Abstract 321 Poster Session I, Saturday, 5/1 (poster 153)

The uncoupling proteins (UCPs) are a family of mitochondrial proteins that play a role in adaptive thermogenesis and energy balance. This is accomplished by driving H+ion transport unidirectionally across the inner mitochondrial membrane thereby abolishing the H+gradient necessary for ATP generation. Of the three isoforms characterized to date, UCP-1 is expressed in brown fat, UCP-2 expression is ubiquitous which includes the skeletal muscle, and UCP-3 is mainly expressed in skeletal muscle. Glucose transport mediated by glucose transporter isoforms (basal - Glut 1 and insulin-responsive-Glut 4) is the rate-limiting step in fueling skeletal muscle ATP synthesis, thereby regulating the energy homeostasis. To examine the role of excess glucose transport, without perturbations in the hormonal and environmental milieu, in regulating postnatal skeletal muscle UCP-2 and UCP-3 expression, we employed the heterozygous human Glut 4 overexpressing (Pessin et al, J. Biol. Chem. 1993) (OE: n=10) transgenic and their wild type (WT; n=10) littermate age-matched 7d and 14d suckling mice. We have shown that skeletal muscle from the suckling Glut 4 OE mice demonstrates a 2-fold increase in Glut 4, no change in Glut 1, and hypoglycemia reflective of increased skeletal muscle glucose transport/uptake (Ped Res 1999). Skeletal muscle mRNA was subjected to a semi-quantitative RT-PCR using murine specific UCP-2 and UCP-3 sense and antisense primers with bovine rhodopsin mRNA at the RT-PCR control. At both ages, no significant change in UCP-2 mRNA was observed in the OE vs WT. In contrast, UCP-3 mRNA was increased at 7d and 14d in the OE vs WT (Results = mean+SEM; WT 7d and 14d = 1.0; OE d7 - 2.35±0.36*; OE d14 = 2.32±0.36*; p<0.05). We conclude that Glut 4 OE with hypoglycemia caused an increase in UCP-3 mRNA with no change in UCP-2 expression, consistent with a differential regulation of the two isoforms. Since enhanced UCP-3 expression reflects increased energy expenditure, and assuming the observed mRNA changes translate to the protein level, we speculate that excess intracellular glucose alone can enhance energy expenditure by upregulating the neonatal skeletal muscle specific UCP-3. This change maintains a substrate/fuel-energy homeostatic balance even in the absence of hormonal or environmentally triggered energy consumption, thereby protecting against substrate-induced somatic overgrowth during the postnatal period.