RESUMO
The intestinal L cell secretes a diversity of biologically active hormones, most notably the glucagon-like peptides, GLP-1 and GLP-2. The highly successful introduction of GLP-1-based drugs into the clinic for the treatment of patients with type 2 diabetes and obesity, and of a GLP-2 analog for patients with short bowel syndrome, has led to the suggestion that stimulation of the endogenous secretion of these peptides may serve as a novel therapeutic approach in these conditions. Situated in the intestinal epithelium, the L cell demonstrates complex relationships with not only circulating, paracrine, and neural regulators, but also ingested nutrients and other factors in the lumen, most notably the microbiota. The integrated input from these numerous secretagogues results in a variety of temporal patterns in L cell secretion, ranging from minutes to 24 hours. This review combines the findings of traditional, physiological studies with those using newer molecular approaches to describe what is known and what remains to be elucidated after 5 decades of research on the intestinal L cell and its secreted peptides, GLP-1 and GLP-2.
Assuntos
Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Diabetes Mellitus Tipo 2/tratamento farmacológico , Células Enteroendócrinas/metabolismo , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon , Peptídeo 2 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon/metabolismo , Humanos , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , SecretagogosRESUMO
The intestinal L-cell incretin, glucagon-like peptide-1 (GLP-1), exhibits a circadian pattern of secretion, thereby entraining diurnal insulin release. Secretagogin (Scgn), an actin-binding regulatory protein, is essential for the temporal peak of GLP-1 secretion in vitro. To interrogate the role of Scgn in diurnal GLP-1 secretion in vivo, peak and trough GLP-1 release were evaluated in knockout mice (Scgn-/-, Gcg-CreERT2/+; Scgnfl/fl and Vil-CreERT2/+; Scgnfl/fl), and RNA sequencing (RNA-Seq) was conducted in Scgn knockdown L-cells. All 3 knockout models demonstrated loss of the diurnal rhythm of GLP-1 secretion in response to oral glucose. Gcg-CreERT2/+; Scgnfl/fl mice also lost the normal pattern in glucagon secretion, while Scgn-/- and Vil-CreERT2/+; Scgnfl/fl animals demonstrated impaired diurnal secretion of the related incretin, glucose-dependent insulinotrophic polypeptide. RNA-Seq of mGLUTag L-cells showed decreased pathways regulating vesicle transport, transport and binding, and protein-protein interaction at synapse, as well as pathways related to proteasome-mediated degradation including chaperone-mediated protein complex assembly following Scgn knockdown. Scgn is therefore essential for diurnal L-cell GLP-1 secretion in vivo, likely mediated through effects on secretory granule dynamics.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Secretagoginas , Actinas/metabolismo , Animais , Proteínas de Transporte , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose , Incretinas , Insulina/metabolismo , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Secretagoginas/genéticaRESUMO
Metabolism and circadian rhythms are intimately linked, with circadian glucagon-like peptide-1 (GLP-1) secretion by the intestinal L-cell entraining rhythmic insulin release. GLP-1 secretion has been explored in the context of obesogenic diets, but never in a rodent model of type 2 diabetes (T2D). There is also considerable disagreement regarding GLP-1 levels in human T2D. Furthermore, recent evidence has demonstrated decreased expression of the ß-cell exocytotic protein secretagogin (SCGN) in T2D. To extend these findings to the L-cell, we administered oral glucose tolerance tests at 6 time points in 4-hour intervals to the high-fat diet/streptozotocin (HFD-STZ) mouse model of T2D. This revealed a 10-fold increase in peak GLP-1 secretion with a phase shift of the peak from the normal feeding period into the fasting-phase. This was accompanied by impairments in the rhythms of glucose, glucagon, mucosal clock genes (Arntl and Cry2), and Scgn. Immunostaining revealed that L-cell GLP-1 intensity was increased in the HFD-STZ model, as was the proportion of L-cells that expressed SCGN; however, this was not found in L-cells from humans with T2D, which exhibited decreased GLP-1 staining but maintained their SCGN expression. Gcg expression in isolated L-cells was increased along with pathways relating to GLP-1 secretion and electron transport chain activity in the HFD-STZ condition. Further investigation into the mechanisms responsible for this increase in GLP-1 secretion may give insights into therapies directed toward upregulating endogenous GLP-1 secretion.
Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Animais , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , CamundongosRESUMO
The incretin hormone glucagon-like peptide-1 (GLP-1) is secreted by the intestinal L cell in response to nutrient intake. However, GLP-1 secretion also follows a circadian rhythm which is disrupted by the saturated fatty acid palmitate in vitro and high-fat diet (HFD) feeding in vivo. The flavonoid nobiletin is a clock enhancer which improves metabolic homeostasis. Therefore, the aim of this study was to elucidate whether and how nobiletin mitigates the negative effects of palmitate and HFD-feeding on rhythmic GLP-1 release. Pre-treatment of murine GLUTag L cells with palmitate dampened the GLP-1 secretory response at the normal peak of secretion, while nobiletin co-treatment restored GLP-1 secretion and upregulated the 'metabolic pathway' transcriptome. Mice fed a HFD also lost their GLP-1 secretory rhythm in association with markedly increased GLP-1 levels and upregulation of L cell transcriptional pathways related to 'sensing' and 'transducing' cellular stimuli at the normal peak of GLP-1 release. Nobiletin co-administration reduced GLP-1 levels to more physiological levels and upregulated L cell 'oxidative metabolism' transcriptional pathways. Furthermore, nobiletin improved colonic microbial 16S rRNA gene diversity and reduced the levels of Proteobacteria in HFD-fed mice. Collectively, this study establishes that nobiletin improves the normal rhythm in GLP-1 secretion following fat-induced disruption.
Assuntos
Células Enteroendócrinas , Peptídeo 1 Semelhante ao Glucagon , Animais , Células Enteroendócrinas/metabolismo , Flavonas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Camundongos , Palmitatos/farmacologia , RNA Ribossômico 16S/metabolismoRESUMO
BACKGROUND & AIMS: Leucine-rich repeat-containing G-protein-coupled receptor-5 (Lgr5)+/olfactomedin-4 (Olfm4)+ intestinal stem cells (ISCs) in the crypt base are crucial for homeostatic maintenance of the epithelium. The gut hormone, glucagon-like peptide-21-33 (GLP-2), stimulates intestinal proliferation and growth; however, the actions of GLP-2 on the Lgr5+ ISCs remain unclear. The aim of this study was to determine whether and how GLP-2 regulates Lgr5+ ISC cell-cycle dynamics and numbers. METHODS: Lgr5-Enhanced green-fluorescent protein - internal ribosome entry site - Cre recombinase - estrogen receptor T2 (eGFP-IRES-creERT2) mice were acutely administered human Glycine2 (Gly2)-GLP-2, or the GLP-2-receptor antagonist, GLP-23-33. Intestinal epithelial insulin-like growth factor-1-receptor knockout and control mice were treated chronically with human Gly2 (hGly2)-GLP-2. Cell-cycle parameters were determined by 5-Ethynyl-2'-deoxyuridine (EdU), bromodeoxyuridine, antibody #Ki67, and phospho-histone 3 labeling and cell-cycle gene expression. RESULTS: Acute hGly2-GLP-2 treatment increased the proportion of eGFP+EdU+/OLFM4+EdU+ cells by 11% to 22% (P < .05), without affecting other cell-cycle markers. hGly2-GLP-2 treatment also increased the ratio of eGFP+ cells in early to late S-phase by 97% (P < .001), and increased the proportion of eGFP+ cells entering S-phase by 218% (P < .001). hGly2-GLP-2 treatment induced jejunal expression of genes involved in cell-cycle regulation (P < .05), and increased expression of Mcm3 in the Lgr5-expressing cells by 122% (P < .05). Conversely, GLP-23-33 reduced the proportion of eGFP+EdU+ cells by 27% (P < .05), as well as the expression of jejunal cell-cycle genes (P < .05). Finally, chronic hGly2-GLP-2 treatment increased the number of OLFM4+ cells/crypt (P < .05), in an intestinal epithelial insulin-like growth factor-1-receptor-dependent manner. CONCLUSIONS: These findings expand the actions of GLP-2 to encompass acute stimulation of Lgr5+ ISC S-phase entry through the GLP-2R, and chronic induction of Lgr5+ ISC expansion through downstream intestinal insulin-like growth factor-1 signaling.
