Teodoro Bottiglieri Ph.D.

Posted April 15th 2016

PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.

Erland Arning Ph.D.

Erland Arning, Ph.D.

Nicholls, R. E., J. M. Sontag, H. Zhang, A. Staniszewski, S. Yan, C. Y. Kim, M. Yim, C. M. Woodruff, E. Arning, B. Wasek, D. Yin, T. Bottiglieri, E. Sontag, E. R. Kandel and O. Arancio (2016). “PP2A methylation controls sensitivity and resistance to beta-amyloid-induced cognitive and electrophysiological impairments.” Proc Natl Acad Sci U S A 113(12): 3347-3352.

Full text of this article.

Elevated levels of the beta-amyloid peptide (Abeta) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer’s disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Abeta exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Abeta-induced impairments. Neither transgene affected Abeta production or the electrophysiological response to low concentrations of Abeta, suggesting that these manipulations selectively affect the pathological response to elevated Abeta levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Abeta levels in AD patients.


Posted March 15th 2016

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri, Ph.D.

Ejaz, A., L. Martinez-Guino, A. B. Goldfine, F. Ribas-Aulinas, V. De Nigris, S. Ribo, A. Gonzalez-Franquesa, P. M. Garcia-Roves, E. Li, J. M. Dreyfuss, W. Gall, J. K. Kim, T. Bottiglieri, F. Villarroya, R. E. Gerszten, M. E. Patti and C. Lerin (2016). “Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.” Diabetes. Feb 8. [Epub ahead of print]

Full text of this article.

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin resistant humans, and correlate closely with insulin sensitivity. Moreover, betaine administration to diet-induced obese mice prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating Fgf21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21-/- mice, demonstrating that Fgf21 is necessary for betaine’s beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice, and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.