Monocarboxylates such as pyruvate, lactate and ketone bodies are crucial for energy supply of all tissues, especially during energy restriction. The transport of monocarboxylates across the plasma membrane of cells is mediated by monocarboxylate transporters (MCTs). Out of 14 known mammalian MCTs, six isoforms have been functionally characterized to transport monocarboxylates and short chain fatty acids (MCT1-4), thyroid hormones (MCT8, -10) and aromatic amino acids (MCT10). Knowledge on the regulation of the different MCT isoforms is rare. In an attempt to get more insights in regulation of MCT expression upon energy deprivation, we carried out a comprehensive analysis of tissue specific expression of five MCT isoforms upon 48 h of fasting in mice. Due to the crucial role of peroxisome proliferator-activated receptor (PPAR)-α as a central regulator of energy metabolism and as known regulator of MCT1 expression, we included both wildtype (WT) and PPARα knockout (KO) mice in our study. Liver, kidney, heart, small intestine, hypothalamus, pituitary gland and thyroid gland of the mice were analyzed. Here we show that the expression of all examined MCT isoforms was markedly altered by fasting compared to feeding. Expression of MCT1, MCT2 and MCT10 was either increased or decreased by fasting dependent on the analyzed tissue. MCT4 and MCT8 were down-regulated by fasting in all examined tissues. However, PPARα appeared to have a minor impact on MCT isoform regulation. Due to the fundamental role of MCTs in transport of energy providing metabolites and hormones involved in the regulation of energy homeostasis, we assumed that the observed fasting-induced adaptations of MCT expression seem to ensure an adequate energy supply of tissues during the fasting state. Since, MCT isoforms 1–4 are also necessary for the cellular uptake of drugs, the fasting-induced modifications of MCT expression have to be considered in future clinical care algorithms.
Sources of AGEs induce the transcription of Fgf23 in UMR cells. At least in part, the effect is mediated through up-regulation of NFκB and subsequent SOCE. AGE-induced FGF23 production may contribute to increased FGF23 serum levels observed in chronic disease.
Peroxisome proliferator-activated receptor-a (PPARa) plays a pivotal role in regulating metabolic response to fasting and is an inhibitor of inflammatory pathways in immune cells. It represents a therapeutic target for treatment of several diseases, mainly hyperlipidemia. To shed light on PPARa expression changes in response to fasting, young healthy male and female volunteers were fed or fasted for 24 hours. Monocytes were analyzed every 2 hours to compile both profiles of mRNA and protein expression of PPARa and its interactive partner, the circadian pacemaker brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1). We found that women change their diurnal expression profiles of PPARa and BMAL1 when switching from the fed to the fasted state, whereas men do not. Interestingly, the PPARa and BMAL1 profiles of men and women in the fed state are different, whereas the profiles in the fasted state are virtually identical. The finding of diametrically opposite responses of male and female PPARa expression in the fed state might have practical implication in human medicine as PPARa activators like fibrates are used for the therapy of chronic lymphocytic leukemia, microvascular complications in diabetes, and kidney diseases.-Wege, N., Schutkowski, A., Boenn, M., Bialek, J., Schlitt, A., Noack, F., Grosse, I., Stangl, G. I. Men and women differ in their diurnal expression of monocyte peroxisome proliferator-activated receptor-a in the fed but not in the fasted state. FASEB J. 29, 2905-2911 (2015). www.fasebj.org Key Words: caloric intake • nuclear receptor • circadian pacemaker FOOD SHORTAGE IS A FREQUENT phenomenon in nature. Hence, organisms have evolved a metabolic program to survive periods of food shortage. During fasting, organisms suspend growth and reproduction, induce defense molecules, and shift whole-body fuel utilization from both carbohydrates and fat to almost exclusively fat (1). This metabolic flexibility is vital to survival. Adaptations to fasting are mediated by peroxisome proliferator-activated receptor-a (PPARa), a nuclear hormone receptor, which plays a pivotal role as a nutritional state sensor and key regulator in the mediation of metabolic responses to fasting (2, 3). Besides its pivotal role in fasting adaptation, there is emerging evidence that PPARa exerts antiinflammatory effects in cells and animals (4-6) and that it mediates the delay of aging and the extension of lifespan in response to caloric restriction (7). It further serves as receptor for therapeutic PPARa agonists such as fibrates that have been widely used as drugs to reduce high lipid levels in plasma (8). Human PPARa is expressed among various tissues with high expression levels in immune cells (4). Its expression is, among other factors, regulated by brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1), a basic helix-loop-helix protein that functions as circadian pacemaker (9, 10) and that is involved in regulation of energy homeostasis (11).Despite the significant phys...
Data from thyrotrope cells revealed that PPARα could contribute to the fasting-associated downregulation of the TSHβ mRNA expression. In a mouse model, fasting led to a significant reduction in TSHβ mRNA level, but unexpectedly this effect was stronger in mice lacking PPARα than in WT mice.
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