Sirt6 Protects Against Metabolic Damages and Obesity of HFD by Reducing Hypothalamic Inflammation

Sirt6 is a NAD+-dependent nuclear deacylase and a mono ADP-ribosylase. Neural-specific deletion of Sirt6 in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels, and ultimately obesity. Recently, it was shown that old mice overexpressing Sirt6 have a moderate youthful metabolic profile; they have improved glucose tolerance and are more active relative to WT littermates. Sirt6 transgenic mice fed a HFD are protected against white adipose tissue accumulation, elevated triglyceride and LDL cholesterol levels, and impaired glucose tolerance. Substantial evidence indicates that the brain, particularly the hypothalamus, is primarily responsible for the regulation of the altered energy homeostasis.

This study evaluated the effects of overexpression of Sirt6 on inflammation and energy metabolism parameters in the brain of mice subjected to high-fat diet-induced obesity.

Male C57BL mice were divided into control (purified low-fat diet) and obese (purified high-fat diet) groups. After 18 weeks, the animals were sacrificed and the brain was removed. Sirt6 overexpression had a beneficial effect on the hypothalamus of obese animals; it reversed the increase in inflammatory parameters and attenuated the insensitivity in glucose metabolism.

RNA-seq analysis of the hypothalamic transcriptome revealed that the positive effect of Sirt6 overexpression in mice fed with HFD is associated with down regulation of a select set of inflammatory genes, such as genes involved in the interferon signaling, which were suggested as potential targets to control inflammation and the metabolic syndrome. Brain inflammation has been linked to obesity and weight gain in HFD and understanding and controlling this pathway has a great therapeutic potential.