuronal marker) or CNP:ase (an oligodendrocyte marker). In summary, IL-6Rα is present on PPG neurons in the NTS, and IL-6 can stimulate these cells by increasing influx of Ca2+ to the cytosol from the extracellular space. © 2016 the American Physiological Society.
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| 8. |
- Egecioglu, Emil, 1977, et al.
(författare)
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Interleukin-6 is important for regulation of core body temperature during long-term cold exposure in mice
- 2018
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Ingår i: Biomedical Reports. - : Spandidos Publications. - 2049-9434 .- 2049-9442. ; 9:3, s. 206-212
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-6 (IL6) is a cytokine important for inducing the fever response during infection and has been reported to uphold core body temperature during acute cold exposure. Recently it has also been indicated that IL6 in serum increases in cold-exposed mice. The aim of the present study was to investigate if IL6 is important for core body temperature regulation following a long-term cold exposure in mice. Experiments were performed with global IL6 deficient (-/-) mice, mice with conditional IL6 receptor α (IL6Rα) knockdown in the central nervous system (CNS; IL6RαNesCre) and appropriate wild-type (Wt) controls. All mice were placed in a cold environment (4˚C) for 6 days. Core body temperature and oxygen consumption were measured by telemetry probes and indirect calorimetry at room temperature (20˚C), and during the first and last day of cold exposure. Brain stem, hypothalamus and white and brown adipose tissues from the cold-exposed mice were subjected to gene expression analysis. After 6 days in 4˚C, the IL6-/- mice exhibited significantly lower body temperature and oxygen consumption compared with Wt mice (P<0.05). The IL6RαNesCre mice also exhibited lower body temperature compared with WtNesCre controls during the last day of cold exposure (P<0.05). Furthermore, an increase in the mRNA level of brain-derived neurotrophic factor (Bdnf) was detected in the brain stem of both IL6-/- and IL6RαNesCre mice compared with the Wt groups (P<0.05). The finding that body temperature was decreased in IL6-/- and IL6RαNesCre mice indicates a decrease in thermogenesis in these animals. Bdnf has previously been indicated to increase body temperature and could in the present study be a mechanistic factor involved in counteracting the low body temperature in IL6-/- and IL6RαNesCre mice. These results suggest that IL6 is not only involved in body temperature regulation during infection, but also during long-term cold exposure, probably through mechanisms in the CNS.
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| 9. |
- Fagman, Johan Bourghardt, 1980, et al.
(författare)
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The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
- 2015
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860 .- 0892-6638. ; 29:4, s. 1540-1550
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have important cardiometabolic actions in males, but their metabolic role in females is unclear. To determine the physiologic androgen receptor (AR)-dependent actions of androgens on atherogenesis in female mice, we generated female AR-knockout (ARKO) mice on an atherosclerosis-prone apolipoprotein E (apoE)-deficient background. After 8 weeks on a high-fat diet, but not on a normal chow diet, atherosclerosis in aorta was increased in ARKO females (+59% vs. control apoE-deficient mice with intact AR gene). They also displayed increased body weight (+18%), body fat percentage (+62%), and hepatic triglyceride levels, reduced insulin sensitivity, and a marked atherogenic dyslipidemia (serum cholesterol, +52%). Differences in atherosclerosis, body weight, and lipid levels between ARKO and control mice were abolished in mice that were ovariectomized before puberty, consistent with a protective action of ovarian androgens mediated via the AR. Furthermore, the AR agonist dihydrotestosterone reduced atherosclerosis (-41%; thoracic aorta), subcutaneous fat mass (-44%), and cholesterol levels (-35%) in ovariectomized mice, reduced hepatocyte lipid accumulation in hepatoma cells in vitro, and regulated mRNA expression of hepatic genes pivotal for lipid homeostasis. In conclusion, we demonstrate that the AR protects against diet-induced atherosclerosis in female mice and propose that this is mediated by modulation of body composition and lipid metabolism.-Fagman, J. B., Wilhelmson, A. S., Motta, B. M., Pirazzi, C., Alexanderson, C., De Gendt, K., Verhoeven, G., Holmäng, A., Anesten, F., Jansson, J. -O., Levin, M., Borén, J., Ohlsson, C., Krettek, A., Romeo, S., Tivesten, A. The androgen receptor confers protection against diet-induced atherosclerosis, obesity, and dyslipidemia in female mice.
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| 10. |
- Jansson, John-Olov, 1954, et al.
