Diabetes mellitus (DM) is a severe chronic disease that results in high morbidity and mortality. DM causes endothelial injury (DEI) as a basis for cardiovascular complications of DM with few effective approaches developed for its intervention. Krill oil (KO) possesses anti-inflammatory and anti-oxidative activities, but its effect on DEI is unknown. Hence, the aims of this study were to investigate the effect and molecular mechanism of KO on DEI. To investigated the preventive effect of KO on DEI, streptozotocin and high-fat diet-induced type 2 diabetic mice were fed with KO for 6 months. RNA sequencing for endothelial cells (ECs) was used to explore the mechanism of KO’s protective function. To clarify the role of nuclear factor erythroid 2-related factor 2 (Nfe2l2 or NRF2) signaling in KO’s protection against DEI, Nfe2l2 gene-silenced ECs or knockout mice were treated with KO. Molecular docking assay and surface plasmon resonance assay were carried out to reveal binding between Kelch like ECH associated protein 1 (KEAP1) and major components of KO. KO significantly alleviated DEI and aortic pathological injury in the wild-type diabetic mice. RNA sequencing revealed that KO dramatically activated NRF2 antioxidant signaling in high glucose-challenged ECs, the effect of which was further confirmed in the diabetic aortas. Nfe2l2 gene deletion or silencing completely abolished KO’s protection against DEI in vivo and in vitro, demonstrating that NRF2 was required for KO’s action. Further, molecular docking assay and surface plasmon resonance assay identified that KO’s functional component astaxanthin (AST), but not docosahexaenoic acid and eicosapentaenoic acid, was able to bind the Kelch domain of KEAP1, promoting nuclear translocation of NRF2 which activated antioxidant gene expression. The comparison of the effects of KO and AST on endothelial NRF2 nuclear translocation suggested that KO might activate NRF2 at least partially through AST-KEAP1 interaction. KO activates NRF2 to prevent diabetic endothelial injury in part through AST-induced inhibition of KEAP1.

Obesity is associated with skeletal muscle mass loss and physical dysfunction. Krill oil (KO) has been shown to be beneficial in human health. However, the effect of KO on obesity-induced skeletal muscle atrophy is still unclear. In this study, the male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, and then were intragastric administration with 400 mg/kg bw KO for an additional 6 weeks. The results showed that KO treatment reduced body weight, fat accumulation and serum pro-inflammatory cytokines in HFD-induced obese mice. Importantly, KO treatment attenuated skeletal muscle atrophy in HFD-fed mice, as evidenced by preserving skeletal muscle mass, average myofiber cross-sectional area and grip strength. KO administration also mitigated obesity-induced ectopic lipid deposition and inflammatory response in skeletal muscle. Additionally, KO treatment inhibited the transcriptional activities of nuclear factor-κB (NF-κB ) p65 and forkhead box O 3a (FoxO3a), and then down-regulated muscle atrophy F-box (MAFbx) and muscle-specific RING finger protein 1 (MuRF1) protein levels in skeletal muscle from HFD-fed mice. KO administration also improved obesity-induced impaired muscle protein synthesis via activating PI3K/Akt pathway. Furthermore, KO treatment enhanced muscle mitochondrial biogenesis in HFD-induced obese mice via activating PGC-1α pathway. Collectively, KO might be developed as a potential nutritional supplement for the prevention and treatment of obesity-induced skeletal muscle atrophy.

With the prevalence of obesity and obesity-related metabolic syndrome, such as insulin resistance in recent years, it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome. Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources, mainly derived from marine products. Palmitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation. However, it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance. Here, we investigated the effects of palmitoleic acid on chow diet (CD)-fed and high-fat diet (HFD)-fed mice, which were fed CD or HFD for 12 weeks before administration. We administrated mice with BSA (control), oleic acid, or palmitoleic acid for 6 weeks on top of CD or HFD feeding. We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR. Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population. In colon, palmitoleic acid increased intestinal tight junction integrity and reduced inflammation. Moreover, palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue. Diacylglycerol (DAG) in tissue (for example, liver) is found to positively correlated with HOMA-IR. HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study. Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver. Therefore, in HFD-fed mice, palmitoleic acid reduced insulin resistance by an independent-manner of DAGs. It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition, improving of intestinal barrier function, and downregulating the inflammation in colon, liver, and adipose tissue.