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

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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.