权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结