Jumpstart fat-burning mechanisms typically spurred by starvation, and you’ve got a strategy for preventing obesity-related disorders and maybe other diseases of aging. Thinking along this line, scientists figured they had struck gold with resveratrol, a compound in red wine that mimics the life-extending effects of eating fewer calories. Now, a new study adds to evidence that seems to link these benefits to resveratrol’s activation of the histone deacetylase SIRT1, by showing that specific SIRT1 activation in mice wards off diet-induced metabolic problems. Another recent paper strengthens the link between high-fat diet and AD, highlighting how the extra fat worsens Abeta and tau pathologies in an Alzheimer disease mouse model (3xTg-AD).

That resveratrol activates SIRT1 has been known for some time. But this natural polyphenol also kicks into action other molecules, including AMP-activated protein kinase (AMPK), a sensor of cellular energy levels (Baur et al., 2006; Dasgupta et al., 2007). In the 5 November issue of Cell Metabolism, researchers led by Johan Auwerx at the Institute of Genetic and Molecular and Cellular Biology in Illkirch, France, describe their efforts to untangle these effects. In mice fed a high-fat diet, first author Jerome Feige and colleagues evaluated the effects of a robust SIRT1 activator (SRT1720) found in a prior screen for small-molecule SIRT1 agonists (Milne et al., 2007).

In a mass spectrometry deacetylation assay, the compound induced SIRT1 activity 8.7-fold (versus 2.6-fold for resveratrol). It was highly potent, boosting SIRT1 activity by 50 percent increase at just 0.23 micromolar, compared with 47.6 micromolar for resveratrol. Furthermore, SRT1720 boosted energy expenditure, measured as oxygen consumption rates in C2C12 myotubes; this effect was blocked by SIRT1 knockdown using short hairpin RNA. SRT1720 had an additive effect when assessed in these cells in combination with the AMPK activator metformin but not with resveratrol. In addition, SRT1720—unlike resveratrol or another AMPK activator—did not trigger significant phosphorylation of AMPKα or its downstream target, acetylCoA carboxylase (ACC), in C2C12 myotubes or in mouse calf muscle four hours after a single intraperitoneal injection (500 mg/kg). These data suggest that SRT1720 revs up energy expenditure by activating SIRT1 and does not directly stimulate AMPK.

When mixed into high-fat mouse chow, low doses of the drug (100 mg/kg/day) started keeping off extra pounds in wild-type animals only after 10 weeks of treatment, whereas the high dose (500 mg/kg/day) prevented diet-induced weight gain right from the get-go. The high dose also correlated with increased energy expenditure, read out as higher rates of oxygen consumption and carbon dioxide release. These effects did not derive from differences in food intake or locomotor activity.

Compared with their untreated counterparts, mice that got six weeks of the SRT1720 mixed into their high-fat diet had lower plasma levels of lipids, glucose and insulin after 16 hours of fasting. SRT1720-treated animals also had better tolerance to glucose load, increased insulin sensitivity, stronger muscles, and ran about twice as far as control animals in an endurance exercise test. Even mice on a normal diet had better endurance when given the drug for six weeks. Underlying the enhanced endurance in SRT1720-treated animals was a slew of calf muscle gene expression changes—for example, higher mRNA levels of three slow-twitch fiber markers and lower levels of a fast-twitch glycolytic marker.

SRT1720 triggered upregulation of several genes promoting fatty acid oxidation but had little effect on a handful of genes controlling mitochondrial function and oxidative phosphorylation. Gene expression studies in the liver revealed that SRT1720-treated animals had small or inconsistent changes in genes controlling glycolysis and gluconeogenesis, and higher mRNA levels of factors that regulate fatty acid oxidation. In addition, these animals had smaller brown fat cells and activated a number of genes controlling energy expenditure (e.g. peroxisome proliferators-activated receptor (PPAR) α and β, thyroid hormone receptors (TR) α and β, and PPARγ coactivator 1 (PGC-1) α).

In toto, the gene profiling data suggested that transcriptional mechanisms underlie some of SRT1720’s metabolic effects. Therefore, the researchers looked at several SIRT1 transcriptional targets. They immunoprecipitated three such proteins—PGC-1α and Forkhead transcription factor family O1 (FOXO1) from muscle, and p53 from liver—and found them highly deacetylated in SRT1720-treated mice (500 mg/kg/day). Though SRT1720 did not seem to activate AMPK signaling in cultured cells or upon acute exposure in vivo, chronic exposure with 500 mg/kg/day for more than 20 weeks did result in phosphorylation of AMPKα and its downstream target ACC in muscle, liver and brown adipose tissue.

All told, the authors showed that, in mice, SRT1720 mimics the metabolic changes induced by resveratrol. However, the two compounds differ in how they induce these changes. While resveratrol acts primarily on mitochondrial biogenesis and function, SRT1720 seems to have more limited mitochondrial effects in instead activates pathways that control fatty acid oxidation. Still, the new data, along with two recent studies showing increased metabolic efficiency in SIRT1 transgenic mice (Pfluger et al., 2008; Banks et al., 2008), suggest that SIRT1 is indeed the protein to target in human trials, several of which are underway (see ARF related news story).

Meanwhile, another paper—published last month in the Neurobiology of Aging online by Frederic Calon and colleagues at Centre Hospitalier de l'Universitie Laval (CHUL) Research Center, Quebec, Canada—solidifies the connection between high-fat diet and AD. Previous work has established that fattier fare boosts brain Aβ levels and makes AD mice dumber (Ho et al.,2004; Li et al., 2003). Now, first author Carl Julien and colleagues extend the diet’s damage to tau and the postsynaptic marker drebrin. Specifically, they show that 3xTg-AD mice fed a “westernized diet” containing 35 percent fat (compared with 5 percent fat in standard mouse chow) had increased tau pathology and decreased cortical levels of the dendritic spine protein drebrin. The findings beg the question of whether treating diet-induced complications (e.g. metabolic syndrome, cardiovascular disease), which can be done with existing drugs, might also have benefits for AD, Calon told ARF.—Esther Landhuis.

References
Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metabolism. 5 Nov 2008;8:347-358.

Julien C, Tremblay C, Phivilay A, Berthiaume L, Emond V, Julien P, Calon F. High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging. 2008 Oct 14. Abstract

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References

News Citations

  1. SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir?

Paper Citations

  1. . Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. PubMed.
  2. . Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22. PubMed.
  3. . Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6. PubMed.
  4. . Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9793-8. PubMed.
  5. . SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008 Oct;8(4):333-41. PubMed.
  6. . Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 2004 May;18(7):902-4. PubMed.
  7. . Association of aortic atherosclerosis with cerebral beta-amyloidosis and learning deficits in a mouse model of Alzheimer's disease. Am J Pathol. 2003 Dec;163(6):2155-64. PubMed.
  8. . High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging. 2010 Sep;31(9):1516-31. PubMed.

Other Citations

  1. 3xTg-AD

Further Reading

Papers

  1. . Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9793-8. PubMed.
  2. . SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008 Oct;8(4):333-41. PubMed.

News

  1. SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir?
  2. Sirtuin Inhibitor Boosts Cognition, Reduces Phospho-tau