Sirtuin 6 Builds a Wall Against Inflammation, Trumping Diabetes

In 2014, more than two-thirds of U.S. adults were overweight or obese (1). These numbers have more than doubled over the past 50 years; ominously, obesity increasingly afflicts younger individuals, including children (2). Numerous deleterious health consequences are associated with obesity, including hypertension, dyslipidemia, type 2 diabetes, heart disease, and cancer (3,4). The costs associated with obesity in the U.S. are estimated to top $500 billion/year over the next two decades (5,6). Substantial literature has documented key roles for adipose tissue macrophages and hepatic Kupffer cells in driving chronic systemic inflammation and insulin resistance and their downstream sequelae in obesity (7). The sirtuins (SIRT1–7) are NAD+-dependent lysine deacetylases/deacylases critical for maintaining cellular and organismal homeostasis. A large body of work has demonstrated roles of sirtuins in regulating inflammatory responses and signaling through the insulin/IGF-1, mTOR, and AMPK pathways, all of which help mediate the adverse health consequences of obesity (8). SIRT6 is a chromatin-associated sirtuin implicated in metabolism, inflammation, stress responses, and genomic stability. Whole-body Sirt6 knockouts (KOs) die by a month of age …