IL-1R-IRAKM-Slc25a1 signaling axis reprograms lipogenesis in adipocytes to promote diet-induced obesity in mice

Abstract

Toll-like receptors/Interleukin-1 receptor signaling plays an important role in high-fat diet-induced adipose tissue dysfunction contributing to obesity-associated metabolic syndromes. Here, we show an unconventional IL-1R-IRAKM-Slc25a1 signaling axis in adipocytes that reprograms lipogenesis to promote diet-induced obesity. Adipocyte-specific deficiency of IRAKM reduces high-fat diet-induced body weight gain, increases whole body energy expenditure and improves insulin resistance, associated with decreased lipid accumulation and adipocyte cell sizes. IL-1β stimulation induces the translocation of IRAKM Myddosome to mitochondria to promote de novo lipogenesis in adipocytes. Mechanistically, IRAKM interacts with and phosphorylates mitochondrial citrate carrier Slc25a1 to promote IL-1β-induced mitochondrial citrate transport to cytosol and de novo lipogenesis. Moreover, IRAKM-Slc25a1 axis mediates IL-1β induced Pgc1a acetylation to regulate thermogenic gene expression in adipocytes. IRAKM kinase-inactivation also attenuates high-fat diet-induced obesity. Taken together, our study suggests that the IL-1R-IRAKM-Slc25a1 signaling axis tightly links inflammation and adipocyte metabolism, indicating a potential therapeutic target for obesity.

Double-edged effect of sodium citrate in Nile tilapia (Oreochromis niloticus): Promoting lipid and protein deposition vs. causing hyperglycemia and insulin resistance

“…4% sodium citrate treatment resulted in a significant decrease in the expression of the pro-inflammatory-related genes tnfa and il8 in the liver of Nile tilapia, while elevated gene expression of il1b . Recently, a close relationship between citrate and inflammation has been reported ( Branco et al., 2021 ; Liu et al., 2022 ; Liu et al., 2022 ). Under normal conditions, dietary supplementation of citrate leads to polarization of mouse liver macrophages toward the M1 type and promotes inflammation ( Branco et al., 2021 ).…”

“…Under normal conditions, dietary supplementation of citrate leads to polarization of mouse liver macrophages toward the M1 type and promotes inflammation ( Branco et al., 2021 ). On the other hand, blocking the citrate shuttle can alleviate inflammation by reshaping cellular metabolic patterns ( Liu et al., 2022 ) and blocking inflammatory signaling pathways ( Liu et al., 2022 ). Meanwhile, the significant activation of hepatic p65 phosphorylation in the sodium citrate-treated group reinforced the conviction that 4% sodium citrate treatment could induce liver inflammation in Nile tilapia.…”

Piperine alleviates nonalcoholic steatohepatitis by inhibiting NF-κB-mediated hepatocyte pyroptosis

“…Christian von Loeffelholz et al found that IL-6 activates the IL-6-STAT3 pathway and stimulates mIndy expression by binding to its receptor, which increases the hepatic uptake of citrate and hepatic lipogenesis of circulating citrate in vivo [ 51 ]. In addition, in an animal experiment, it was shown that IL-1β stimulation induced IRAKM to interact with and phosphorylate the mitochondrial citrate carrier Slc25a1, which promoted IL-1β-induced mitochondrial citrate transport to the cytoplasm and adipocytes to regenerate fat [ 52 ]. In a high-fructose diet-induced mouse model, Jelena Todoric et al showed that the deterioration of the intestinal barrier and subsequent endotoxemia caused by high-fructose intake triggers liver-induced upregulation of the ACC1, FAS and SREBP1 lipid genes for lipogenesis.…”

Mutations in the Vicinity of the IRAK3 Guanylate Cyclase Center Impact Its Subcellular Localization and Ability to Modulate Inflammatory Signaling in Immortalized Cell Lines

“…Since IRAK3 is considered mainly as a cytoplasmic protein that under certain conditions, including cell stimulation [44], may undergo nuclear or even mitochondrial transportation [45], we verified the subcellular distribution of the wild type and mutated versions of the C-terminally eGFP-tagged IRAK3 proteins transiently expressed in HEK293T cells. Most constructs showed cytoplasmic and, to a lesser extent, nuclear localization.…”