Obesity is one of the most common metabolic diseases around the world, which is distinguished by the abnormal buildup of triglycerides within adipose cells. Recent research has revealed that autophagy regulates lipid mobilization to maintain energy balance. TIGAR (Trp53 induced glycolysis regulatory phosphatase) has been identified as a glycolysis inhibitor, whether it plays a role in the metabolism of lipids is unknown. Here, we found that TIGAR transgenic (TIGAR+/+) mice exhibited increased fat mass and trended to obesity phenotype. Non-target metabolomics showed that TIGAR caused the dysregulation of the metabolism profile. The quantitative transcriptome sequencing identified an increased levels of LRRK2 and RAB7B in the adipose tissue of TIGAR+/+ mice. It was confirmed in vitro that TIGAR overexpression increased the levels of LRRK2 by inhibiting polyubiquitination degradation, thereby suppressing macroautophagy and chaperone-mediated autophagy (CMA) while increasing lipid accumulation which were reversed by the LRRK2 inhibitor DNL201. Furthermore, TIGAR drove LRRK2 to interact with RAB7B for suppressing lysosomal degradation of lipid droplets, while the increased lipid droplets in adipocytes were blocked by the RAB7B inhibitor ML282. Additionally, fat-specific TIGAR knockdown of TIGAR+/+ mice alleviated the symptoms of obesity, and adipose tissues-targeting superiority DNL201 nano-emulsion counteracted the obesity phenotype in TIGAR+/+ mice. In summary, the current results indicated that TIGAR performed a vital function in the lipid metabolism through LRRK2-mediated negative regulation of macroautophagy and CMA in adipocyte. The findings suggest that TIGAR has the potential to serve as a viable therapeutic target for treating obesity and its associated metabolic dysfunction.
Manganese is vital for plant growth and disease resistance but remains underutilized as a bioactive agent due to its toxicity at high concentrations. Here, an effective antiviral nanopesticide system utilizing Mn ions (Mn 2+ ) within safe limits is described. Briefly, cellulose nanocrystals (CNCs) are employed as bio-sourced carrier surfaces and polydopamine (PDA) as a stabilizing and chelating agent for Mn 2+ . By impregnating Mn 2+ onto PDA-coated CNCs, the stable CNC@PDA@Mn 2+ (CPM) composite is fabricated. The CPM composite exhibits a substantially strengthened inhibitory effect on virus infectivity and curtails virus accumulation in Nicotiana benthamiana . The synergistic effects of CPM stem from its ability to directly disrupt viral particles and activate the plant-immunity-related antioxidant systems. Additionally, H 2 O 2 generated by the CPM-activated superoxide dismutase potentially serves as a molecular signal to overexpress the disease-resistance gene harpin-induced 1 ( NbHin1 ) by sulfinylating CCA1 Hiking Expedition and enhance its binding to NbHin1 promoter. Subsequently, this upregulation coordinates the activation of NbHin1 -dependent macroautophagy, triggering multiple antiviral defense mechanisms. Thus, this design achieves highly potent broad-spectrum antiviral activity at low concentrations of manganese (16 µg mL −1 ). Notably, this work pioneers the use of Mn 2+ in triggering plant antiviral defense, offering a solid foundation for designing novel antiviral agents.
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