Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Significance: Adipose tissue dysfunction such as impaired insulin action in adipocytes is causally implicated in obesity-related metabolic disorders. However, molecular mechanisms underlying obesity-related adipocyte insulin resistance remain unclear. Here we identify a mechanism in the regulation of adipocyte insulin signaling by Fam13a, which is impaired in obesity. We revealed that Fam13a protects IRS1 from proteasomal degradation by recruiting PP2A and consequently accentuates adipocyte insulin signal cascade. We further demonstrated that genetic loss of Fam13a exacerbated obesity-related metabolic disorders, while targeted activation of Fam13a in adipocytes improved it by altering adipose tissue insulin sensitivity. Our data unveiled a previously unknown mechanism underlying obesity-related adipocyte insulin resistance through Fam13a, highlighting Fam13a as a vital player in the pathogenesis of obesity-related metabolic disorders.

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Unusual clinical course Chemotherapy based on 5-fluorouracil (5-FU) is a well-established treatment for solid cancers, including metastatic or advanced colon cancer. Despite its efficacy, 5-FU can cause rare but serious adverse events such as acute neurotoxicity, which presents as symptoms similar to stroke. We report the case of a patient who was diagnosed with stage IV colorectal cancer and who underwent chemotherapy with a high dose of 5-FU as part of the FOLFIRI (Folinic Acid, Fluorouracil, Irinotecan) treatment plan. During the seventh, eighth, and ninth cycles of chemotherapy, the patient suffered from severe encephalopathy, and the cause of this condition was determined to the 46-hour continuous intravenous infusion of 5-FU, which was part of the FOLFIRI regimen. 5-FU-induced hyperammonemic encephalopathy is a rare but serious adverse event that requires immediate recognition and treatment. The first step in managing this condition is to halt the 5-FU infusion and provide the patient with high volumes of fluid. Although most cases of 5-FU-induced encephalopathy resolve spontaneously, recurrence is possible if the drug is re-administered to the same patient. Therefore, it is crucial for healthcare providers to closely monitor patients receiving 5-FU chemotherapy and be aware of the signs and symptoms of hyperammonemic encephalopathy. Early intervention can prevent further complications and ensure the best possible outcome for the patient. It is important to note that while 5-FU-induced hyperammonemic encephalopathy is rare, it highlights the importance of closely monitoring patients receiving chemotherapy to identify and treat adverse events promptly. This can help improve patient outcomes and prevent serious long-term complications.