ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

International audienceBACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome

AMP-Activated Protein Kinase Plays an Important Evolutionary Conserved Role in the Regulation of Glucose Metabolism in Fish Skeletal Muscle Cells

AMPK, a master metabolic switch, mediates the observed increase of glucose uptake in locomotory muscle of mammals during exercise. AMPK is activated by changes in the intracellular AMP∶ATP ratio when ATP consumption is stimulated by contractile activity but also by AICAR and metformin, compounds that increase glucose transport in mammalian muscle cells. However, the possible role of AMPK in the regulation of glucose metabolism in skeletal muscle has not been investigated in other vertebrates, including fish. In this study, we investigated the effects of AMPK activators on glucose uptake, AMPK activity, cell surface levels of trout GLUT4 and expression of GLUT1 and GLUT4 as well as the expression of enzymes regulating glucose disposal and PGC1α in trout myotubes derived from a primary muscle cell culture. We show that AICAR and metformin significantly stimulated glucose uptake (1.6 and 1.3 fold, respectively) and that Compound C completely abrogated the stimulatory effects of the AMPK activators on glucose uptake. The combination of insulin and AMPK activators did not result in additive nor synergistic effects on glucose uptake. Moreover, exposure of trout myotubes to AICAR and metformin resulted in an increase in AMPK activity (3.8 and 3 fold, respectively). We also provide evidence suggesting that stimulation of glucose uptake by AMPK activators in trout myotubes may take place, at least in part, by increasing the cell surface and mRNA levels of trout GLUT4. Finally, AICAR increased the mRNA levels of genes involved in glucose disposal (hexokinase, 6-phosphofructokinase, pyruvate kinase and citrate synthase) and mitochondrial biogenesis (PGC-1α) and did not affect glycogen content or glycogen synthase mRNA levels in trout myotubes. Therefore, we provide evidence, for the first time in non-mammalian vertebrates, suggesting a potentially important role of AMPK in stimulating glucose uptake and utilization in the skeletal muscle of fish

Cloning of somatolactin alpha, beta forms and the somatolactin receptor in Atlantic salmon: Seasonal expression profile in pituitary and ovary of maturing female broodstock

<p>Abstract</p> <p>Background</p> <p>Somatolactin (Sl) is a fish specific adenohypophyseal peptide hormone related to growth hormone (Gh). Some species, including salmonids, possess two forms: Sl alpha and Sl beta. The somatolactin receptor (slr) is closely related to the growth hormone receptor (ghr). Sl has been ascribed many physiological functions, including a role in sexual maturation. In order to clarify the role of Sl in the sexual maturation of female Atlantic salmon (Salmo salar), the full length cDNAs of slr, Sl alpha and Sl beta were cloned and their expression was studied throughout a seasonal reproductive cycle using real-time quantitative PCR (RTqPCR).</p> <p>Methods</p> <p>Atlantic salmon Sl alpha, Sl beta and slr cDNAs were cloned using a PCR approach. Gene expression of Sl alpha, SL beta and slr was studied using RTqPCR over a 17 month period encompassing pre-vitellogenesis, vitellogenesis, ovulation and post ovulation in salmon females. Histological examination of ovarian samples allowed for the classification according to the degree of follicle maturation into oil drop, primary, secondary or tertiary yolk stage.</p> <p>Results</p> <p>The mature peptide sequences of Sl alpha, Sl beta and slr are highly similar to previously cloned salmonid forms and contained the typical motifs. Phylogenetic analysis of Atlantic salmon Sl alpha and Sl beta shows that these peptides group into the two Sl clades present in some fish species. The Atlantic salmon slr grouped with salmonid slr amongst so-called type I ghr. An increase in pituitary Sl alpha and Sl beta transcripts before and during spawning, with a decrease post-ovulation, and a constant expression level of ovarian slr were observed. There was also a transient increase in Sl alpha and Sl beta in May prior to transfer from seawater to fresh water and ensuing fasting.</p> <p>Conclusion</p> <p>The up-regulation of Sl alpha and Sl beta during vitellogenesis and spawning, with a subsequent decrease post-ovulation, supports a role for Sl during gonadal growth and spawning. Sl could also be involved in calcium/phosphate mobilization associated with vitellogenesis or have a role in energy homeostasis associated with lipolysis during fasting. The up-regulation of both Sl alpha and Sl beta prior to fasting and freshwater transfer, suggests a role for Sl linked to reproduction that may be independent of the maturation induced fasting.</p

Glucose Transporter 1 and Monocarboxylate Transporters 1, 2, and 4 Localization within the Glial Cells of Shark Blood-Brain-Barriers

