Lysine-Specific Demethylase 1 in Energy Metabolism: A Novel Target for Obesity

Abstract

Obesity develops from an imbalance of energy homeostasis and is associated with the development of metabolic disorders including insulin resistance and type 2 diabetes. Identification of the underlying molecular mechanisms and effective therapeutic approaches are highly needed. Lysine-specific demethylase 1 (LSD1), a FAD-dependent amine oxidase, is implicated in a wide variety of biological processes including tumorigenesis, stem cell fate decisions, and embryonic development. Recent studies suggested a vital role of LSD1 in regulating adaptive thermogenesis, mitochondrial biogenesis, glucose and lipid metabolism. More recently, LSD1 activity was found to be regulated by nutrients, energy status, and hormonal signals, suggesting that it may act as a novel sensor for nutritional regulation of metabolic health. Here, we firstly discuss the effects of LSD1 on physiological phenotypes, including body weight, fat mass, body temperature and glucose homeostasis. We also summarized recent understanding of the physiological roles and underlying mechanisms of LSD1 in controlling metabolic functions of adipose and other tissues. Hopefully, a better understanding of the roles of LSD1 in metabolic regulation may provide new perspectives for the nutritional prevention and treatment of obesity.

Prmt6 represses the pro-adipogenic Ppar-gamma–C/ebp-alpha transcription factor loop

“…There is an interplay between arginine methyl transferases and lysine demethylases. KDM1A promotes adipocyte differentiation through repressing Wnt signaling, which is important for osteogenic differentiation 37 . As PRMT6 and KDM1A interact 38 , 39 , it is conceivable that PRMT6 and KDM1A concomitantly regulate the branching between adipogenesis and osteogenesis.…”

Identification of gene regulatory networks affected across drug-resistant epilepsies

“…In addition, KDM1A increased oxidative stress and ferroptosis promoting renal ischemia and reperfusion injury through activation of TLR4/NOX4 pathway in mice 52 . However, while multiple studies showed KDM1A pro-oxidative stress effect, KDM1A beneficial anti-obesity effects, skeletal muscle regeneration, and the ability of acting as a metabolic sensor for nutritional regulation of metabolic health were reported 53 . Although our results were in line with the literature, exploring the complexity of KDM1A nature in a simplistic model, like the stimulated primary astrocytes in culture, limits the possibility of understanding the underlying molecular mechanisms of KDM1A.…”

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

“…Overexpressed LSD1 in cancer cells promotes glucose uptake and glycolytic activity and upregulates the expression of GLUT1 and glycolytic enzymes; however, it strongly downregulates the expression of mitochondrial metabolism-related genes ( Luo et al, 2021 ). Knockdown or pharmacological inhibition of LSD1 can activate the transcriptional activity of the gluconeogenesis genes FBP1 and G6Pase, resulting in increased de novo glucose synthesis and decreased intracellular glycogen content ( Wang D. et al, 2022 ). Inhibition of LSD1 activity in oesophageal cancer cells can significantly reduce the extracellular acidification rate (ECAR) and increase the oxygen consumption rate (OCR) and OCR/ECAR ratio ( Kosumi et al, 2016 ).…”

“…LSD1 may contribute to the malignant behaviour of oesophageal cancer by regulating metabolism, glycolytic pathway, and mitochondrial respiration. In addition, LSD1 plays an important role in regulating adaptive thermogenesis and lipid metabolism and may be a novel target for treating obesity ( Wang D. et al, 2022 ).…”