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：
10536358
负责人：
Robert F Rosencrans
金额：
$ 4万
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/10536358
关键词：
Ablation 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 Brain 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 Pharmacology 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 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（T2D）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。尽管这些疾病存在许多治疗方法，但没有任何靶向大脑感染。这个差距是重要的是因为动物模型显示了调节大脑区域的代谢中炎症的迅速诱导例如下丘脑，特别是在饱和脂肪暴露时。下丘脑炎症是关键原因慢性交感神经系统（SNS）多动症。社交媒体通过去甲醇的神经递质来调节大多数组织，该神经肾上腺素的结合和 肾上腺素受体（-AR）。在T2D和Mets中，交感神经在许多组织中都是多动的，包括白脂肪组织。在健康的脂肪组织中，交感神经驱动脂解：释放游离脂肪酸和该电路的外源刺激临床促进葡萄糖稳态。但是，在疾病状态，脂肪组织下调了-AR，并表现出脂肪分解受损而响应SNS输入（脂肪儿茶酚胺耐药性）。慢性多动交感神经可能会驱动-ar 下调，但目前没有数据直接显示这一点，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，我们烧毁了内源性抗炎细胞的生长抑素能（SST）神经元人口，在下丘脑的室室中。这种干预诱发了下丘脑炎症和内脏脂肪儿茶酚胺耐药性，但没有详细研究胰岛素/葡萄糖在Chow或高脂饮食下，在该模型中进行了体内平衡或交感神经活动进食。这就是我们的中心假设是下丘脑SST神经元（SST-DTA）的消融恶化的HFD诱导内脏脂肪儿茶酚胺耐药性和葡萄糖耐药性下丘脑炎症和脂肪交感神经活动的增加。这个假设提出了 SST-DTA通过增加交感神经活动来驱动脂肪儿茶酚胺耐药性的预测。这是我们的目标是阐明消融下丘脑生长抑素能神经元对在正常饮食和HFD。这符合NIDDK的使命，因为它解决了重要的基本和 Mets和T2D发展的翻译方面。由于拟议的研究，我们希望在调节SNS活性的调节中开发新的靶标，这应该被证明可用于恢复脂肪组织对儿茶酚胺的敏感性。重要的是，生长抑素类似物已经被FDA批准，可以针对下丘脑表明我们的数据可以支持治疗药物的方法下丘脑炎症和恢复脂肪组织脂解功能。该提议的完成也将通过获得关键技术和基本技能，为我作为物理科学家的培训做出了贡献。