Assuntos
Peptídeo 2 Semelhante ao Glucagon , Fator de Crescimento Insulin-Like I , Animais , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Mucosa Intestinal , Intestinos , Camundongos , Receptores Acoplados a Proteínas G/metabolismo , Células-Tronco/metabolismoRESUMO
It is now well established that, beyond its role in nutrient processing and absorption, the intestine and its accompanying gut microbiome constitute a major site of immunological and endocrine regulation that mediates whole-body metabolism. Despite the growing field of host-microbe research, few studies explore what mechanisms govern this relationship in the context of pregnancy. During pregnancy, significant maternal metabolic adaptations are made to accommodate the additional energy demands of the developing fetus and to prevent adverse pregnancy outcomes. Recent data suggest that the maternal gut microbiota may play a role in these adaptations, but changes to maternal gut physiology and the underlying intestinal mechanisms remain unclear. In this review, we discuss selective aspects of intestinal physiology including the role of the incretin hormone, glucagon-like peptide 1 (GLP-1), and the role of the maternal gut microbiome in the maternal metabolic adaptations to pregnancy. Specifically, we discuss how bacterial components and metabolites could mediate the effects of the microbiota on host physiology, including nutrient absorption and GLP-1 secretion and action, and whether these mechanisms may change maternal insulin sensitivity and secretion during pregnancy. Finally, we discuss how these pathways could be altered in disease states during pregnancy including maternal obesity and diabetes.
Assuntos
Microbiota , Feminino , Glucose/metabolismo , Homeostase , Humanos , Incretinas/metabolismo , Intestinos , GravidezRESUMO
BACKGROUND: Short bowel syndrome (SBS) is characterized by malabsorption requiring parenteral nutrition. The intestinotrophic glucagon-like peptide (GLP)-2 receptor agonist, h[Gly2]GLP2, is used to treat patients with SBS. Evidence suggests that GLP-1 receptor agonists such as exendin-4 (Ex4) may be beneficial in SBS given their ability to increase intestinal growth and delay gastric emptying (GE). METHODS: Intestinal growth, body weight (BW), food intake (FI), GE, gastrointestinal (GI) transit, intestinal permeability, and glucose tolerance were investigated in male and female C57/BL6 mice following vehicle, h[Gly2]GLP2, or Ex4 treatment, alone or in combination at "low," "medium," and "high" doses (0.1, 0.5, 1.0 and 0.01, 0.05, 0.1 µg/g, respectively). RESULTS: Only the h[Gly2]GLP2 low/Ex4 high-dose combination additively increased small intestinal (SI) weight compared with vehicle and both monoagonists (P < 0.01-0.001), via increased villus height (P < 0.01) and SI length (P < 0.05). This combination had no effects on BW; FI; and fat, liver, spleen, heart, and kidney weights but reduced GI transit (P < 0.001) versus low-dose h[Gly2]GLP2 monotreatment and abrogated the inhibitory effects of high-dose Ex4 on GE (P < 0.01) and of low-dose h[Gly2]GLP2 on intestinal permeability (P < 0.05). Ex4-induced improvements in glucose homeostasis were maintained upon combination with h[Gly2]GLP2 (P < 0.001). CONCLUSIONS: These findings suggest that combining specific doses of GLP-2- and GLP-1 receptor agonists additively improves SI growth and GI transit without detrimental effects on BW, FI, GE, and glucose homeostasis, and may be useful for the treatment of patients with SBS.
Assuntos
Peptídeo 2 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1 , Síndrome do Intestino Curto , Animais , Feminino , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose/uso terapêutico , Intestino Delgado , Masculino , Camundongos , Síndrome do Intestino Curto/tratamento farmacológicoRESUMO
Cross-talk between peripheral tissues is essential to ensure the coordination of nutrient intake with disposition during the feeding period, thereby preventing metabolic disease. This mini-review considers the interactions between the key peripheral tissues that constitute the metabolic clock, each of which is considered in a separate mini-review in this collation of articles published in Endocrinology in 2020 and 2021, by Martchenko et al (Circadian rhythms and the gastrointestinal tract: relationship to metabolism and gut hormones); Alvarez et al (The microbiome as a circadian coordinator of metabolism); Seshadri and Doucette (Circadian regulation of the pancreatic beta cell); McCommis et al (The importance of keeping time in the liver); Oosterman et al (The circadian clock, shift work, and tissue-specific insulin resistance); and Heyde et al (Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism). The use of positive- and negative-feedback signals, both hormonal and metabolic, between these tissues ensures that peripheral metabolic pathways are synchronized with the timing of food intake, thus optimizing nutrient disposition and preventing metabolic disease. Collectively, these articles highlight the critical role played by the circadian clock in maintaining metabolic homeostasis.