Metabolic defects in mice with adipocyte-specific deletion of Akt2

描述（由申请方提供）：肥胖发生率的上升以及随后非酒精性脂肪肝、胰岛素抵抗和II型糖尿病（T2DM）患病率的增加导致需要了解控制能量代谢的机制。申办者的实验室和其他实验室为了解胰岛素信号传导和肝脏、肌肉和脂肪组织中胰岛素抵抗的发生做出了重大贡献。脂肪细胞中的代谢信号对我们理解T2DM至关重要。脂肪组织不仅是一种专门用于营养储存的器官，而且还具有对控制全身葡萄糖和脂质稳态很重要的内分泌功能。目前胰岛素抵抗发展的一个有吸引力的模型是，它首先开始于脂肪组织，然后传播到其他胰岛素敏感器官。这项提案将提出：脂肪组织中的信号缺陷对其他关键器官的胰岛素抵抗有什么影响？为了提出这个问题，我们将使用具有Akt2的脂肪特异性缺失和Akt1与Akt2同时缺失的模型系统。我们将首先探索破坏Akt依赖性胰岛素信号传导的局部后果以及胰岛素在脂肪细胞中的哪些作用是Akt非依赖性的。通过增强我们对体内脂肪细胞中Akt2和Akt1/Akt2缺失的细胞自主效应的理解，我们将能够更好地解释脂肪组织中胰岛素抵抗的非自主效应，并确定当细胞缺乏Akt2时Akt1是否具有代偿作用。数据表明，胰岛素抵抗可以从脂肪细胞特异性传播到全身;然而，在文献中仍然存在许多争议。我们的脂肪细胞特异性Akt2和Akt1/Akt2缺失模型将解决这个问题。我们假设脂肪细胞中Akt的缺失会影响其他代谢器官，从而导致胰岛素敏感性降低和葡萄糖耐受不良。该建议中的实验与理解肥胖经常导致脂肪组织、肝脏和肌肉中的胰岛素抵抗的机制高度相关。

DESCRIPTION (provided by applicant): The rise in the incidence of obesity and the subsequent increase in the prevalence of nonalcoholic fatty liver disease, insulin resistance, and Type II Diabetes (T2DM) have led to a need to understand the mechanisms that control energy metabolism. The sponsor's laboratory and others have contributed significantly to understanding insulin signaling and the onset of insulin resistance in the liver, muscle, and adipose tissue. Metabolic signaling in fat cells is critical to our understanding of T2DM. Adipose tissue is an organ devoted not only to nutrient storage, but also has an endocrine function important to the control of systemic glucose and lipid homeostasis. A current attractive model for the development of insulin resistance is that it first begins in adipose tissue and is then propagated to other insulin sensitive organs. This proposal will ask: what are the effects of defective signaling in adipose tissue on insulin resistance in other key organs? To ask this question, we will use model systems with adipose- specific deletion of Akt2 and Akt1 deleted concurrently with Akt2. We will first probe the local consequences of disrupting Akt-dependent insulin signaling and what actions of insulin are Akt- independent in adipocytes. By enhancing our understanding of the cell-autonomous effects of Akt2 and Akt1/Akt2 deletion in adipocytes in vivo, we will be able to better interpret the non- autonomous effects of insulin resistance in adipose tissue and ascertain whether there is a compensatory role for Akt1 when cells are deficient for Akt2. Data have suggested that insulin resistance can be propagated from adipocyte-specific to the whole body; however, much controversy remains in the literature. Our models with adipocyte-specific Akt2 and Akt1/Akt2 deletion will address this question. We hypothesize that loss of Akt in adipocytes will affect other metabolic organs, conferring a phenotype of decreased insulin sensitivity and glucose intolerance. The experiments in this proposal are highly relevant to understanding the mechanisms by which obesity frequently leads to insulin resistance in adipose tissue, liver and muscle.