Adrenergic stimulation of brown adipocytes alters mitochondrial dynamics, including the mitochondrial fusion protein optic atrophy 1 (OPA1). However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response, by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, that is activated independently of BAT thermogenic function.
Study Type – Aetiology (case series) Level of Evidence 4
OBJECTIVE
To present the molecular rationale and potential clinical benefit of topoisomerase II (TopoII)‐inhibiting therapy for renal medullary carcinoma (RMC), a rare but extremely lethal form of kidney cancer that classically afflicts young men with sickle‐cell trait. The current therapeutic approach with these aggressive tumours is radical nephrectomy followed by systemic chemotherapy, but the prognosis remains dismal.
MATERIALS AND METHODS
The whole‐genome expression was analysed in four RMC tumours. We also report a case of metastatic RMC in which a complete response was achieved for 9 months using a TopoII‐inhibiting therapy.
RESULTS
Expanded whole‐genome expression analysis showed increases of TopoII in all cases. There was also overall deregulation of DNA remodelling and repair, and an ontological association between RMC and urothelial carcinoma. Using a TopoII‐inhibiting agent, there was a complete response for 9 months in a patient with metastatic RMC.
CONCLUSION
This report provides molecular evidence for the rational use of TopoII inhibitors in the treatment of RMC.
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