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.

Abstract

The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels 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 lactating 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 fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, 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-␣ subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-␥, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly 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 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation.

Expression of uncoupling protein-3 mRNA in rat skeletal muscle is acutely stimulated by thiazolidinediones: an exercise-like effect?

“…In agreement with previous findings on female mice [5], expression of UCP-3 mRNA was distinctly elevated in gastrocnemius muscle of male rats after 24 h of starvation as well as 6 h after a single i.p. injection of 225 µmol/kg troglitazone (Fig.…”

“…Due to its high content of DMSO, the vehicle caused a transient increase in plasma NEFA, but independently of the vehicle effect and at variance with the study on mice [5], increased UCP-3 expression was associated with elevated plasma NEFA (Table 1), which contrasts with the NEFA-lowering effect of chronic TZD administration. Since NEFA are known to induce UCP-3 expression in skeletal muscle [7], their increase could have mediated the effect of TZDs.…”

“…Since the hypoxia-or exercise-like effects in vivo. A characteristic response to contractions and hypoxia is an immediate increase in the expression of uncoupling protein-3 (UCP-3) in skeletal muscle [4], which has also been observed only 6 h after the injection of troglitazone in mice [5]. Though interesting, the latter observation cannot be extrapolated uncritically to the whole class of TZDs, because troglitazone, which was used at a high dose [5], is superior to other TZDs as an inhibitor of cell respiration in vitro [1].…”

Uncoupling Proteins Prevent Glucose-Induced Neuronal Oxidative Stress and Programmed Cell Death

“…The specificity of the UCP antibodies was confirmed using blocking peptides (Fig. 1B) (27) and also by comparison with assays of mRNA expression (27,40). The data obtained using the UCP2 antibody were less convincing.…”

Reptilian uncoupling protein: functionality and expression in sub-zero temperatures

“…In rodents, situations resulting in high circulating free fatty acid (FFA) levels (such as starvation and cold exposure) are associated with upregulation of UCP3 mRNA expression (Schrauwen et al, 2006), but its expression is low when the FFA levels decrease, as in lactation (Pedraza et al, 2000).…”