Genomic loci mispositioning inTmem120aknockout mice yields latent lipodystrophy

Abstract

Little is known about the proteins that direct the highly conserved patterns of spatial genome organisation in fat. Here we report that adipocyte-specific knockout of the gene encoding nuclear envelope protein Tmem120a disrupts fat genome organisation, thus causing a novel lipodystrophy syndrome. Tmem120a deficiency broadly suppresses lipid metabolism pathway gene expression and induces myogenic gene expression by repositioning genes, enhancers and miRNA-encoding loci between the nuclear periphery and interior. Tmem120a-/- mice, particularly females, exhibit a lipodystrophy syndrome similar to human familial partial lipodystrophy FPLD2, with profound insulin resistance and metabolic defects that manifests upon exposure to an obesogenic diet. Interestingly, similar genome organisation defects occurred in cells from FPLD2 patients that harbour nuclear envelope protein laminA mutations. Our data suggest TMEM120A may mediate/instigate novel categories of adipose tissue dysfunction across the adiposity spectrum and provide a new miRNA-based mechanism possibly driving the unexplained muscle hypertrophy in human lipodystrophy.

PIEZO channels and newcomers in the mammalian mechanosensitive ion channel family

“…TACAN hosted a coenzyme A (CoA) molecule within each of its C-terminal TM domains, suggesting a functional role as a membrane-embedded enzyme in CoA transport and metabolism. In consonance with this, early functional experiments suggested a role of TMEM120A in regulating fat tissue differentiation (Batrakou et al, 2015), whereas recent knocking down experiments pointed out a role in insulin resistance and metabolic defects in high-fat diet mice (Czapiewski et al, 2022). Recent data also point out a role for TMEM120A as a key activator of the antiviral signaling of STING (Li et al, 2022).…”

Cryo-EM structures of human TMEM120A and TMEM120B

“…TMEM120A/B were originally identified as a nuclear membrane localized protein that plays an important role in adipocyte differentiation 3,4 . A recent study shows that adipocyte-specific knockout of TMEM120A leads to latent lipodystrophy 5 . The molecular basis underlying the physiological functions of TMEM120A is elusive.…”

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

“…Instead, structural and biochemical analyses indicate that TMEM120A forms a symmetrical homodimer and each protomer binds specifically to a coenzyme-A (CoASH) molecule (Niu et al, 2021;Rong et al, 2021;Xue et al, 2021). These observations led to the proposal that TMEM120A has an undefined role in lipid metabolism, which correlates with its requirement for adipogenesis (Batrakou et al, 2015;Czapiewski et al, 2021).…”