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Long-term restricted feeding alters circadian expression and reduces the level of inflammatory and disease markers.

Sherman H, Frumin I, Gutman R, Chapnik N, Lorentz A, Meylan J, le Coutre J, Froy O - J. Cell. Mol. Med. (2011)

Bottom Line: However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR.We found that circadian rhythmicity is more robust and is phase advanced in most of the genes and proteins tested under RF.Our results suggest that RF may share some benefits with those of CR.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.

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Suggested model for RF effects and interactions in various mouse tissues. (A) In the liver, RF is believed to lead to an increase in both NAD+ and AMP levels that could explain the observed AMPK activity up-regulation and increased Sirt1 mRNA leading to presumed increased activity levels. AMPK phosphorylates PGC-1α and the observed increase in its mRNA levels alongside those of Sirt1, assuming a parallel increase at the protein level, may lead to the arrest of glycolysis and fat storage and increase in gluconeogenesis and fatty acid oxidation. SIRT1 also inhibits NF-κB activity, as observed, which leads to down-regulation of pro-inflammatory cytokines (IL-6 and TNF-α). Combined with the observed up-regulation of the anti-inflammatory cytokine Il-10 mRNA, assuming similar effect at the protein level, this yields reduced inflammation. (B) In the jejunum, RF increases Pparα mRNA levels, which leads to fatty acid oxidation, assuming a parallel increase at the protein level. PPAR-α is also known to inhibit NF-κB. Pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) are down-regulated and together with an increase of the anti-inflammatory cytokine IL-10 ultimately lead to reduced inflammation. This suggests a novel pathway by which RF can influence the inflammatory processes in the gut. (C) In WAT, inflammatory processes are inhibited in fat tissue as well. In addition, RF decreases Pparγ mRNA and assuming a parallel decrease at the protein level, this could result in reduced fat storage.
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fig10: Suggested model for RF effects and interactions in various mouse tissues. (A) In the liver, RF is believed to lead to an increase in both NAD+ and AMP levels that could explain the observed AMPK activity up-regulation and increased Sirt1 mRNA leading to presumed increased activity levels. AMPK phosphorylates PGC-1α and the observed increase in its mRNA levels alongside those of Sirt1, assuming a parallel increase at the protein level, may lead to the arrest of glycolysis and fat storage and increase in gluconeogenesis and fatty acid oxidation. SIRT1 also inhibits NF-κB activity, as observed, which leads to down-regulation of pro-inflammatory cytokines (IL-6 and TNF-α). Combined with the observed up-regulation of the anti-inflammatory cytokine Il-10 mRNA, assuming similar effect at the protein level, this yields reduced inflammation. (B) In the jejunum, RF increases Pparα mRNA levels, which leads to fatty acid oxidation, assuming a parallel increase at the protein level. PPAR-α is also known to inhibit NF-κB. Pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) are down-regulated and together with an increase of the anti-inflammatory cytokine IL-10 ultimately lead to reduced inflammation. This suggests a novel pathway by which RF can influence the inflammatory processes in the gut. (C) In WAT, inflammatory processes are inhibited in fat tissue as well. In addition, RF decreases Pparγ mRNA and assuming a parallel decrease at the protein level, this could result in reduced fat storage.

Mentions: Robust oscillation and a phase advance were also observed in most of the metabolical markers in both liver and jejunum under RF. As expected, under AL, Ampk mRNA oscillation peaked during the light phase, the time of inactivity, whereas under RF, it peaked before food availability. This is in agreement with the low energy levels when the animals were asleep under the AL regimen or devoid of food under the RF regimen. Under RF, when AMP levels increase, AMPK is activated, as indeed is demonstrated by the higher pAMPK/AMPK ratio (Fig. 4), to boost production of ATP and inhibit its usage. Similarly, the NAD+ histone deacetylase SIRT1 activity is up-regulated in response to changes in the energy status. SIRT1 activation promotes transcription of genes that mediate the metabolic response to stress or starvation, among which is PGC-1α (Fig. 10), as was reported [78]. Indeed, PGC-1α involvement in the switch from glycolysis to gluconeogenesis under fasting conditions in the liver is well documented [79–81] and fits well with the temporal food restriction inherent to the RF model.


Long-term restricted feeding alters circadian expression and reduces the level of inflammatory and disease markers.

