Myeloid-specific deletion of SIRT1 increases hepatic steatosis and hypothalamic inflammation in mice fed a high-fat diet

Abstract

Obesity-induced fatty liver disease is associated with increased hypothalamic inflammation. Previous reports have demonstrated that the deletion of SIRT1 in hepatocytes increases hepatic steatosis and inflammation. Using myeloid cell-specific SIRT1 knockout (KO) mice, we investigated whether ablation of SIRT1 in macrophages plays a role in regulating hepatic steatosis and hypothalamic inflammation. When challenged with a high-fat diet (HFD) for 24 weeks, hyperleptinemia, hyperinsulinemia, hepatic steatosis and macrophage infiltrations in HFD-fed KO mice were increased compared with HFD-fed WT mice. Hypothalamic expression levels of iba1 were increased in HFD-fed KO mice compared with HFD-fed WT mice. In particular, the expression levels of choline acetyltransferase were decreased in the hypothalamus of HFD-fed KO mice compared with HFD-fed WT mice. Thus, our findings suggest that SIRT1 plays a key role for hepatic steatosis and hypothalamic inflammation and that anti-inflammatory effect of SIRT1 may be important for the prevention of obesity-induced metabolic syndromes.

Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans

“…Cases with the strongest radiologic evidence for MBH gliosis also had elevations of both fasting plasma insulin levels and HOMA‐IR that were not fully explained by their higher BMIs. These data in humans echo evidence from animal models showing that glucose homeostasis might be impaired independently by inflammatory responses in the hypothalamus . The MBH and specifically the arcuate nucleus play a critical role in the regulation of energy homeostasis, glucose metabolism , and non‐insulin‐mediated glucose disposal .…”

Emerging roles of SIRT1 in fatty liver diseases

“…Consequently, the deletion of SIRT1 exacerbates the development of hepatic inflammation and fatty liver diseases when challenged with high-fat diet or even mediate-fat diet 27 , 28 . Consistent with these observations, myeloid cell-specific disruption of SIRT1 in mice reveals that SIRT1 deficiency in macrophages induces NF-κB hyperacetylation and increases NF-κB transcriptional activation in the liver, resulting in hepatic inflammation 114 and hepatic steatosis upon high-fat diet 115 , whereas overexpression of SIRT1 in transgenic mice shows beneficial effects on fatty liver induced by high-fat diet and lower activation of pro-inflammatory cytokines, such as IL-6 and TNF-α, via down-regulation of NF-κB activity 30 . These results are consistent to those with activation of SIRT1 by resveratrol or nicotinamide riboside treatment under high-fat or high-fat plus high-sucrose diet conditions 78 , 80 , 87 , 107 , 116 .…”

The Role of SHIP1 on Apoptosis and Autophagy in the Adipose Tissue of Obese Mice

“…For double immunofluorescence, sections of deparaffinized epididymal fat tissue were incubated at 4 °C overnight with the primary antibodies ( Table S3 ). Double immunofluorescence procedures were performed as previously described [ 38 ]. Additionally, we performed double immunofluorescence staining for SHIP1 and TUNEL to measure the degree of SHIP1-positive apoptotic adipocytes using an in situ cell death detection kit (Roche Molecular Biochemicals, Mannheim, Germany) according to the manufacturer’s instructions.…”