Lsd1 Ablation Triggers Metabolic Reprogramming of Brown Adipose Tissue

Abstract

SummaryPrevious work indicated that lysine-specific demethylase 1 (Lsd1) can positively regulate the oxidative and thermogenic capacities of white and beige adipocytes. Here we investigate the role of Lsd1 in brown adipose tissue (BAT) and find that BAT-selective Lsd1 ablation induces a shift from oxidative to glycolytic metabolism. This shift is associated with downregulation of BAT-specific and upregulation of white adipose tissue (WAT)-selective gene expression. This results in the accumulation of di- and triacylglycerides and culminates in a profound whitening of BAT in aged Lsd1-deficient mice. Further studies show that Lsd1 maintains BAT properties via a dual role. It activates BAT-selective gene expression in concert with the transcription factor Nrf1 and represses WAT-selective genes through recruitment of the CoREST complex. In conclusion, our data uncover Lsd1 as a key regulator of gene expression and metabolic function in BAT.

Mfn2 is critical for brown adipose tissue thermogenic function

“…Our results support the view that reduced BAT thermogenic function and oxidative capacity in adipose tissues can also be beneficial for overall insulin sensitivity in certain scenarios, such as those allowing for improved adipose tissue expandability. Our results are in line with recent evidence from mouse models for adipose‐specific impairments in fatty acid catabolism, either through the deletion of the adipose triglyceride lipase (ATGL) (Schoiswohl et al , 2015), the TCA cycle enzyme fumarate hydratase (Yang et al , 2016), or the epigenetic regulator lysine‐specific demethylase 1 (Lsd1) (Duteil et al , 2016), all of which displayed impaired thermogenesis yet prevention against diet‐induced insulin resistance. Nevertheless, there is a remarkable variability on how the genetic ablation of mitochondrial proteins specifically in adipose tissues influences diet‐induced metabolic damage (Vernochet et al , 2014; Lee et al , 2015), likely reflecting the different impacts of these genes on the multiple functions of adipose tissue mitochondria beyond thermogenesis.…”

Brown and Beige Adipose Tissues in Health and Disease

“…Cold exposure or β3 agonist stimulation increase LSD1 expression in iWAT (71). LSD1 appears to directly promote recruitments/activation of BAT and beige fat; in line with this notion, brown/beige adipocyte-specific deletion of LSD1 impairs both brown and beige adipogenesis, decreases energy expenditure, and increases adiposity in mice (72, 267), whereas global overexpression of LSD1 increases browning of WAT and protects LSD1 transgenic mice from HFD-induced obesity (71). Cold exposure stimulates PKA-mediated phosphorylation of Jmjd1a (also known as Jhdm2a or Kdm3a) and activates Jmjd1a (1).…”

GPS2 regulates mitochondria biogenesis via mitochondrial retrograde signaling and chromatin remodeling of nuclear-encoded mitochondrial genes

“…Our data indicate that in mammalian cells, demethylation is partially achieved, but not limited to the action of the histone demethylase JMJD2/KDM4A. Other demethylases that are known to play a role in the regulation of mitochondrial functions are likely to contribute (Duteil et al, 2016;Hino et al, 2012;Liu and Secombe, 2015;Merkwirth et al, 2016;Tian et al, 2016). In fact, the use of specific demethylases might be important for providing specificity to the regulation of different subsets of mitochondrial genes.…”