Sherman H, Frumin I, Gutman R, Chapnik N, Lorentz A, Meylan J, le Coutre J, Froy O - J. Cell. Mol. Med. (2011)

Suggested model for RF effects and interactions in various mouse tissues. (A) In the liver, RF is believed to lead to an increase in both NAD+ and AMP levels that could explain the observed AMPK activity up-regulation and increased Sirt1 mRNA leading to presumed increased activity levels. AMPK phosphorylates PGC-1α and the observed increase in its mRNA levels alongside those of Sirt1, assuming a parallel increase at the protein level, may lead to the arrest of glycolysis and fat storage and increase in gluconeogenesis and fatty acid oxidation. SIRT1 also inhibits NF-κB activity, as observed, which leads to down-regulation of pro-inflammatory cytokines (IL-6 and TNF-α). Combined with the observed up-regulation of the anti-inflammatory cytokine Il-10 mRNA, assuming similar effect at the protein level, this yields reduced inflammation. (B) In the jejunum, RF increases Pparα mRNA levels, which leads to fatty acid oxidation, assuming a parallel increase at the protein level. PPAR-α is also known to inhibit NF-κB. Pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) are down-regulated and together with an increase of the anti-inflammatory cytokine IL-10 ultimately lead to reduced inflammation. This suggests a novel pathway by which RF can influence the inflammatory processes in the gut. (C) In WAT, inflammatory processes are inhibited in fat tissue as well. In addition, RF decreases Pparγ mRNA and assuming a parallel decrease at the protein level, this could result in reduced fat storage.
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fig10: Suggested model for RF effects and interactions in various mouse tissues. (A) In the liver, RF is believed to lead to an increase in both NAD+ and AMP levels that could explain the observed AMPK activity up-regulation and increased Sirt1 mRNA leading to presumed increased activity levels. AMPK phosphorylates PGC-1α and the observed increase in its mRNA levels alongside those of Sirt1, assuming a parallel increase at the protein level, may lead to the arrest of glycolysis and fat storage and increase in gluconeogenesis and fatty acid oxidation. SIRT1 also inhibits NF-κB activity, as observed, which leads to down-regulation of pro-inflammatory cytokines (IL-6 and TNF-α). Combined with the observed up-regulation of the anti-inflammatory cytokine Il-10 mRNA, assuming similar effect at the protein level, this yields reduced inflammation. (B) In the jejunum, RF increases Pparα mRNA levels, which leads to fatty acid oxidation, assuming a parallel increase at the protein level. PPAR-α is also known to inhibit NF-κB. Pro-inflammatory cytokines (IL-1, IL-6 and TNF-α) are down-regulated and together with an increase of the anti-inflammatory cytokine IL-10 ultimately lead to reduced inflammation. This suggests a novel pathway by which RF can influence the inflammatory processes in the gut. (C) In WAT, inflammatory processes are inhibited in fat tissue as well. In addition, RF decreases Pparγ mRNA and assuming a parallel decrease at the protein level, this could result in reduced fat storage.
Mentions: Robust oscillation and a phase advance were also observed in most of the metabolical markers in both liver and jejunum under RF. As expected, under AL, Ampk mRNA oscillation peaked during the light phase, the time of inactivity, whereas under RF, it peaked before food availability. This is in agreement with the low energy levels when the animals were asleep under the AL regimen or devoid of food under the RF regimen. Under RF, when AMP levels increase, AMPK is activated, as indeed is demonstrated by the higher pAMPK/AMPK ratio (Fig. 4), to boost production of ATP and inhibit its usage. Similarly, the NAD+ histone deacetylase SIRT1 activity is up-regulated in response to changes in the energy status. SIRT1 activation promotes transcription of genes that mediate the metabolic response to stress or starvation, among which is PGC-1α (Fig. 10), as was reported [78]. Indeed, PGC-1α involvement in the switch from glycolysis to gluconeogenesis under fasting conditions in the liver is well documented [79–81] and fits well with the temporal food restriction inherent to the RF model.

Bottom Line: However, it is not known whether RF can delay the occurrence of age-associated changes similar to CR.We found that circadian rhythmicity is more robust and is phase advanced in most of the genes and proteins tested under RF.Our results suggest that RF may share some benefits with those of CR.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.

Show MeSH
Related in: MedlinePlus