The proinflammatory adipokine lipocalin-2 is upregulated in obese individuals and is thought to drive renal injuries; however, the source of lipocalin-2 during kidney dysfunction is not fully understood. In this episode, Wai Yan Sun, Bo Bai, and colleagues used multiple murine models of chronic and acute kidney injury to evaluate the role of lipocalin-2. Adipose-tissue-specific deletion, but not whole-body or kidney-specific deletion, of lipocalin-2 protected mice from aldosterone- and high salt after uninephrectomy-induced kidney damage. Moreover, transplantation of WT fat pads into animals with lipocalin-2 deficient adipose tissue restored sensitivity to renal damage, and mice chronically exposed to a stable variant of human lipocalin-2 developed renal injury. Together, these results identify adipose-generated lipocalin-2 as a driver of acute and chronic kidney dysfunction.
Adult polyglucosan body disease (APBD) is a glycogen storage disorder characterized by the accumulation of polyglucosan bodies in muscle, nerve, and other tissue as the result of mutations in glycogen branching enzyme 1 (GBE1). APBD is characterized by adult-onset neurodegeneration, and recent evidence suggests that reduction of glucose 6-phosphate–stimulated glycogen synthase (GYS) activity may be beneficial. In this episode, Or Kakhlon and colleagues screened FDA-approved compounds for those able to reduce GYS activity and polyglucosan accumulation in APBD fibroblasts. Guaiacol emerged as a potential candidate from this screen and improved grip strength and increased lifespan in murine APBD models. These improvements corresponded with reduced polyglucosans in peripheral nerves, liver and heart. Together, these results support further exploration of guaiacol for treating APBD.
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive pulmonary fibrosis and eventual loss of function. The transcription factor Wilms’ tumor 1 (WT1) promotes cell proliferation and is critical for lung development. This factor has been shown to be upregulated in IPF; however, the role of WT1 in IPF development is not fully understood. In this episode, Satish Madala and colleagues used lineage tracing to show that WT1 promotes fibroblast activation, fibroproliferation, myofibroblast transformation, and ECM production in a murine model of IPF. Moreover, partial loss of WT1 reduced fibrotic phenotypes. Together, these results identify WT1 as an important driver of lung fibrosis and support further exploration of WT1 as a therapeutic target.
White adipose tissue (WAT) serves primarily as energy storage; however, in response to cold or β-adrenergic agonists, WAT develops characteristics of brown adipose tissue (BAT), which expends energy in the form of heat. WAT beiging has proposed as potential strategy for treating obesity. In this episode, Philip Kern and colleagues exposed lean and obese subjects to cold or treatment with the β3 agonist mirabegron and evaluated markers of adipose beiging. Both treatments induced beiging, regardless of obesity status or age. The results of this study support further evaluation of the long-term effects of induced adipose beiging for treatment of obesity and associated metabolic dysfunction.
Spontaneous mutations in the gene encoding the tumor suppressor p53 (TP53) are frequently identified in human cancers and most of these mutations are the result of missense substitutions, which can result in complete loss of p53 function or retention of some activity. In this episode, Jean Gariépy and Nicholas Fischer discuss their work, which reveals that the level of residual transcriptional activity of mutant p53 associates with improved survival in males with glioma and gastric adenocarcinoma. This association was sex-specific, as similar links were not observed in females with p53-mutant cancers. Moreover, evaluation of patients with Li-Fraumeni syndrome (LFS), which results from germline mutations in TP53 revealed a link between residual p53 activity and prolong lifetime cancer survival. Together, these results support p53 transcriptional activity as a prognostic factor for men with glioma and gastric adenocarcinoma.