Mechanism of Gdf3 action to limit insulin sensitivity in obesity

Gdf3 限制肥胖胰岛素敏感性的机制

基本信息

批准号：
10615878
负责人：
ALEXANDER BANKS
金额：
$ 63.8万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615878
关键词：
Acute Address Adipocytes Adipose tissue Affect Affinity Alanine Antidiabetic Drugs Biochemical Blood Glucose Body Temperature Body Weight decreased CRISPR screen CRISPR/Cas technology Cardiovascular Diseases Cells Clinical Continuous Glucose Monitor Death Rate Development Diabetes Mellitus Diabetic mouse Down-Regulation Ectopic Expression Energy Metabolism Experimental Designs Fatty acid glycerol esters Future Gene Expression Genetic Genetic Transcription Glucose Glycosylated hemoglobin A Goals Health High Fat Diet Immune system Impairment In Vitro Indirect Calorimetry Insulin Resistance Investigation Knock-in Knock-out Knockout Mice Ligands Link LoxP-flanked allele Malignant Neoplasms Measurement Mediating Mediator Metabolic Metabolism Methods Modality Modeling Molecular Target Monitor Morbidity - disease rate Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Nutrient availability Obesity PPAR gamma Pathogenesis Pathogenicity Pathway interactions Patients Phosphorylation Population Process Protein Secretion Proteins Reporter Role Serine Signal Transduction Signaling Molecule Stroke System Technology Testing Thermogenesis Thiazolidinediones Thinness Tissues Visualization Weight Gain Work blood glucose regulation bone fragility comorbidity design diabetic patient energy balance experimental study feeding gain of function genome-wide glucose uptake growth differentiation factor 3 improved inhibitor innovation insulin sensitivity large datasets lipid biosynthesis loss of function metabolic rate mortality mouse model novel therapeutics pharmacologic prevent programs receptor response side effect small hairpin RNA therapeutic evaluation therapeutic target tool transcription factor wireless

项目摘要

Project Summary The thiazolidinediones (TZDs) are powerful anti-diabetic drugs whose use in treating type 2 diabetes is limited by adverse side effects. The goal of this proposal is a biochemical investigation into the mechanism that separates the positive metabolic effects of TZDs to lower glucose from their well-characterized negative side effects. PPARγ, a molecular target of the TZDs, regulates systemic insulin sensitivity by promoting formation of new adipocytes. However, we show that the TZDs have a second biochemical function on PPARγ, to block phosphorylation of serine 273 (pS273). We find that phosphorylation of PPARγ at serine 273 promotes insulin resistance without affecting adipogenesis. Reversing this phosphorylation with pharmacological or genetic inhibition is sufficient to promote insulin sensitivity and increase thermogenic responses to cold. We propose that one of the main mechanisms by which phosphorylation of PPARγ at serine 273 promotes insulin resistance is through increased expression of growth differentiation factor 3 (Gdf3). Gdf3 is a secreted protein in the TGF- /BMP superfamily and a negative regulator of BMP signaling. In adipose tissue, BMP proteins contribute to insulin sensitivity and thermogenesis. We therefore propose that elevated levels of Gdf3 in obesity are the cause of insulin resistance mediated by PPARγ S273 phosphorylation. Indeed, we show that ectopic expression of Gdf3 is sufficient to cause insulin resistance in lean mice. In this proposal we examine the contribution of Gdf3 to the pathogenesis of obesity and insulin resistance. We predict that blocking Gdf3 levels or activity will restore whole-body insulin sensitivity and promote thermogenesis. We will interrogate the role of Gdf3 on glucose homeostasis and obesity using both acute gain-of-function and loss-of-function models. We will utilize innovative new wireless continuous glucose monitoring technology concurrently with indirect calorimetry to achieve high- precision measurements of insulin resistance, energy balance, and circulating nutrient availability. We will determine whether Gdf3 is the mechanism linking PPARγ S273 phosphorylation and insulin resistance. We will also determine whether Gdf3 requires BMP signaling through SMAD1/5/8 proteins. Finally, we will perform an unbiased investigation into the pathways required for Gdf3 signaling using a genome-wide CRISPR/Cas9 knockout screen. This hypothesis suggests a new therapeutic modality which harnesses a specific beneficial aspect of TZD treatment which is independent of TZD-associated side effects. The results from this proposal will definitively determine if Gdf3 is a suitable target for promoting metabolic health.

项目概要噻唑烷二酮类 (TZD) 是强效抗糖尿病药物，但在治疗 2 型糖尿病中的应用有限该提案的目标是对产生不良副作用的机制进行生化研究。将 TZD 降低血糖的积极代谢作用与其明显的消极作用区分开来 PPARγ 是 TZD 的分子靶标，通过促进胰岛素的形成来调节全身胰岛素敏感性。然而，我们发现 TZD 对 PPARγ 具有第二种生化功能，即阻断 PPARγ。丝氨酸 273 (pS273) 的磷酸化我们发现 PPARγ 丝氨酸 273 的磷酸化可促进胰岛素的产生。通过药理学或遗传逆转这种磷酸化。我们认为抑制足以促进胰岛素敏感性并增加对寒冷的生热反应。 PPARγ 丝氨酸 273 处的磷酸化促进胰岛素抵抗的主要机制之一是通过增加生长分化因子 3 (Gdf3) 的表达，Gdf3 是 TGF-β 中的一种分泌蛋白。 /BMP 超家族和 BMP 信号传导的负调节因子在脂肪组织中，BMP 蛋白有助于调节 BMP 信号。因此，我们认为肥胖中 Gdf3 水平升高是原因。事实上，我们发现 PPARγ S273 磷酸化介导的胰岛素抵抗的异位表达。 Gdf3 足以引起瘦小鼠的胰岛素抵抗。在本提案中，我们研究了 Gdf3 的贡献。我们预测阻断 Gdf3 水平或活性将会恢复。我们将探究 Gdf3 对葡萄糖的作用。我们将利用创新的功能获得和功能丧失模型来研究体内平衡和肥胖。新型无线连续血糖监测技术与间接量热法同时实现高我们将精确测量胰岛素抵抗、能量平衡和循环营养可用性。确定 Gdf3 是否是连接 PPARγ S273 磷酸化和胰岛素抵抗的机制。还确定 Gdf3 是否需要通过 SMAD1/5/8 蛋白进行 BMP 信号传导。使用全基因组 CRISPR/Cas9 对 Gdf3 信号传导所需的途径进行公正的研究这一假设提出了一种利用特定有益效果的新治疗方式。 TZD 治疗的一个方面与 TZD 相关的副作用无关。最终确定 Gdf3 是否是促进代谢健康的合适靶点。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Not so fast: Paradoxically increased variability in the glucose tolerance test due to food withdrawal in continuous glucose-monitored mice.

DOI：
10.1016/j.molmet.2023.101795
发表时间：
2023-11
期刊：
MOLECULAR METABOLISM
影响因子：
8.1
作者：
Rubio, William B.;Cortopassi, Marissa D.;Ramachandran, Deepti;Walker, Samuel J.;Balough, Elizabeth M.;Wang, Jiefu;Banks, Alexander S.
通讯作者：
Banks, Alexander S.