Inositol hexakisphosphate kinase-1 As a Novel Target in Obesity

 描述（由申请人提供）：超过三分之一的美国人口肥胖。肥胖相关的合并症，如2型糖尿病和心脏病的流行强调了需要共同努力预防和治疗肥胖。体重减少≥5%可显著降低人类心血管风险，这清楚地表明了体重管理的紧迫性。生活方式干预是主要的，但在长期体重管理中还不够。因此，我们需要抗肥胖药物。由于目前的抗肥胖药物的部分作用是抑制食物摄入或吸收，最近的焦点已经转向提高代谢组织中的能量消耗。脂肪组织是能量代谢的主要调节器。因此，脂肪组织在正常和肥胖条件下的功能正在被广泛研究。由于脂肪组织的复杂性，对其代谢的机制和调控仍然缺乏完整的了解。发现脂肪组织代谢的所有主要成分肯定有助于设计治疗策略。在这个提议中，我们引入了IP 6 K1作为具有治疗潜力的一个这样的组分。我们的实验室对使用小鼠模型了解正常和肥胖条件下脂肪组织代谢的机制和调节感兴趣。利用肌醇六磷酸激酶1（IP 6 K1）敲除（K1-KO）小鼠，我们先前发现这些小鼠抵抗体重增加和胰岛素抵抗，尽管它们的食物摄入量没有改变。本提案的目的是使用全身和脂肪组织特异性IP 6 K1小鼠模型来确定IP 6 K1促进脂肪组织中脂质积累的机制。中心假设是IP 6 K1是脂肪组织中能量代谢的主要调节剂。为了检验这一假设，将确定IP 6 K1在以下方面的作用：1）脂肪组织布朗宁和产热; 2）脂解;和3）脂肪生成，并且将鉴定IP 6 K1调节这些过程的潜在机制。拟议的研究在概念上是创新的，因为它代表了一种新的和实质性的偏离现状，即确定IP 6 K1调节脂肪量的机制。这一贡献意义重大，因为它是一系列研究的第一步，这些研究有望导致肥胖症新药理学策略的发展。因此，预计拟议项目将对改善生活质量产生重大影响。

 DESCRIPTION (provided by applicant): More than one-third of U.S. population is obese. The prevalence of obesity-related comorbidities such as type-2 diabetes and heart diseases emphasizes the need for concerted efforts to prevent and treat obesity. A decrease in ≥5% of the body weight significantly reduces cardiovascular risk in humans which clearly demonstrates the urgency of weight management. Lifestyle intervention is primary albeit not sufficient in long term weight management. Thus, we need anti-obesity drugs. Due to partial effects of the current anti-obesity drugs that inhibit food intake or absorption, recent focus has shifted towards enhancing energy expenditure in metabolic tissues. Adipose tissue is a major regulator of energy metabolism. Therefore, adipose tissue function in normal and obese conditions are being extensively studied. Because of the complexity of the adipose tissue, a complete understanding of the mechanism and regulation of its metabolism is still lacking. Discovery of all the major components of adipose tissue metabolism will certainly help to design therapeutic strategies. In this proposal, we introduce IP6K1 as one such component with therapeutic potential. Our laboratory is interested in understanding the mechanism and regulation of adipose tissue metabolism in normal and obese conditions using mouse models. Utilizing the inositol hexakisphosphate kinase 1 (IP6K1) knockout (K1-KO) mice, we previously discovered that these mice are resistant to weight gain and insulin resistance, despite their unaltered food intake. The objective of the current proposal is to determine the mechanisms by which IP6K1 promotes lipid accumulation in the adipose tissue using whole body and adipose tissue specific IP6K1 mouse models. The central hypothesis is that IP6K1 is a major regulator of energy metabolism in the adipose tissue. To test this hypothesis, role of IP6K1 in; 1) adipose tissue browning and thermogenesis; 2) lipolysis and; 3) adipogenesis will be determined and underlying mechanisms by which IP6K1 regulates these processes will be identified. The proposed research is conceptually innovative, because it represents a new and substantive departure from the status quo, namely determining the mechanisms by which IP6K1 regulates adipose mass. The contribution is significant because it is the first step in a continuum of research that is expected to lead to development of novel pharmacologic strategies in obesity. Therefore, the proposed project is expected to have significant impacts on improving quality of life.