Biomedical Fast Takes


In Huntington’s disease, resveratrol can help …

Conserve Fat-Burning Power

Pharmacological resveratrol increases expression of PGC-1alpha (PGC-1α), as well as its downstream targets, nuclear respiratory factor-1 and uncoupling protein-1 in brown adipose tissue (BAT), according to a new study conducted at Weill Cornell Medical College, Department of Neurology and Neuroscience, in New York City.1

Through a principal mechanism, resveratrol has been reported to activate sirtuins,* which have been found to regulate important biologic processes including transcription, cell survival and metabolism. When SIRT1, a mammalian sirtuin, is activated by resveratrol, extended longevity and increased neuronal survival results.


* Sirtuins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity and are found in organisms ranging from bacteria to humans.



When SIRT1, a mammalian sirtuin, is
activated by resveratrol,
extended longevity and increased
neuronal survival results.


An important substrate of SIRT1 is peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1α), a principal regulator of energy metabolism, whose function is significantly impaired in Huntington’s disease (HD). HD is a neurodegenerative disorder characterized by progressive motor and cognitive impairment. It is caused by a polyglutamine repeat expansion (a polyQ mutation) in the huntingtin gene.

We now know that the natural disaccharide trehalose protects cells against certain environmental stresses (for example, by acting as an osmolyte). Furthermore, a recent paper2 identifies trehalose as an enhancer of autophagy, a cell-digesting process that can help clear aggregate-prone proteins such as mutant huntingtin fragments (Huntington’s disease), other polyQ mutations, mutant alpha-synucleins (as in Parkington’s and Alzheimer’s diseases), and tau (as in Alzheimer’s). (See “Another Autophagy Inducer: Trehalose” in the Volume 13 No. 2, April 2010 issue of Durk & Sandy’s Life Extension News.)


Resveratrol’s activation of PGC-1α
helps treat metabolic impairments in
brown adipose tissue caused by
Huntington’s disease.


Prior studies have shown that mitochondrial dysfunction which accompanies HD neurodegeneration is due to defective PGC-1α activity. In the Weill Cornell Medical College study, pharmacological resveratrol was studied in a transgenic mouse model of HD. Motor performance, survival, central and peripheral pathology and levels of PGC-1α expression were analyzed.

Resveratrol increased expression of PGC-1α, as well as its downstream targets—nuclear respiratory factor-1 (NRF-1) and uncoupling protein-1 (UCP-1)—in brown adipose (fat) tissue (BAT). It also reduced BAT vacuolation—indicating a greater ability of BAT to burn fat—and decreased elevated blood glucose levels.


Brown fat cells are rich in mitochondria, which determine their color. Mitochondria may be thought of as “cellular power plants” because they produce most cellular adenosine triphosphate (ATP), the universal energy molecule which is used for chemical energy. Arginine has previously been found to increase the mass of brown adipose tissue due to nitric oxide-induced mitochondrial biogenesis.


NRF-1 activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. It has also been associated with the regulation of neuron survival and development, and found to be important for the upregulation of antioxidant and metabolizing enzymes during oxidative stress. UCP-1 is associated with increased energy expenditure and reduced oxidative stress.

Resveratrol’s ability to activate the PGC-1α signaling pathway is an effective strategy for treating the metabolic impairments in BAT in HD and may prove to have additional benefits.

References

  1. Ho DJ, Calingasan NY, Wille E, Dumont M, Beal MF. Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol 2010 Sep;225(1):74-84.

  2. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant Huntingtin and alpha-synuclein. J Biol Chem 2007;282(8):5641-52.

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