(författare)
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A Body Weight Sensor Regulates Prepubertal Growth via the Somatotropic Axis in Male Rats
- 2021
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 162:6
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Tidskriftsartikel (refereegranskat)abstract
- In healthy conditions, prepubertal growth follows an individual specific growth channel. Growth hormone (GH) is undoubtedly the major regulator of growth. However, the homeostatic regulation to maintain the individual specific growth channel during growth is unclear. We recently hypothesized a body weight sensing homeostatic regulation of body weight during adulthood, the gravitostat. We now investigated if sensing of body weight also contributes to the strict homeostatic regulation to maintain the individual specific growth channel during prepubertal growth. To evaluate the effect of increased artificial loading on prepubertal growth, we implanted heavy (20% of body weight) or light (2% of the body weight) capsules into the abdomen of 26-day-old male rats. The body growth, as determined by change in biological body weight and growth of the long bones and the axial skeleton, was reduced in rats bearing a heavy load compared with light load. Removal of the increased load resulted in a catch-up growth and a normalization of body weight. Loading decreased hypothalamic growth hormone releasing hormone mRNA, liver insulin-like growth factor (IGF)-1 mRNA, and serum IGF-1, suggesting that the reduced body growth was caused by a negative feedback regulation on the somatotropic axis and this notion was supported by the fact that increased loading did not reduce body growth in GH-treated rats. Based on these data, we propose the gravitostat hypothesis for the regulation of prepubertal growth. This states that there is a homeostatic regulation to maintain the individual specific growth channel via body weight sensing, regulating the somatotropic axis and explaining catch-up growth.
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| 11. |
- Jansson, John-Olov, 1954, et al.
(författare)
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Body weight homeostat that regulates fat mass independently of leptin in rats and mice.
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 115:2, s. 427-432
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Tidskriftsartikel (refereegranskat)abstract
- Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.
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| 12. |
- Jansson, John-Olov, 1954, et al.
(författare)
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The dual hypothesis of homeostatic body weight regulation, including gravity-dependent and leptin-dependent actions.
- 2023
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Ingår i: Philosophical transactions of the Royal Society of London. Series B, Biological sciences. - 1471-2970. ; 378:1888
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Forskningsöversikt (refereegranskat)abstract
- Body weight is tightly regulated when outside the normal range. It has been proposed that there are individual-specific lower and upper intervention points for when the homeostatic regulation of body weight is initiated. The nature of the homeostatic mechanisms regulating body weight at the lower and upper ends of the body weight spectrum might differ. Previous studies demonstrate that leptin is the main regulator of body weight at the lower end of the body weight spectrum. We have proposed that land-living animals use gravity to regulate their body weight. We named this homeostatic system the gravitostat and proposed that there are two components of the gravitostat. First, an obvious mechanism involves increased energy consumption in relation to body weight when working against gravity on land. In addition, we propose that there exists a component, involving sensing of the body weight by osteocytes in the weight-bearing bones, resulting in a feedback regulation of energy metabolism and body weight. The gravity-dependent homeostatic regulation is mainly active in obese mice. We, herein, propose the dual hypothesis of body weight regulation, including gravity-dependent actions (= gravitostat) at the upper end and leptin-dependent actions at the lower end of the body weight spectrum. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
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| 13. |
- Richard, Jennifer E., et al.
(författare)
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GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence
- 2014
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 155:11, s. 4356-4367
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Tidskriftsartikel (refereegranskat)abstract
- The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.
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| 14. |
- Schéle, Erik, 1980, et al.
(författare)
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Interrelation between interleukin-1 (IL-1), IL-6 and body fat regulating circuits of the hypothalamic arcuate nucleus.
