Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice

Abstract

shown that Sirt1 is involved in regulation of inflammation response and inhibits inflammatory pathways in macrophages and dendritic cells (6, 7). In 3T3-L1 adipocytes, Sirt1 can attenuate TNF--induced insulin resistance and inflammation (3,8). Resveratrol (RES) is a natural polyphenolic compound known for its beneficial effects on energy homeostasis (9, 10). Studies have shown that RES attenuates inflammation of adipocytes and vascular endothelial cells by activating Sirt1 and inducing autophagy (11-13). However, the regulatory mechanism of RES on Sirt1 and adipose inflammation remains unclear.The Akt/mammalian target of rapamycin (mTOR) pathway plays an important role in the regulation of cellular gluconeogenesis and metabolism (14,15). mTOR is highly conserved serine/threonine kinase that is expressed in cancer cells, adipocytes, and hepatocytes, and can be directly phosphorylated by activated . During development of obesity, adipose pro-inflammatory responses are closely associated with the development of insulin resistance in adipose tissue (19,20). A recent study showed that phosphorylation of Akt in macrophages could activate mTOR signal and then led to inflammation and insulin resistance in high-fat diet (HFD)-induced obesity (21). Moreover, Pang et al. (22) reported that Sirt1 directly bound protein kinase B (Akt2) and then inhibited adipogenesis in porcine adipocytes. Busch et al. (23) also suggested that Akt was one of the main upstream stimulatory kinases that modulated by Sirt1. However, whether the interaction between Sirt1 and Akt2 can regulate adipose inflammation has not been studied.We suggested that RES would attenuate HFD-induced obesity and adipose inflammation by activating Sirt1. We found that RES promoted the interaction of Sirt1 and Akt2, and then inhibited adipose inflammation by activating the mTOR/S6K1 pathway. These findings identify a novel function of Sirt1 in the regulation of adipose inflammation Sirtuin type 1 (Sirt1) is a member of the silencing information regulator 2 (Sir2) family called sirtuins, and is wellknown for its deacetylation in regulation of gene silencing, energy homeostasis, and apoptosis (1-3). The overloaded calorie intake leads to dysfunction of adipocytes and causes obesity (4). Obesity is closely associated with chronic inflammation and characterized by abnormal cytokine production, increased acute-phase reactants, and an activated network of inflammatory signal pathways (5 Abbreviations: Akt2, protein kinase B; HFD, high-fat diet; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; mTOR, mammalian target of rapamycin; NAM, nicotinamide; RES, resveratrol; Sirt1, sirtuin type 1.

Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue

“…Sirt1 adipocyte-specific knockout mice present low-grade chronic inflammation along with glucose intolerance and insulin resistance [4]. Our previous study confirms that Sirt1 decreases white adipose inflammation (WAT) via interacting with Akt2 and activating mTOR/S6K pathway [5]. Sirt1 also reduces fat accumulation and improves whole-body energy expenditure in white adipocytes [2, 6].…”

Melatonin and inflammation—Story of a double‐edged blade

“…Other cases in which anti‐inflammatory actions of SIRT1 were reported concern mTOR (mechanistic target of rapamycin), in particular, via mTORC1 (mTOR complex 1). For instance, SIRT1 was shown to decrease adipose inflammation by inhibiting mTORC1 signaling . In experiments on liver steatosis, hepatocyte‐specific deletion of SIRT1 enhanced mTORC1 activity .…”

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…As the rate‐limiting enzyme of the NAD + salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) was recently reported to play a role in WAT plasticity and the development of obesity . Similar to what is seen with NAMPT, the expression of adipose sirtuins (SIRTs) that use NAD + as their substrate is lower in obese subjects and decreases in mice on HFD . The reputation of SIRTs in integrating metabolism and immunity is emphasized by the increased number of adipose‐resident and M1 macrophages found in mice with adipocyte‐selective SIRT1 deletion .…”