Peroxisome proliferator–activated receptor α and enzymes of carnitine biosynthesis in the liver are down-regulated during lactation in rats

Downregulation of peroxisome proliferator-activated receptor α and its coactivators in liver and skeletal muscle mediates the metabolic adaptations during lactation in mice

“…downregulation of Ucps in brown adipose tissue (Ucp1 and Ucp3) and skeletal muscle (Ucp3) additionally diminishes thermogenesis and oxidation of fuels, which are spared for milk synthesis. As recently shown, hepatic enzymes of carnitine synthesis are concomitantly also reduced during lactation, which, in turn, leads to a reduced carnitine content in liver and skeletal muscle (Gutgesell et al 2009). As carnitine is involved in b-oxidation by transferring fatty acids into the mitochondrion, inhibition of carnitine synthesis can be regarded also as a means to diminish fatty acid oxidation during lactation.…”

“…It suggests that downregulation of Ppara and its coactivators in tissues with high rates of fatty acid utilization, such as liver, skeletal muscle, and heart, and subsequently reduced utilization of fatty acids by these tissues during lactation mediates an increased flow of NEFA from white adipose tissues and TAG-rich lipoproteins into the mammary gland, and thus helps to spare energy and metabolic substrates for milk production. The physiologically increased availability of fatty acids in the mammary gland during lactation (Williamson 1986, Dewey 1997, Smith & Grove 2002) is reflected by the marked upregulation of fatty acid transporters (Fat/Cd36 and Fatp) and Lpl, which mediate the uptake of albumin-bound NEFA and fatty acids released from TAG-rich lipoproteins respectively in the mammary gland and the reduced concentrations of NEFA and TAG (Gutgesell et al 2009) in plasma of lactating animals in both genotypes. In addition, expression of the lipogenic enzyme Fas, which is critical for de novo fatty acid synthesis, was strongly increased in the mammary gland of lactating mice of both genotypes.…”

“…Upon activation by either nonesterified fatty acids (NEFA) released from adipose tissue and taken up into tissues or exogenous ligands (diet-derived fatty acids or fibrates), Ppara upregulates genes involved in all aspects of fatty acid catabolism including cellular fatty acid uptake and transport, mitochondrial and peroxisomal fatty acid oxidation, as well as ketogenesis (Mandard et al 2004). We have recently observed that lactating rats have reduced mRNA concentrations of Ppara and Ppara-regulated genes involved in fatty acid utilization in the liver compared with nonlactating rats (Gutgesell et al 2009). This finding suggested that downregulation of genes involved in fatty acid uptake and oxidation as well as Ucp during lactation is mediated by suppression of Ppara.…”

Remote Communication through Solute Carriers and ATP Binding Cassette Drug Transporter Pathways: An Update on the Remote Sensing and Signaling Hypothesis

“…Under normal physiological conditions, the primary site of carnitine production is in the liver. During lactation, the production of carnitine in the mammary gland increases, apparently at the expense of production in the mother's liver, which is also accompanied by reduced hepatic enzymatic and transcriptional activity, as well as solute carrier activities associated with carnitine synthesis and handling (Gutgesell et al, 2009). This complex physiological regulation of carnitine synthesis and handling is necessary to provide the infant with carnitine for ␤-oxidation and energy production to use fatty acids.…”

Treatment of lactating sows with clofibrate as a synthetic agonist of PPARα does not influence milk fat content and gains of litters

“…Down-regulation of proteins involved in fatty acid uptake and oxidation in liver and skeletal muscle and a decreased thermogenesis contribute to these energy sparing effects [3-6]. We have observed that these effects in lactating rodents are mediated by a suppression of peroxisome proliferator-activated receptor α (PPARα), a transcription factor which controls the expression of many genes involved in lipid catabolism [7,8]. In lactating rats, it has been moreover observed that an activation of PPARα by feeding an oxidized fat causes a disturbance of those metabolic adaptations.…”