Abstract
Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1(-/-) mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired activation of the master tumor suppressor p53 and treatment with an Scd1 inhibitor extended survival of tumor-prone TP53(-/-) mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression mediated by hepatic SirT1 and resulting in the activation of a key lipid synthetic enzyme, with potential therapeutic implications.
Highlights
The rising prevalence of obesity and overweight is expected to result in ~500,000 excess deaths from cancer by 2030 (Wang et al, 2011)
Given the pivotal functions of SirT1 in the pathophysiology of metabolic disorders, we investigated whether its native inhibitor Dbc1 plays a role in metabolism
Since ablation of Dbc1 increases SirT1 activity (Escande et al, 2010; Escande et al, 2015), we expected that Dbc1−/− mice would be more insulin-sensitive and protected against obesity-induced diabetes (Banks et al, 2008; Pfluger et al, 2008)
Summary
The rising prevalence of obesity and overweight is expected to result in ~500,000 excess deaths from cancer by 2030 (Wang et al, 2011). SirT1 deacetylates proteins with complex roles in metabolism, inflammation, aging, cancer cell proliferation, and apoptosis. It regulates hepatic gluconeogenesis through FOXO1 (Frescas et al, 2005; Qiang et al, 2010), white fat remodeling through peroxisome proliferator-activated receptor gamma (PPARγ) (Qiang et al, 2012), mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) (Rodgers et al, 2005), cholesterol metabolism through liver X receptor (LXR) (Li et al, 2007b), and other metabolic processes. To date, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1
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