Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule

Yabut, Julian M.; Crane, Justin D.; Green, Alex E.; Keating, Damien J.; Khan, Waliul I.; Steinberg, Gregory R.

doi:10.1210/er.2018-00283

Cited by 227 publications

(198 citation statements)

References 188 publications

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“…Central and peripheral serotonin systems are functionally separated as serotonin cannot pass the blood-brain barrier. Serotonin functions either as a central neurotransmitter or a circulatory hormone, and play distinct physiological roles depending on binding with specific serotonin receptors (HTRs) [27,28]. For instance, central serotonin increases adipose tissue thermogenesis, while peripheral serotonin inhibits it [27].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Modifications in the Porcine Intramuscular Adipocytes during Differentiation and Exogenous Stimulation with TNF-α and Serotonin

Tada

Islam

Kober

et al. 2020

IJMS

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Adipocytes are dynamic cells that have critical functions to maintain body energy homeostasis. Adipocyte physiology is affected by the adipogenic differentiation, cell program, as well as by the exogenous stimulation of biochemical factors, such as serotonin and TNF-α. In this work, we investigated the global transcriptome modifications when porcine intramuscular preadipocyte (PIP) was differentiated into porcine mature adipocyte (pMA). Moreover, we studied transcriptome changes in pMA after stimulation with serotonin or TNF-α by using a microarray approach. Transcriptome analysis revealed that the expression of 270, 261, and 249 genes were modified after differentiation, or after serotonin and TNF-α stimulation, respectively. Expression changes in APP, HNF4A, ESR1, EGR1, SRC, HNF1A, FN1, ALB, STAT3, CBL, CEBPB, AR, FOS, CFTR, PAN2, PTPN6, VDR, PPARG, STAT5A and NCOA3 genes which are enriched in the ‘PPAR signaling’ and ‘insulin resistance’ pathways were found in adipocytes during the differentiation process. Dose-dependent serotonin stimulation resulted in a decreased fat accumulation in pMAs. Serotonin-induced differentially expressed genes in pMAs were found to be involved in the significant enrichment of ′GPCR ligand-binding′, ‘cell chemotaxis’, ‘blood coagulation and complement’, ‘metabolism of lipid and lipoproteins’, ‘regulation of lipid metabolism by PPARA’, and ‘lipid digestion, mobilization and transport’ pathways. TNF-α stimulation also resulted in transcriptome modifications linked with proinflammatory responses in the pMA of intramuscular origin. Our results provide a landscape of transcriptome modifications and their linked-biological pathways in response to adipogenesis, and exogenous stimulation of serotonin- and TNF-α to the pMA of intramuscular origin.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Modifications in the Porcine Intramuscular Adipocytes during Differentiation and Exogenous Stimulation with TNF-α and Serotonin

Tada

Islam

Kober

et al. 2020

IJMS

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“…Our data have several implications; they highlight how similar EEC specification is between mouse and human and that ISX-9 alone or in combination with iNotch and iMEK can be used to enrich human organoids with EC cells allowing functional exploration of these rare and difficult to study cells. EC cells modulate GI motility, bone formation, hepatic gluconeogenesis, thermogenesis, insulin resistance, and regulation of fat mass (Yabut et al, 2019). Understanding how these cells function in the human has important implications.…”

Section: Discussionmentioning

confidence: 99%

ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human

Tsakmaki

Pedro

Pavlidis

et al. 2019

Preprint

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18Enteroendocrine cells (EECs) survey the gut luminal environment and co-ordinate hormonal, 19 immune and neuronal responses to it. They exhibit well characterised physiological roles ranging from 20 the control of local gut function to whole body metabolism, but little is known regarding the regulatory 21 networks controlling their differentiation, especially in human gut. 22The small molecule Isoxazole-9 (ISX-9) stimulates neuronal and pancreatic beta-cell 23 differentiation, both closely related to EEC differentiation. We used ISX-9 as a tool to explore EEC 24 specification in mouse and human intestinal organoids. ISX-9 increased the number of neurogenin3 25 (Ngn3) positive endocrine progenitor cells and upregulated NeuroD1 and Pax4, transcription factors 26 which play roles in mouse EEC specification. Single cell analysis revealed induction of Pax4 expression 27 in a developmentally late Ngn3 + population of cells and potentiation of genes associated with 28 progenitors biased towards serotonin-producing enterochromaffin (EC) cells. This coincided with 29 enrichment of organoids with functional EC cells which was partly dependent on stimulation of 30 calcium signalling in a population of cells residing outside the crypt base. Inducible Pax4 31 overexpression, in ileal organoids, uncovered its importance as a component of early human 32 endocrine specification and highlighted the potential existence of two major endocrine lineages, the 1 early appearing enterochromaffin lineage and the later developing peptidergic lineage which contains 2 classical gut hormone cell types. 3 Our data provide proof-of-concept for the controlled manipulation of specific endocrine 4 lineages with small molecules, whilst also shedding new light on human EEC differentiation and its 5 similarity to mouse. Given their diverse roles, understanding endocrine lineage plasticity and its 6 control could have multiple therapeutic implications. 7 8 10 every 4-5 days and is composed of 5 terminally differentiated cell types; the absorptive enterocytes 11 and the secretory Paneth, goblet, tuft and enteroendocrine cells (Gehart and Clevers, 2019). These 12 cells are constitutively generated by cycling Lgr5 + crypt stem cells and together they orchestrate the 13 epithelium's major functions, nutrient absorption and defence. Despite representing only 1% of the 14 epithelium, the enteroendocrine cells (EECs) constitute the largest hormone producing tissue and 15 have been described as the gut's sentinels. They sample the luminal, circulating and local tissue 16 environments and co-ordinate an appropriate response from the epithelium, immune and nervous 17 systems (Gribble and Reimann, 2016). For example, they play a key role in controlling the response to 18 a meal, fine tuning physiology to ensure optimal fuel absorption, use and storage (Sam et al., 2012). 19 Gut hormones exhibit actions ranging from the local control of gut motility, absorption and secretion, 20 to the regulation of whole-body metabolism (Melvin et al., 2016). Whilst there i...