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano , Comportamento Alimentar , Homeostase , Fígado/fisiologia , Adipócitos/citologia , Animais , Endocrinologia/métodos , Ingestão de Energia , Metabolismo Energético/fisiologia , Retroalimentação Fisiológica , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Intestinos/fisiologia , Ilhotas Pancreáticas/citologia , Mamíferos/fisiologia , Doenças Metabólicas/metabolismo , Microbiota , Modelos Biológicos , Células Musculares/citologia , Músculo Esquelético/fisiologiaRESUMO
Intestinal functions demonstrate circadian rhythms thought to be entrained, in part, by an organisms' intrinsic feeding and fasting periods as well as by the intestinal microbiome. Circadian disruption as a result of ill-timed nutrient exposure and obesogenic feeding poses an increased risk to disease. As such, the aim of this study was to assess the relationships between dietary timing, composition, and the microbiome with regard to rhythmic small intestinal structure and mucosal immunity. Rodent chow (RC)-mice exhibited time-dependent increases in small intestinal weight, villus height, and crypt depth as well as an increased proportion of CD8αα+ cells and concomitant decrease in CD8αß+ cells at the onset of the feeding period (p < 0.05-0.001). Western diet (WD)-animals displayed disrupted time-dependent patterns in intestinal structure and lymphocyte populations (p < 0.05-0.01). Antibiotic-induced microbial depletion abrogated the time- and diet-dependent patterns in both RC- and WD-mice (p < 0.05-0.001). However, although germ-free-mice displayed altered rhythms, fecal microbial transfer from RC-mice was generally unsuccessful in restoring structural and immune changes in these animals. This study shows that adaptive changes in the small intestine at the onset of the feeding and fasting periods are disrupted by WD-feeding, and that these changes are dependent, in part, on the intestinal microbiome.
Assuntos
Ritmo Circadiano/fisiologia , Microbioma Gastrointestinal/fisiologia , Intestino Delgado/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Disbiose/fisiopatologia , Jejum , Comportamento Alimentar/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologiaRESUMO
OBJECTIVE: Recent studies using whole-body clock-disrupted animals identified a disruption in the circadian rhythm of the intestinal L-cell incretin hormone, glucagon-like peptide-1 (GLP-1). Although GLP-1 plays an essential role in metabolism through enhancement of both glucose-stimulated insulin secretion and satiety, recent evidence has also demonstrated its importance in regulating intestinal and microbial homeostasis. Therefore, using in vivo and in vitro models, this study assessed the role of the core circadian clock gene Arntl in the regulation of time-dependent GLP-1 secretion and its impact on the intestinal environment. METHODS: Oral glucose tolerance tests were conducted at zeitgeber time 2 and 14 in control and inducible Gcg-Arntl knockout (KO) mice. Colonic intraepithelial lymphocytes were isolated, mucosal gene expression analysis was conducted, and 16S rRNA gene sequencing of colonic feces as well as analysis of microbial metabolites were performed. Time-dependent GLP-1 secretion and transcriptomic analysis were conducted in murine (m) GLUTag L-cells following siRNA-mediated knockdown of Arntl. RESULTS: Gcg-Arntl KO mice displayed disrupted rhythmic release of GLP-1 associated with reduced secretion at the established peak time point. Analysis of the intestinal environment in KO mice revealed a decreased proportion of CD4+ intraepithelial lymphocytes in association with increased proinflammatory cytokine gene expression and increased colonic weight. Moreover, increased Actinobacteria within the colonic microbiome was found following L-cell Arntl disruption, as well as reductions in the microbial products, short chain fatty acids, and bile acids. Finally, siRNA-mediated knockdown of Arntl in mGLUTag L-cells resulted in both impaired time-dependent GLP-1 secretion and the disruption of pathways related to key cellular processes. CONCLUSIONS: These data establish, for the first time, the essential role of Arntl in the intestinal L-cell in regulating time-dependent GLP-1 secretion. Furthermore, this study revealed the integral role of L-cell Arntl in mediating the intestinal environment, which ultimately may provide novel insight into the development of therapeutics for the treatment of intestinal and metabolic disorders.
