Constitutively Elevated Blood Serotonin Is Associated with Bone Loss and Type 2 Diabetes in Rats

Serotonin was first discovered in the gut, and its conventional actions as an intercellular signaling molecule in the intrinsic and extrinsic enteric reflexes are well recognized, as are a number of serotonin signaling pharmacotherapeutic targets for treatment of nausea, diarrhea, or constipation. Recent discoveries have greatly broadened our understanding of non-conventional actions of peripheral serotonin within the GI tract and in a number of other tissues. For example, it is now clear that bacteria within the lumen of the bowel influence serotonin synthesis and release by enterochromaffin cells. Also, serotonin can act both as a pro- and anti-inflammatory signaling molecule in the intestinal mucosa via activation of 5-HT7 or 5-HT4 receptors, respectively. For decades, serotonin receptors have been known to exist in a variety of tissues outside of the gut, but recent studies have provided strong evidence for physiological roles of serotonin in several important processes, including hematopoiesis, metabolic homeostasis, and bone metabolism. Furthermore, there is emerging evidence for serotonin synthesis in peripheral tissues outside of the gut. In this review, we expand the discussion beyond GI functions to highlight the roles of peripheral serotonin in colitis, hematopoiesis, energy and bone metabolism, and how serotonin is influenced by the gut microbiome.

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“…When circulating concentrations of 5-HT were decreased or increased, increases and decreases in bone volume were observed 58,59 .…”

Section: Serotonin and Bone Remodelingmentioning

confidence: 99%

Non-conventional features of peripheral serotonin signalling — the gut and beyond

Spohn

Mawe

2017

Nat Rev Gastroenterol Hepatol

215

198

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“…Generally, animals from the high-5HT subline are considered constitutionally hyperserotonergic in comparison to animals the from the low-5HT subline. One of the consequences of described genetic selection was an overweight phenotype of high-5HT animals, associated with bone loss, adiposity, and peripheral insulin resistance (Erjavec et al, 2016). In the present study, we investigated phenotypic/functional differences between animals from 5HT sublines and searched how endogenous, lifelong alteration in 5HT signaling shapes hypothalamic expression status of key body weight-regulating molecules.…”

Section: Introductionmentioning

confidence: 99%

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

et al. 2020

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Central and peripheral pools of biogenic monoamine serotonin (5-hydroxytryptamine [5HT]) exert opposite effects on the body weight regulation: increase in brain 5HT activity is expected to decrease body weight, whereas increase in peripheral 5HT activity will increase body weight and adiposity. In a genetic model of rats with constitutionally highor low-5HT homeostasis (hyperserotonergic/hyposerotonergic rats), we have studied how individual differences in endogenous 5HT tone modulate net energy balance of the organism. The high-5HT and low-5HT sublines of the model were developed by selective breeding toward extreme platelet activities of 5HT transporter, a key molecule determining 5HT bioavailability/activity. In animals from high-5HT and low-5HT sublines, we assessed physiological characteristics associated with body weight homeostasis and expression profile of a large scale of body weight-regulating genes in hypothalamus, a major brain region controlling energy balance. Results showed that under standard chow diet animals from the high-5HT subline, as compared to low-5HT animals, have lifelong increased body weight (by 12%), higher absolute daily food intake (by 9%), and different pattern of fat distribution (larger amount of white adipose tissue and lower amount of brown adipose tissue). A large number of body weight-regulating hypothalamic genes were analyzed for their mRNA expression: 24 genes by reverse transcription-quantitative polymerase chain reaction (n = 9-10 rats/subline) including neuropeptides and their receptors, growth factors, transcriptional factors, and receptors for peripheral signals, and a total of 84 genes of various classes by polymerase chain reaction array (pools of six rats/subline). Only few genes showed significant differences in mRNA expression levels between 5HT sublines (e.g. neuropeptide Y receptor, fibroblast growth factor 10), but high-5HT animals displayed a clear trend to upregulation of mRNAs for a number of orexigenic signaling peptides, their receptors, and other molecules with orexigenic activity. Receptors for peripheral signals (leptin, insulin) and molecules in their downstream signaling were not altered, indicating no changes in central insulin/leptin resistance. At the protein level, there were no differences in the Frontiers in Neuroscience | www.frontiersin.org 1 March 2020 | Volume 14 | Article 219 Kesić et al. Serotonin and Body Weight Regulationcontent of hypothalamic leptin receptor between 5HT sublines, but significant sex and age effects were observed. Results show that higher constitutive/individual 5HT tone favors higher body weight and adiposity probably due to concurrent upregulation of several hypothalamic orexigenic pathways.

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“…In subcutaneous rat assay, bone formation was scanned in vivo after 14 days using SkyScan 1076 micro-CT device (SkyScan/ Bruker) at 18 mm resolution, as previously described. (48,49) Scanning parameters were 50 kV/200 mA, 0.5 mm aluminum filter, 0.8°rotational shift throughout the 198°and frame averaging value set at 2. Obtained images were reconstructed using NRecon (Bruker) and the quantification was performed using CTAn (Bruker) software.…”

Section: Micro-ct Quantificationmentioning

confidence: 99%

Recombinant Human Bone Morphogenetic Protein 6 Delivered Within Autologous Blood Coagulum Restores Critical Size Segmental Defects of Ulna in Rabbits

et al. 2018

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BMP2 and BMP7, which use bovine Achilles tendon–derived absorbable collagen sponge and bovine bone collagen as scaffold, respectively, have been approved as bone graft substitutes for orthopedic and dental indications. Here, we describe an osteoinductive autologous bone graft substitute (ABGS) that contains recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) scaffold. The ABGS is created as an injectable or implantable coagulum gel with rhBMP6 binding tightly to plasma proteins within fibrin meshwork, as examined by dot‐blot assays, and is released slowly as an intact protein over 6 to 8 days, as assessed by ELISA. The biological activity of ABGS was examined in vivo in rats (Rattus norvegicus) and rabbits (Oryctolagus cuniculus). In a rat subcutaneous implant assay, ABGS induced endochondral bone formation, as observed by histology and micro‐CT analyses. In the rabbit ulna segmental defect model, a reproducible and robust bone formation with complete bridging and restoration of the defect was observed, which is dose dependent, as determined by radiographs, micro‐CT, and histological analyses. In ABGS, ABC scaffold provides a permissive environment for bone induction and contributes to the use of lower doses of rhBMP6 compared with BMP7 in bovine bone collagen as scaffold. The newly formed bone undergoes remodeling and establishes cortices uniformly that is restricted to implant site by bridging with host bone. In summary, ABC carrier containing rhBMP6 may serve as an osteoinductive autologous bone graft substitute for several orthopedic applications that include delayed and nonunion fractures, anterior and posterior lumbar interbody fusion, trauma, and nonunions associated with neurofibromatosis type I. © 2018 American Society for Bone and Mineral Research.

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Constitutively Elevated Blood Serotonin Is Associated with Bone Loss and Type 2 Diabetes in Rats

Cited by 32 publications

References 49 publications

Non-conventional features of peripheral serotonin signalling — the gut and beyond

Non-conventional features of peripheral serotonin signalling — the gut and beyond

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis

Recombinant Human Bone Morphogenetic Protein 6 Delivered Within Autologous Blood Coagulum Restores Critical Size Segmental Defects of Ulna in Rabbits

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