Although previous studies showed that glucose is used to support the metabolic activity of the cartilaginous fish brain, the distribution and expression levels of glucose transporter (GLUT) isoforms remained undetermined. Optic/ultrastructural immunohistochemistry approaches were used to determine the expression of GLUT1 in the glial blood-brain barrier (gBBB). GLUT1 was observed solely in glial cells; it was primarily located in end-feet processes of the gBBB. Western blot analysis showed a protein with a molecular mass of 50 kDa, and partial sequencing confirmed GLUT1 identity. Similar approaches were used to demonstrate increased GLUT1 polarization to both apical and basolateral membranes in choroid plexus epithelial cells. To explore monocarboxylate transporter (MCT) involvement in shark brain metabolism, the expression of MCTs was analyzed. MCT1, 2 and 4 were expressed in endothelial cells; however, only MCT1 and MCT4 were present in glial cells. In neurons, MCT2 was localized at the cell membrane whereas MCT1 was detected within mitochondria. Previous studies demonstrated that hypoxia modified GLUT and MCT expression in mammalian brain cells, which was mediated by the transcription factor, hypoxia inducible factor-1. Similarly, we observed that hypoxia modified MCT1 cellular distribution and MCT4 expression in shark telencephalic area and brain stem, confirming the role of these transporters in hypoxia adaptation. Finally, using three-dimensional ultrastructural microscopy, the interaction between glial end-feet and leaky blood vessels of shark brain was assessed in the present study. These data suggested that the brains of shark may take up glucose from blood using a different mechanism than that used by mammalian brains, which may induce astrocyte-neuron lactate shuttling and metabolic coupling as observed in mammalian brain. Our data suggested that the structural conditions and expression patterns of GLUT1, MCT1, MCT2 and MCT4 in shark brain may establish the molecular foundation of metabolic coupling between glia and neurons

Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGO–Virgo run O3b

We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTC–2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate

Receptors for insulin-like growth factor-I (IGF-I) predominate over insulin receptors in skeletal muscle throughout the life cycle of Brown Trout, Salmo trutta

nsulin and IGF-I binding has been studied in brown trout (Salmo trutta) wheat germ agglutinin semipurified receptors from embryos (organogenesis), larvae (yolk sac), juveniles (2.98 ± 0.21 g bw) and adults (111.6 ± 6.92 and 522 ± 53 g bw). Embryos and larvae were sampled at 5 and 12 weeks after fertilization (December 1999 and February 2000) and juvenile and adults were taken simultaneously (July 1999) and under the same feeding conditions to minimize potential nutritional and seasonal effects. Insulin receptor number was maximal at 12 weeks (144 fmol/mg glycoprotein) and progressively decreased in subsequent samplings. No alterations in affinity were detected (Kd range, 0.21–0.32 nM) and changes in number of receptor paralleled changes in total specific binding. IGF-I receptor number was highest at 5 weeks (1044 fmol/mg) and was significantly higher than values for insulin in all samplings. The affinity of IGF-I receptor did not change (Kd range, 0.11–0.18 nM) but was consistently higher than that for the insulin receptor. A more rapid decrease of IGF-I binding and receptor number was found with age. However, the ratio of insulin/IGF-I binding established in 12-week-old larvae (0.18 ± 0.01) was thereafter maintained at very similar values in juveniles and adults (0.15–0.17). Tyrosine kinase activity (TKA) for insulin receptors ranged between 136 and 183% and there were no significant changes with age. For the IGF-I receptor, TKA ranged from 174 to 281% and was significantly higher in 5-week-old larvae coincident with the highest levels of receptor number and declined gradually in parallel with binding levels. In conclusion, the greater abundance of IGF-I receptors during embryonic and larval development is maintained throughout juvenile and adult stages. This would suggest a key role for IGF-I in the growth and metabolism of trout muscle

Effects of sustained exercise on GH-IGFs axis in gilthead sea bream (Sparus aurata)

The endocrine system regulates growth mainly through the growth hormone (GH)/insulin-like growth factors (IGFs) axis and, although exercise promotes growth, little is known about its modulation of these factors. The aim of this work was to characterize the effects of 5 wk of moderate sustained swimming on the GH-IGFs axis in gilthead sea bream fingerlings. Plasma IGF-I/GH ratio and tissue gene expression of total IGF-I and three splice variants, IGF-II, three IGF binding proteins, two GH receptors, two IGF-I receptors, and the downstream molecules were analyzed. Fish under exercise (EX) grew more than control fish (CT), had a higher plasma IGF-I/GH ratio, and showed increased hepatic IGF-I expression (mainly IGF-Ia). Total IGF-I expression levels were similar in the anterior and caudal muscles; however, IGF-Ic expression increased with exercise, suggesting that this splice variant may be the most sensitive to mechanical action. Moreover, IGFBP-5b and IGF-II increased in the anterior and caudal muscles, respectively, supporting enhanced muscle growth. Furthermore, in EX fish, hepatic IGF-IRb was reduced together with both GHRs; GHR-II was also reduced in anterior muscle, while GHR-I showed higher expression in the two muscle regions, indicating tissue-dependent differences and responses to exercise. Exercise also increased gene and protein expression of target of rapamycin (TOR), suggesting enhanced muscle protein synthesis. Altogether, these data demonstrate that moderate sustained activity may be used to increase the plasma IGF-I/GH ratio and to potentiate growth in farmed gilthead sea bream, modulating the gene expression of different members of the GH-IGFs axis (i.e., IGF-Ic, IGF-II, IGFBP-5b, GHR-I, and TOR).E. J. Vélez and A. Millán-Cubillo are supported by a predoctoral fellowship from the Ministerio de Ciencia e Innovación (MICINN). This study was supported by the projects from the MICINN AGL2009-12427 and AGL2012-39768 to J. Gutiérrez, and the Xarxa de Refèrencia d’R+D+I en Aqüicultura and the SGR2009-00402 from the Generalitat de CatalunyaPeer reviewe