Assuntos
Fatores de Transcrição ARNTL/metabolismo , Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Homeostase , Intestinos/metabolismo , Fatores de Transcrição ARNTL/deficiência , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos TransgênicosRESUMO
Circadian rhythms are 24-h internal biological rhythms within organisms that govern virtually all aspects of physiology. Interestingly, metabolic tissues have been found to express cell-autonomous clocks that govern their rhythmic activity throughout the day. Disruption of normal circadian rhythmicity, as induced by environmental factors such as shift work, significantly increases the risk for the development of metabolic diseases, including type 2 diabetes and obesity. More recently, obesogenic feeding and its fatty acid components have also been shown to be potent disruptors of normal circadian biology. Two key hormones that are released in response to nutrient intake are the anti-diabetic incretin hormone glucagon-like peptide-1, from intestinal L cells, and insulin secreted by pancreatic ß cells, both of which are required for the maintenance of metabolic homeostasis. This review will focus on the circadian function of the L and ß cells and how both obesogenic feeding and the saturated fatty acid, palmitate, affect their circadian clock and function. Following introduction of the core biological clock and the hierarchical organization of the mammalian circadian system, the circadian regulation of normal L and ß cell function and the importance of GLP-1 and insulin in establishing metabolic control are discussed. The central focus of the review then considers the circadian-disrupting effects of obesogenic feeding and palmitate exposure in L and ß cells, while providing insight into the potential causative role in the development of metabolic disease.
Assuntos
Relógios Circadianos/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Ácidos Graxos não Esterificados/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Animais , Homeostase/fisiologia , HumanosRESUMO
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin's discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin's role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry's role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Assuntos
Indústria Farmacêutica/história , Insulina , Animais , História do Século XX , História do Século XXI , Humanos , Insulina/química , Insulina/história , Insulina/metabolismo , Insulina/uso terapêutico , Pâncreas/química , Pâncreas/metabolismoRESUMO
BACKGROUND: Short-bowel syndrome is the leading cause of pediatric intestinal failure, resulting in dependency on long-term parenteral nutrition (PN). To promote enteral autonomy in neonates, a key outcome may be intestinal growth in length. The purpose of this study was to determine if intestinal lengthening persists following discontinuation of treatment with 1 of 2 GLP-2 analogues with different pharmacokinetic profiles. METHODS: Neonatal short-bowel piglets were assigned to saline control (S), 7-day treatment with teduglutide (T) (0.05 mg/kg twice daily), or 7-day treatment with apraglutide (A) (5 mg/kg twice weekly). Comparisons were made between day 7 and day 14 endpoints using analysis of variance. Data included small-intestine length, weight, histology, and quantitative polymerase chain reaction analysis of mucosal transcripts for peptide growth factors and their receptors, nutrient transporters, and tight-junction proteins. RESULTS: Compared with control, 7 days of GLP-2 analogue treatment induced mucosal adaptation based on villus hyperplasia (P = .003), which was not durable 7 days after treatment cessation (day 14; P = .081). Treatment increased intestinal growth in length by day 7 (P = .005), which was maintained (by T) or further increased (by A) at day 14 (P < .001). No significant differences in mucosal transcripts were detected. CONCLUSION: Unlike mucosal adaptation, intestinal growth appears to be a lasting outcome of treatment with long-acting GLP-2 analogues in a neonatal piglet short-bowel model. This has significant clinical implications for neonates, given their potential for intestinal growth. Intestinal lengthening varies between analogues with different half-lives; however, molecular mechanisms require further elucidation.
Assuntos
Peptídeo 2 Semelhante ao Glucagon , Síndrome do Intestino Curto , Adaptação Fisiológica , Animais , Modelos Animais de Doenças , Humanos , Peptídeos , Síndrome do Intestino Curto/tratamento farmacológico , SuínosRESUMO
Circadian rhythms are 24-hour biological rhythms within organisms that have developed over evolutionary time due to predefined environmental changes, mainly the light-dark cycle. Interestingly, metabolic tissues, which are largely responsible for establishing diurnal metabolic homeostasis, have been found to express cell-autonomous clocks that are entrained by food intake. Disruption of the circadian system, as seen in individuals who conduct shift work, confers significant risk for the development of metabolic diseases such as type 2 diabetes and obesity. The gastrointestinal (GI) tract is the first point of contact for ingested nutrients and is thus an essential organ system for metabolic control. This review will focus on the circadian function of the GI tract with a particular emphasis on its role in metabolism through regulation of gut hormone release. First, the circadian molecular clock as well as the organization of the mammalian circadian system is introduced. Next, a brief overview of the structure of the gut as well as the circadian regulation of key functions important in establishing metabolic homeostasis is discussed. Particularly, the focus of the review is centered around secretion of gut hormones; however, other functions of the gut such as barrier integrity and intestinal immunity, as well as digestion and absorption, all of which have relevance to metabolic control will be considered. Finally, we provide insight into the effects of circadian disruption on GI function and discuss chronotherapeutic intervention strategies for mitigating associated metabolic dysfunction.
