Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation - Fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene

The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dra matically reduced during lactation in mice. The reduction in UCP-3 mRNA lev els lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactat ing and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fa tty acids, which are reduced in lactation and are upregulated due to weanin g or fasting. Modifications in the energy nutritional stress of lactating d ams achieved by manipulating litter sizes do not influence UCP-3 mRNA level s in skeletal muscle. Conversely, when mice are fed a high-fat diet after p arturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due t o lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafib rate, an activator of the peroxisome proliferator-activated receptor (PPAR) , raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic incr ease in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamm a, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not s ignificantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gen e is regulated in skeletal muscle during lactation in response to changes i n circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involveme nt of UCP-3 gene regulation in the reduction of the use of fatty acids as f uel by the skeletal muscle and in impaired adaptative thermogenesis, both o f which are major metabolic adaptations that occur during lactation.