- 2013
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Ingår i: Journal of neuroendocrinology. - : Wiley. - 1365-2826 .- 0953-8194. ; 25:6, s. 580-589
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-1 (IL-1) and interleukin-6 (IL-6) are immune modulating cytokines that also affect metabolic functions, as both IL-1 receptor I deficient (IL1RI -/-) and IL-6 deficient (IL-6 -/-) mice develop late-onset obesity and leptin resistance. Both IL-1 and IL-6 appear to target the central nervous system (CNS) to increase energy expenditure. The hypothalamic arcuate nucleus (ARC) is a major relay between the periphery and CNS in body fat regulation, e g by being a target of leptin. We aimed to investigate possible mechanisms for the effects exerted by endogenous IL-1 and IL-6 on body fat at the level of the ARC, as well as possible interactions between IL-1 and IL-6. Therefore, we measured the gene expression of neuropeptides of the ARC involved in energy balance in IL-1RI -/- and IL-6-/- mice. We also investigated the interactions between expression of IL-1 and IL-6 in these mice, and mapped IL-6 receptor α (IL-6Rα) in the ARC The expression of the obesity promoting peptide neuropeptide Y (NPY), found in ARC, was increased in IL-1RI -/- mice. The expression of NPY and agouti-related peptide (AgRP), known to be co-expressed with NPY in ARC neurons, was increased in cold exposed IL-6 -/- mice. IL-6Rα immunoreactivity was densely localized in the ARC, especially in the medial part, and there partly found in NPY positive cell bodies and also α-MSH positive cell bodies. The expression of hypothalamic IL-6 was decreased in IL-1RI -/- mice, while IL-1ß expression was increased in IL-6 -/- mice. The present results indicate that depletion of the activity of the fat suppressing cytokines IL-1 and IL-6 in knockout mice can increase the expression of the obesity promoting neuropeptide NPY in the ARC. Depletion of IL-1 activity suppresses IL-6 expression, and IL-6Rα -like immunoreactivity is present in neurons in the medial ARC including neurons containing NPY. Therefore, IL-6, IL-1 and NPY/AgRP could interact at the level of the hypothalamic ARC in regulation of body fat. © 2013 British Society for Neuroendocrinology.
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| 15. |
- Shirazi, Rozita H., et al.
(författare)
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Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 110:40, s. 16199-16204
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1), produced in the intestine and the brain, can stimulate insulin secretion from the pancreas and alleviate type 2 diabetes. The cytokine interleukin-6 (IL-6) may enhance insulin secretion from beta-cells by stimulating peripheral GLP-1 production. GLP-1 and its analogs also reduce food intake and body weight, clinically beneficial actions that are likely exerted at the level of the CNS, but otherwise are poorly understood. The cytokines IL-6 and interleukin 1 beta (IL-1 beta) may exert an anti-obesity effect in the CNS during health. Here we found that central injection of a clinically used GLP-1 receptor agonist, exendin-4, potently increased the expression of IL-6 in the hypothalamus (11-fold) and the hindbrain (4-fold) and of IL-1 beta in the hypothalamus, without changing the expression of other inflammation-associated genes. Furthermore, hypothalamic and hindbrain interleukin-associated intracellular signals [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and suppressor of cytokine signaling-1 (SOCS1)] were also elevated by exendin-4. Pharmacologic disruption of CNS IL-1 receptor or IL-6 biological activity attenuated anorexia and body weight loss induced by central exendin-4 administration in a rat. Simultaneous blockade of IL-1 and IL-6 activity led to a more potent attenuation of exendin-4 effects on food intake. Mice with global IL-1 receptor gene knockout or central IL-6 receptor knockdown showed attenuated decrease in food intake and body weight in response to peripheral exendin-4 treatment. GLP-1 receptor activation in the mouse neuronal Neuro2A cell line also resulted in increased IL-6 expression. These data outline a previously unidentified role of the central IL-1 and IL-6 in mediating the anorexic and body weight loss effects of GLP-1 receptor activation.
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| 16. |
- Zlatkovic, Jovana, 1992, et al.
(författare)
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Reduction of body weight by increased loading is associated with activation of norepinephrine neurones in the medial nucleus of the solitary tract.
- 2023
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Ingår i: Journal of neuroendocrinology. - 1365-2826. ; 35:12
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Tidskriftsartikel (refereegranskat)abstract
- We previously provided evidence supporting the existence of a novel leptin-independent body weight homeostat ("the gravitostat") that senses body weight and then initiates a homeostatic feed-back regulation of body weight. We, herein, hypothesize that this feed-back regulation involves a CNS mechanism. To identify populations of neurones of importance for the putative feed-back signal induced by increased loading, high-fat diet-fed rats or mice were implanted intraperitoneally or subcutaneously with capsules weighing ∼15% (Load) or ∼2.5% (Control) of body weight. At 3-5days after implantation, neuronal activation was assessed in different parts of the brain/brainstem by immunohistochemical detection of FosB. Implantation of weighted capsules, both subcutaneous and intraperitoneal, induced FosB in specific neurones in the medial nucleus of the solitary tract (mNTS), known to integrate information about the metabolic status of the body. These neurones also expressed tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DbH), a pattern typical of norepinephrine neurones. In functional studies, we specifically ablated norepinephrine neurones in mNTS, which attenuated the feed-back regulation of increased load on body weight and food intake. In conclusion, increased load appears to reduce body weight and food intake via activation of norepinephrine neurones in the mNTS.
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