Assuntos
Ritmo Circadiano/fisiologia , Hormônios Gastrointestinais/metabolismo , Trato Gastrointestinal/metabolismo , Animais , Relógios Circadianos/fisiologia , Homeostase/fisiologia , HumanosRESUMO
The incretin glucagon-like peptide 1 (GLP-1) is secreted by the intestinal L cell upon nutrient ingestion. GLP-1 also exhibits a circadian rhythm, with highest release at the onset of the feeding period. Similarly, microbial composition and function exhibit circadian rhythmicity with fasting-feeding. The circadian pattern of GLP-1 release was found to be dependent on the oral route of glucose administration and was necessary for the rhythmic release of insulin and diurnal glycemic control in normal male and female mice. In mice fed a Western (high-fat/high-sucrose) diet for 16 weeks, GLP-1 secretion was markedly increased but arrhythmic over the 24-h day, whereas levels of the other incretin, glucose-dependent insulinotropic polypeptide, were not as profoundly affected. Furthermore, the changes in GLP-1 secretion were shown to be essential for the maintenance of normoglycemia in this obesogenic environment. Analysis of the primary L-cell transcriptome, as well as of the intestinal microbiome, also demonstrated time-of-day- and diet-dependent changes paralleling GLP-1 secretion. Finally, studies in antibiotic-induced microbial depleted and in germ-free mice with and without fecal microbial transfer, provided evidence for a role of the microbiome in diurnal GLP-1 release. In combination, these findings establish a key role for microbiome-dependent circadian GLP-1 secretion in the maintenance of 24-h metabolic homeostasis.
Assuntos
Ritmo Circadiano , Microbioma Gastrointestinal , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Homeostase , Animais , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/genética , Glucose/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , SacaroseRESUMO
OBJECTIVES: Short bowel syndrome (SBS) remains the leading cause of neonatal intestinal failure. Milk fat globule epidermal growth factor-8 (MFG-E8), present in human milk, has homology with epidermal growth factor (EGF), known to enhance adaptation in SBS. In this pilot study, the role of oral MFG-E8 treatment in SBS was explored in neonatal piglets. METHODS: Neonatal piglets underwent 75% intestinal resection, either distal (jejunal-colonic [JC] anastomosis) or mid-intestinal (jejunal-ileal [JI] anastomosis). Piglets were randomized to intragastric treatment with MFG-E8 â(5âmg/kg per day) or saline and were maintained on parenteral nutrition and enteral nutrition for 7 days. Adaptation was assessed by intestinal length and weight, histopathology, fecal fat analysis and RT-qPCR analysis of mucosal transcripts, including growth factors. RESULTS: JI piglets demonstrated intestinal lengthening (Pâ<â0.001), 2-fold greater in ileum than jejunum (Pâ=â0.02), where lengthening was increased by MFG-E8 treatment (Pâ=â0.02). JC piglets did not exhibit jejunal lengthening, regardless of treatment. Fat absorption was greater for JI piglets (Pâ=â0.02), unaffected by treatment. In JI piglets, expression of Egf was increased in the ileum (Pâ<â0.01) and MFG-E8 treatment increased Egfr (receptor) expression (Pâ=â0.02). CONCLUSIONS: MF-EG8 demonstrated site-specific trophic effects, only with JI anatomy. This may limit the utility of this treatment for SBS, except for rare patients with retained ileum. The mechanisms of these site-specific effects, however, and the role of MFG-E8 in neonatal gut growth and in diseases, such as necrotizing enterocolitis that commonly target ileum, warrant further exploration.
Assuntos
Fator VIII , Proteínas do Leite , Animais , Animais Recém-Nascidos , Família de Proteínas EGF , Glicolipídeos , Glicoproteínas , Humanos , Recém-Nascido , Gotículas Lipídicas , Projetos Piloto , SuínosAssuntos
Peptídeo 2 Semelhante ao Glucagon , Síndrome do Intestino Curto , Animais , Humanos , Camundongos , Peptídeos , Sódio , Junções ÍntimasRESUMO
BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and ß-klotho (>3-fold, P < 0.05). CONCLUSIONS: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21.