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“…Serotonin, a prominent neurotransmitter in CNS, is also a major regulator of appetite and promotion of energy expenditure in addition to its association in behaviour and anxiety [97,98]. In addition, peripheral serotonin prevents obesity and insulin resistance [95]. The changes in circadian rhythm and meal induced release of circulating serotonin have been implicated with increased release of serotonin into circulation from GIT in condition such as obesity and type 2 diabetes [95,99].…”

Section: Obesity and Satietymentioning

confidence: 99%

“…In addition, peripheral serotonin prevents obesity and insulin resistance [95]. The changes in circadian rhythm and meal induced release of circulating serotonin have been implicated with increased release of serotonin into circulation from GIT in condition such as obesity and type 2 diabetes [95,99]. Conclusive evidence in support of appetite regulation emerged from the studies showing the inhibition of AgRP/NPY and stimulation of POMC neurons by hypothalamic serotonin in a similar manner as seen with the use of leptin [98,100,101].…”

Section: Obesity and Satietymentioning

confidence: 99%

“…Recently, the presence of inhibitory GABAergic and excitatory glutamatergic neurons in LHA with opposing effects on food-seeking and satiety added new neuronal circuits in the regulation of food intake [66,94]. Furthermore, GABA released upon activation of AgRP/NPY neurons inhibits POMC neurons in hypothalamus and resulted in suppressed food intake [95]. Recent studies have included a new brain region that might play a crucial role in the regulation of food intake and energy balance.…”

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confidence: 99%

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Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

Kumar

Singh

2020

IJMS

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Obesity is one of the major social and health problems globally and often associated with various other pathological conditions. In addition to unregulated eating behaviour, circulating peptide-mediated hormonal secretion and signaling pathways play a critical role in food intake induced obesity. Amongst the many peptides involved in the regulation of food-seeking behaviour, somatostatin (SST) is the one which plays a determinant role in the complex process of appetite. SST is involved in the regulation of release and secretion of other peptides, neuronal integrity, and hormonal regulation. Based on past and recent studies, SST might serve as a bridge between central and peripheral tissues with a significant impact on obesity-associated with food intake behaviour and energy expenditure. Here, we present a comprehensive review describing the role of SST in the modulation of multiple central and peripheral signaling molecules. In addition, we highlight recent progress and contribution of SST and its receptors in food-seeking behaviour, obesity (orexigenic), and satiety (anorexigenic) associated pathways and mechanism.Contrary to obesity, satiety is a sense of fullness due to ephemeral lack of interest in further ingestion of food, which eventually leads to the suppression of appetite. Fullness is supposed to have a vital role in weight management because it will impact the frequency and amount of food and drink consumed later [53]. The feeling of satiety is a well-organized and biologically oriented process [54,55]. Satiety is a well-articulated process which reduces gastric distension and cholecystokinin (CCK) release in gut post ingestion of nutrients and importantly has been associated with signals from periphery via vagal afferent fibers that terminate in nucleus of the tractus solitaries (NTS) in the brain stem [56]. Besides, leptin, a hormone secreted by adipocytes, is also associated with satiety signals and studies further indicate that satiety response to CCK that was blocked in leptin receptor-deficient rat was regained following restoration of the leptin receptor in arcuate nucleus (ARC) [57][58][59]. Studies also support the role of NTS vagus afferent in response to leptin [60,61]. Feeling satiated will, in the long run, smother the inclination for cravings and lead to lesser consumption of food in the next meal. Satiety is not a response; it involves a complex mechanism for its operation, which includes the crucial role of the hypothalamus and peripheral hormones and determines energy expenditure [62]. Measurement of satiation can be done either directly by assessing food intake or indirectly by subjectively rating the urge for appetite [63]. Schwartz et al. demonstrated that hypothalamus is the central brain region responsible for adiposity signal; however, it is not an active participant in satiety [64]. It is interesting to note that most satiety associated information is relayed to NTS afferent fibers from the vagus nerve and afferent from GIT through the spinal cord. Mechanical or chemical stimula...

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Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule

Cited by 227 publications

References 188 publications

Transcriptome Modifications in the Porcine Intramuscular Adipocytes during Differentiation and Exogenous Stimulation with TNF-α and Serotonin

Transcriptome Modifications in the Porcine Intramuscular Adipocytes during Differentiation and Exogenous Stimulation with TNF-α and Serotonin

ISX-9 manipulates endocrine progenitor fate revealing conserved intestinal lineages in mouse and human

Role of Somatostatin in the Regulation of Central and Peripheral Factors of Satiety and Obesity

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