Jichao Liang

Brown and beige adipocytes dissipate energy to generate heat through uncoupled respiration, and the hormone norepinephrine plays an important role in stimulating brown fat thermogenesis and beige adipocyte development in white adipose depots. Increasing energy expenditure by promoting the function and development of brown and beige fat is a potential approach to treat obesity and diabetes. Here, we investigated the effects of macrophage sirtuin 6 (SIRT6 ) on the regulation of the norepinephrine content of brown adipose tissue (BAT) and on obesity in mice. Myeloid SIRT6 deficiency impaired the thermogenic function of BAT, thereby decreasing core body temperatures because of reduced norepinephrine concentrations in BAT and subsequently leading to cold sensitivity. In addition, the oxygen consumption rate was reduced, resulting in severe insulin resistance and obesity. Furthermore, macrophage SIRT6 deficiency inhibited BAT thermogenesis after cold exposure or norepinephrine treatment and cold exposure–induced increases in markers of lipid metabolism and thermogenesis in white adipose tissue. Myeloid-specific SIRT6 deficiency promoted H3K9 acetylation in the promoter regions and the expression of genes encoding the norepinephrine-degrading enzyme MAOA and the norepinephrine transporter SLC6A2 in macrophages in BAT, leading to norepinephrine degradation and obesity. Our findings indicate that SIRT6 in macrophages is essential for maintaining norepinephrine concentrations in BAT in mice.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD.

Reactive oxygen species (ROS) have emerged as a promising treatment option for antibacterial and biofilm eradication. However, their therapeutic efficacy is significantly hampered by the unique microenvironments of diabetic wounds. In this study, we designed and synthesized porphyrin-based Fe covalent organic frameworks (Fe-COF) through a Schiff base condensation reaction. Subsequently, Fe-COF were encapsulated with hyaluronic acid (HA) through electrostatic adsorption, resulting in a novel formulation named HA-Fe-COF for diabetic wound healing. HA-Fe-COF were engineered to respond to hyaluronidase in the infected wound, leading to the controlled release of Fe-COF. Those released Fe-COF served a dual role as photosensitizers, generating singlet oxygen and localized heating when exposed to dual light sources. Additionally, they acted as peroxidase-like nanozymes, facilitating the production of ROS through enzymatic reactions. This innovative approach enabled a synergistic therapeutic effect combining photodynamic, photothermal, and chemodynamic modalities. Furthermore, the sustained release of HA from HA-Fe-COF promoted angiogenesis, collagen deposition, and re-epithelialization during the diabetic wound healing process. This "all-in-one" strategy offers a novel approach for the development of antimicrobial and biofilm eradication strategies that minimize damage to healthy tissues in vivo.

Chemodynamic therapy (CDT) has emerged as a promising approach for treating infected diabetic wounds, while reliable imaging technology for simultaneous monitoring of ROS and therapeutic processes is still a formidable challenge. Herein, smart covalent organic framework (COF) nanoreactors (COF NRs) are constructed by hyaluronic acid (HA) packaged glucose oxidase (GOx) covalently linked Fe‐COF for diabetic wound healing. Upon the breakdown of the HA protective layer, GOx consumes glucose to produce gluconic acid and hydrogen peroxide (H₂O₂), resulting in decreased local pH and H₂O₂ supplementation. Density functional theory (DFT) calculations show that Fe‐COF has high catalytic activity towards H₂O₂, leading to in situ generation of hydroxyl radicals (·OH) for sterilization, and the localized downregulation of glucose effectively improved the microenvironment of diabetic wounds. Meanwhile, based on the near‐infrared photothermal imaging of oxidized 3,3′,5,5′‐tetramethylbenzidine (oxTMB), the authors showed that TMB can be applied for the point‐of‐care testing of ·OH and glucose, and assessing the sterilization progress in vivo. More significantly, the facile photothermal signaling strategy can be extended to monitor various ROS‐mediated therapeutic systems, enabling accurate prediction of treatment outcomes.