Does age-dependent PFKFB3 down-regulation alter adipose tissue function

年龄是2型糖尿病发展的主要危险因素之一，但其潜在机制 这种风险是未知的。糖尿病风险因肥胖而增加，肥胖是一种在整个生命周期中增加的疾病。 这使我们假设，随着年龄的增长和肥胖，糖尿病风险增加可能与变化有关。 与这些生理状态相关的脂肪细胞功能。我们已经证明，脂肪细胞的成熟是 依赖于6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）的上调， 是糖酵解调节剂的同种型。PFKFB 3催化果糖-2，6-二磷酸（F-2，6-bisphosphate）的产生。 BP）变构激活磷酸果糖激酶1（PFK 1），这是厌氧代谢的速率限制步骤。 糖酵解PFKFB 3是一种双功能酶，具有激酶活性和磷酸酶活性， 肽链。在PFKFB 3的情况下，激酶活性比磷酸酶活性高约700，因此 有利于F-2，6-BP的生产PFKFB 3在脂肪组织中的表达水平高于其他组织。 组织中我们发表的数据显示，抑制PFKFB 3会降低GLUT 4的表达，GLUT 4是一种关键蛋白， 调节葡萄糖稳态。值得注意的是，我们还表明，PFKFB 3蛋白表达减少， 禁食动物的脂肪组织，并迅速增加后重新喂养。在初步数据中，我们现在表明， PFKFB 3在衰老脂肪组织中表达显著下调。这些观察使我们 假设PFKFB 3依赖性糖酵解调节在调节脂肪细胞中起关键作用 在整个生命周期中，代谢水平下降，导致代谢疾病的年龄依赖性风险增加。我们将 开始探索这一假说有两个具体的目标：1）确定年龄相关的变化的作用， PFKFB 3表达对整个寿命期间进食和禁食脂肪组织中F-2，6-BP产生的影响; 2） 确定PFKFB 3在调节脂肪细胞功能中的作用。从这个小R 03赠款获得的数据 这一机制将为进一步验证衰老的假说提供有用的模型和重要的功能数据 脂肪组织在与年龄相关的代谢疾病风险中起作用。

Age is one of the major risk factors for the development of Type 2 diabetes, but the mechanisms underlying this risk are unknown. Diabetes risk is enhanced by obesity, a condition that increases through the lifespan. This has led us to hypothesize that increased diabetes risk with aging and obesity may be related to changes in adipocyte function associated with these physiologic states. We have shown that adipocyte maturation was dependent on the upregulation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a PFK2 isoform that is a regulator of glycolysis. PFKFB3 catalyzes the production of fructose-2,6-bisphosphate (F-2,6- BP) to allosterically activate phosphofructokinase 1 (PFK1), the committed rate limiting step for anaerobic glycolysis. PFKFB3 is a bifunctional enzyme with kinase activity and phosphatase activity within the same peptide chain. In the case of PFKFB3, the kinase activity is ~700 more active than the phosphatase, thus favoring F-2,6-BP production. PFKFB3 is expressed at high levels in adipose tissue compared to other tissues. Our published data reveal inhibition of PFKFB3 reduced the expression of GLUT4, a key protein that regulates glucose homeostasis. Notably, we have also shown that PFKFB3 protein expression is reduced in adipose tissue of fasting animals and rapidly increased after refeeding. In preliminary data, we now show that PFKFB3 expression is significantly down-regulated in aging adipose tissue. These observations led us to hypothesize that PFKFB3-dependent regulation of glycolysis plays key roles in regulating adipocyte metabolism over the life-span, leading to increased age-dependent risk of metabolic disease. We will begin exploring this hypothesis with two specific aims: 1) To determine the role of age-related changes in PFKFB3 expression on F-2,6-BP production in fed and fasted adipose tissue through the lifespan; 2) To determine the role of PFKFB3 in regulation of adipocyte function. The data obtained from this small R03 grant mechanism will provide a useful model and important functional data to further test the hypothesis that aged adipose tissue plays a role in age-dependent risk for metabolic diseases.