Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity‐Related Properties

Abstract

The trimethylation on histone H3 lysine 27 (H3k27me3), a transcriptionally repressive epigenetic mark of permissive chromatin, can be removed by the histone lysine demethylase 6a (Kdm6a). However, the physiological function of H3k27me3 and Kdm6a on circadian genes remains largely elusive. With the ChIP-Seq and mRNA microarray assays, a critical role is identified for Kdm6a in the regulation of H3k27me3 to impact the expression of Crytochrome 1 (Cry1) in the hypothalamus of diet induced obesity mice. More importantly, both conditional knockout and pharmacological inhibition of Kdm6a reduce body weight and stabilize blood glucose homeostasis. Although a Kdm6a inhibitor fails to decrease body weight in leptin receptor-deficient db/db mice, it significantly decreases Cry1 expression, enhances sensitivity to exogenous leptin administration, and blocks body weight increases in endo-leptindeficient ob/ob mice. Moreover, gene analysis of the human hypothalamus further reveals a positive correlation between Kdm6a and Cry1. The results show that inhibition of Kdm6a reduces the Cry1 expression and sensitizes leptin signaling to combat obesity-related disease. Therefore, it implicates Kdm6a as an attractive drug target for obesity and metabolic disorders.

The cross-talk between leptin and circadian rhythm signaling proteins in physiological processes: a systematic review

“…Also, there were reduced insulin levels of plasma, improved glucose metabolism, and reduced body weight and fat mass. Thus, the kdm6a inhibitor and low doses of leptin increased leptin sensitivity while each one of them failed to do so separately [27].…”

“…Thus, the link between the circadian clock system and metabolism seems to be essential in a vast variety of cellular and body biology, and different intrinsic and/or environmental factors can affect circadian rhythm proteins and leptin such as sleep quality and quantity, or steroid hormones like glucocorticoids. The crosstalk between leptin and circadian rhythm proteins has been studied in different organs and conditions [1,4,5,9,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Nevertheless, there is not any systematic review to evaluate the effect of these two on each other.…”

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

“…It can reduce obesity-related properties in diet-induced obesity mice via the sensitised leptin signaling. 512 …”

Epigenetics and Beyond: Targeting Histone Methylation to Treat Type 2 Diabetes Mellitus

“…H3K27 methylation is associated with transcription repression, whereas H3K79 is correlated with transcriptional activation ( Lin et al, 2010 ). The correlation of H3K37me3 in metabolic disorders has been identified ( Wei et al, 2021 ). H3K27me3 can be removed by KDM6.…”

“…Pharmacological inhibition of KDM6 members with GSK-J4 relieved the progression of nephropathy in diabetic db/db mice ( Figure 5 ) ( Chen et al, 2021 ). Inhibition of KDM6A reduces Cry1 expression and sensitizes leptin signaling to combat obesity‐related diseases ( Wei et al, 2021 ). Therefore, GSK-J4, a KDM6A inhibitor, could serve as an attractive drug for obesity and metabolic disorders.…”