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Depleting Somatostatinergic Neurons Recapitulates Diabetic Phenotypes In Brain and Adipose Tissue

消耗生长抑素能神经元重现大脑和脂肪组织中的糖尿病表型

基本信息

批准号：
10647698
负责人：
Robert F Rosencrans
金额：
$ 4.53万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647698
关键词：
Ablation Acceleration Acute Address Adipose tissue Adrenergic Receptor Affect Agonist American Animal Model Anti-Inflammatory Agents Binding Blood Glucose Brain Brain region Bypass Cardiovascular system Catecholamines Chronic Clinical Complex Data Development Diet Disease Disease model Down-Regulation Encephalitis Exhibits FDA approved Fasting Functional disorder Glucose Intolerance Glucose tolerance test Glycine Goals Health High Fat Diet Hyperactivity Hyperinsulinism Hypothalamic structure Impairment Inflammation Inflammatory Insulin Insulin Resistance Intervention Kidney Link Lipolysis Liver Measures Mediating Mesentery Metabolic Diseases Metabolic syndrome Metabolism Mission Modeling Mus National Institute of Diabetes and Digestive and Kidney Diseases Nerve Neurons Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Norepinephrine Pancreas Pathology Peptides Phenotype Physicians Physiological Processes Population Primates Property Public Health Regulation Research Resistance Risk Risk Factors Rodent Role Scientist Signal Transduction Somatostatin Sympathetic Nervous System Sympatholytics System Techniques Testing Tissues Training Triglycerides Visceral antagonist blood glucose regulation body system brain tissue clinically significant comparative cytokine desensitization diabetic dietary disability drug repurposing experimental study feeding gamma-Aminobutyric Acid glucose metabolism glucose uptake improved insight insulin signaling insulin tolerance mortality mortality risk mouse model novel pharmacologic receptor response saturated fat skills somatostatin analog

项目摘要

Project Summary Type 2 diabetes (T2D) and metabolic syndrome (METS) are a major public health crisis affecting one in three Americans. Though many treatments exist for these diseases, none target brain inflammation. This gap is important because animal models show rapid induction of inflammation in metabolism regulating brain regions such as the hypothalamus, particularly upon saturated fat exposure. Hypothalamic inflammation is a key cause of chronic sympathetic nervous system (SNS) hyperactivity. The SNS regulates most tissues through norepinephrine, a catecholamine neurotransmitter which binds  and  adrenergic receptors (-AR). In T2D and METS, sympathetic nerves are hyperactive in many tissues, including white adipose tissue. In healthy adipose tissue, sympathetic nerves drive lipolysis: the release of free fatty acids, and the exogenous stimulation of this circuit clinically promotes glucose homeostasis. However, in the disease state, adipose tissue downregulates -AR and exhibits impaired lipolysis in response to SNS input (adipose catecholamine resistance). Chronically hyperactive sympathetic nerves could drive -AR downregulation, but no data directly show this at present, which hampers approaches to restoring endogenous catecholamine sensitivity and improving glucose homeostasis. In the present study, we ablate somatostatinergic (SST) neurons, an endogenous anti-inflammatory cellular population, in the paraventricular region of hypothalamus. This intervention induces both hypothalamic inflammation and visceral adipose catecholamine resistance, but no detailed studies of insulin/glucose homeostasis or sympathetic nerve activity have been performed in this model under chow or high fat diet feeding. Thus, our central hypothesis is that the ablation of hypothalamic SST neurons (SST-DTA) will exacerbate HFD induced visceral adipose catecholamine resistance and glucose intolerance by increasing hypothalamic inflammation and adipose sympathetic nerve activity. This hypothesis makes the prediction that SST-DTA drives adipose catecholamine resistance by increasing sympathetic nerve activity. Thus, our objective is to elucidate the consequences of ablating hypothalamic somatostatinergic neurons on adipose sympathetic nerve activity, adipose catecholamine resistance, and glucose homeostasis, under normal diet and HFD. This is in line with the mission of the NIDDK because it addresses important basic and translational aspects of the development of METS and T2D. As a result of the proposed studies, we expect to develop novel targets in the regulation of SNS activity which should prove useful in restoring adipose tissue sensitivity to catecholamines. Importantly, somatostatin analogues are already FDA approved and can target the hypothalamus, which suggests our data could support a drug repurposing approach to treating hypothalamic inflammation and restoring adipose tissue lipolytic function. Completion of this proposal will also contribute to my training as a physician scientist through the acquisition of key techniques and essential skills.

项目摘要 2型糖尿病（T2 D）和代谢综合征（METS）是影响三分之一的主要公共卫生危机。美国人虽然有许多治疗这些疾病的方法，但没有一种针对大脑炎症。这种差距这一点很重要，因为动物模型显示，在调节代谢的脑区，例如下丘脑，特别是在饱和脂肪暴露时。下丘脑炎症是导致慢性交感神经系统（SNS）过度活跃。 SNS通过去甲肾上腺素调节大多数组织，去甲肾上腺素是一种结合肾上腺素和肾上腺素的儿茶酚胺神经递质。 β-肾上腺素能受体（β-AR）。在T2 D和METS中，交感神经在许多组织中过度活跃，包括白色脂肪组织。在健康的脂肪组织中，交感神经驱动脂解：释放游离脂肪酸。脂肪酸，并且该回路的外源性刺激在临床上促进葡萄糖稳态。但在在疾病状态下，脂肪组织下调β-AR，并表现出对SNS输入的响应性脂解受损（脂肪儿茶酚胺抵抗）。慢性过度活跃的交感神经可以驱动肾上腺素能受体下调，但目前没有数据直接表明这一点，这阻碍了恢复内源性儿茶酚胺敏感性和改善葡萄糖稳态。在本研究中，我们消融生长抑素能（SST）神经元，一种内源性抗炎细胞，人群，位于下丘脑室旁区。这种干预诱导下丘脑炎症和内脏脂肪儿茶酚胺抵抗，但没有详细的研究胰岛素/葡萄糖已经在该模型中在食物或高脂肪饮食下进行了体内平衡或交感神经活动喂食因此，我们的中心假设是，下丘脑SST神经元（SST-DTA）的消融将加重HFD诱导的内脏脂肪儿茶酚胺抵抗和葡萄糖耐受不良，增加下丘脑炎症和脂肪交感神经活动。这一假设使得预测SST-DTA通过增加交感神经活性驱动脂肪儿茶酚胺抵抗。因此，我们的目的是阐明消融下丘脑生长抑素能神经元对脂肪交感神经活性、脂肪儿茶酚胺抵抗和葡萄糖稳态，正常饮食和HFD。这符合国家荒漠化和干旱防治中心的使命，因为它处理重要的基本和 METS和T2 D发展的翻译方面。根据建议的研究结果，我们预期开发新的目标，在调节SNS活动，这应该证明是有用的，在恢复脂肪组织对儿茶酚胺敏感重要的是，生长抑素类似物已经被FDA批准，可以靶向下丘脑，这表明我们的数据可以支持药物再利用的方法来治疗下丘脑炎症和恢复脂肪组织脂解功能。该提案的完成还将通过获得关键技术和基本技能，为我作为一名医生科学家的培训做出贡献。