M Lu, et al., Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues. Journal of Biological Chemistry, 2013. 288(15): 10722-10735.


Metabolon results led to:
- A new model for brain Sirt1 function and its systemic effects
- Implications for development of Sirt1 activators

Key metabolomic observations:
- A clear sign of adipose lipogenesis with increased triglyceride (TAG) and fatty acids 14:0, 16:0, and 16:1n7

Sirt1 is as a cellular energy sensor whose activation has been shown to produce beneficial effects suggesting its potential for treating metabolic disease and aging. However, most of these effects have focused on Sirt1 activation in the periphery and controversy exists as to what the impact would be of Sirt1 in the CNS. Therefore, Olefsky and colleagues sought to determine the effects with a neuronal sirt1 knockout (SINKO). Remarkably, SINKO mice display increased central and peripheral insulin sensitivity and are protected from diet- and aging-induced insulin resistance. Lipidomics showed that one key aspect of this is enhanced adipose tissue lipogenesis. These findings suggest that, in an effort to maintain brain glucose levels, neuronal Sirt1 initiates a program to divert glucose away from peripheral tissues and, in the absence of neuronal Sirt1, peripheral insulin action is amplified. These findings suggest that Sirt1 activators that are not brain-penetrating may have greatest therapeutic potential.

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