A new breakthrough study by researchers From Okinawa Institute of Science and Technology (OIST) Graduate University-Japan and the Institute of Medical Science at the University of Tokyo-Japan have identified a brain protein that plays a key in how the brain regulates appetite and metabolism.
Obesity is an increasingly serious global health issue and it is associated with many metabolic disorders, such as type 2 diabetes and cardiovascular disease. Therefore, understanding the molecular pathology of obesity is critical.
Whole-body energy metabolism is controlled by communication between the central nervous system and peripheral metabolic tissues, including adipose tissue, liver, pancreas, and skeletal muscle (Myers and Olson, 2012). The hypothalamus integrates inputs from various peripheral tissues and regulates feeding and energy expenditure (Timper and Brüning, 2017).
The importance of post-transcriptional regulation, including mRNA degradation, for proper gene expression is increasingly appreciated, because changes in mRNA decay affect transcript levels and subsequent protein abundance (Chen and Shyu, 2011; Garneau et al., 2007).
Moreover, alterations of mRNA stability have been reported in cancer, neurodegenerative disease, diabetes, and obesity (Audic and Hartley, 2004; Linder et al., 2015; Mang et al., 2015). Eukaryotic mRNAs have two characteristic structures, a 7-methyl guanosine cap (m7G cap) at the 5′ end and a poly(A) tail at the 3′ end, which provide effective protection against exoribonucleases and contribute to mRNA stability (Chen and Shyu, 2011; Garneau et al., 2007).
In normal mRNA degradation, the first step is shortening of the 3′ poly(A) tail, a process called deadenylation, regulated by the CCR4-NOT complex and PAN2-PAN3 (Chen and Shyu, 2011; Garneau et al., 2007). After deadenylation, the m7G cap structure is removed from the deadenylated mRNA by the DCP1-DCP2 decapping complex.
These mRNA degradation factors serve multiple functions in gene expression and are responsible for various physiological processes. Not surprisingly, deletion of mRNA degradation machinery leads to various physiological defects in animal models.
For example, mutations in CCR4-NOT subunits in mouse cause defects in energy metabolism, adipocyte and heart function, and maturation of the liver and pancreatic β-cells (Morita et al., 2011; Mostafa et al., 2020; Suzuki et al., 2019; Takahashi et al., 2015, Takahashi et al., 2019, Takahashi et al., 2020; Yamaguchi et al., 2018).
Compared to the well-investigated CCR4-NOT deadenylation complex, physiological studies of 5′–3′ exonucleases in vertebrates are few. In yeast, disruption of the 5′-to-3′ exoribonuclease, Xrn1, causes severe growth defects (Larimer and Stevens, 1990). siRNA-mediated knockdown of Xrn1 in C. elegans causes embryonic lethality due to failure of ventral epithelial enclosure during embryogenesis (Newbury and Woollard, 2004).
Interestingly, hypomorphic mutations in Pacman, the Drosophila homolog of Xrn1, also cause defects in dorsal/thorax closure and epithelial sheet sealing that participates in ventral epithelial enclosure in C. elegans (Grima et al., 2008; Jones et al., 2012).
Pacman is required for both male and female fertility in Drosophila, as mutations cause defects in spermatogenesis and oogenesis (Lin et al., 2008; Zabolotskaya et al., 2008).
In this study, we established a knockout mouse model to investigate the physiological function of XRN1. We provide evidence that a lack of XRN1 in neurons leads to obesity accompanied by leptin resistance, hyperglycemia, hyperinsulinemia, hyperleptinemia, hyperphagia, and decreased energy expenditure in mice. XRN1 depletion leads to aberrant expression of hypothalamic genes associated with regulation of appetite and energy homeostasis.
Our study demonstrates that XRN1 in the brain is required for maintenance of whole-body energy homeostasis.
reference link: https://www.cell.com/iscience/fulltext/S2589-0042(21)01119-6