Involvement of a serotonin/GLP-1 circuit in adolescent isolation-induced diabetes.
Involvement of a serotonin/GLP-1 circuit in adolescent isolation-induced diabetes.
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血清素/GLP-1 回路参与青少年隔离诱发的糖尿病。
DOI：
10.1101/2023.06.12.544498
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Marcinkiewcz,CatherineA
中科院分区：
文献类型：
--
作者：
Kolling,LouisJ;Khan,Kanza;Balasubramanian,Nagalakshmi;Guo,Deng-Fu;Rahmouni,Kamal;Marcinkiewcz,CatherineA
2020年，为了遏制SARS-CoV-2在全球的传播，实施了居家服务命令。与世隔绝对儿童和青少年尤其有害--在大流行期间，2-19岁人群的肥胖率增加了∼37%。肥胖通常与2型糖尿病并存，而2型糖尿病并未在这一人类大流行队列中进行评估。在这里，我们调查了整个青春期被隔离的雄性小鼠是否以与人类肥胖诱导的糖尿病一致的方式发展为2型糖尿病，并探索了这种相互作用可能背后的神经变化。我们发现，在整个青春期隔离C57BL/6J小鼠足以诱发2型糖尿病。我们观察到，与集体饲养的对照组小鼠相比，空腹高血糖、胰岛素耐量试验反应的葡萄糖清除减少、骨骼肌胰岛素信号减少、胰岛胰岛素染色减少、伤害性增加和血浆皮质醇水平降低。使用扑草净代谢表型小室，我们观察到睡眠和饮食行为的失调，以及青春期隔离小鼠呼吸交换率随时间的变化。我们分析了几个大脑区域神经基因转录的变化，发现产生5-羟色胺和产生GLP-1的神经元之间的神经回路受到这种分离范例的影响。总体而言，空间转录数据显示5-羟色胺神经元活性降低(通过减少GLP-1介导的兴奋)和GLP-1神经元活性增加(通过减少5-羟色胺介导的抑制)。该回路可能是进一步研究社会隔离与2型糖尿病之间关系的交叉靶点，也可能是探索5-羟色胺和GLP-1受体激动剂作用的药理相关回路。文章摘要C57BL/6J小鼠在整个青春期期间隔离足以诱发2型糖尿病，表现为空腹高血糖。青少年隔离小鼠胰岛素反应性缺陷，外周胰岛素信号受损，胰腺胰岛素产生减少。整个大脑的转录变化包括内源性大麻、5-羟色胺和GLP-1神经递质和相关受体。神经5-羟色胺/GLP-1回路可能是进一步研究社会隔离与2型糖尿病之间关系的交叉靶点。青春期隔离小鼠产生5-羟色胺的神经元产生较少的GLP-1受体的转录本，GLP-1神经元产生较少的5-HT1-5-羟色胺受体的转录本。
In 2020, stay-at-home orders were implemented to stem the spread of SARS-CoV-2 worldwide. Social isolation can be particularly harmful to children and adolescents—during the pandemic, the prevalence of obesity increased by ∼37% in persons aged 2-19. Obesity is often comorbid with type 2 diabetes, which was not assessed in this human pandemic cohort. Here, we investigated whether male mice isolated throughout adolescence develop type 2 diabetes in a manner consistent with human obesity-induced diabetes, and explored neural changes that may underlie such an interaction. We find that isolating C57BL/6J mice throughout adolescence is sufficient to induce type 2 diabetes. We observed fasted hyperglycemia, diminished glucose clearance in response to an insulin tolerance test, decreased insulin signaling in skeletal muscle, decreased insulin staining of pancreatic islets, increased nociception, and diminished plasma cortisol levels compared to group-housed control mice. Using Promethion metabolic phenotyping chambers, we observed dysregulation of sleep and eating behaviors, as well as a time-dependent shift in respiratory exchange ratio of the adolescent-isolation mice. We profiled changes in neural gene transcription from several brain areas and found that a neural circuit between serotonin-producing and GLP-1-producing neurons is affected by this isolation paradigm. Overall, spatial transcription data suggest decreased serotonin neuron activity (via decreased GLP-1-mediated excitation) and increased GLP-1 neuron activity (via decreased serotonin-mediated inhibition). This circuit may represent an intersectional target to further investigate the relationship between social isolation and type 2 diabetes, as well as a pharmacologically-relevant circuit to explore the effects of serotonin and GLP-1 receptor agonists.Article HighlightsIsolating C57BL/6J mice throughout adolescence is sufficient to induce type 2 diabetes, presenting with fasted hyperglycemia.Adolescent-isolation mice have deficits in insulin responsiveness, impaired peripheral insulin signaling, and decreased pancreatic insulin production.Transcriptional changes across the brain include the endocannabinoid, serotonin, and GLP-1 neurotransmitters and associated receptors.The neural serotonin/GLP-1 circuit may represent an intersectional target to further investigate the relationship between social isolation and type 2 diabetes. Serotonin-producing neurons of adolescent-isolation mice produce fewer transcripts for the GLP-1 receptor, and GLP-1 neurons produce fewer transcripts for the 5-HT1Aserotonin receptor.