Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation

Abstract

Seipin deficiency causes severe congenital generalized lipodystrophy (CGL) and metabolic disease. However, how seipin regulates adipocyte development and function remains incompletely understood. We previously showed that seipin acts as a scaffold protein for AGPAT2, whose disruption also causes CGL. More recently, seipin has been reported to promote adipogenesis by directly inhibiting GPAT3, leading to the suggestion that GPAT inhibitors could offer novel treatments for CGL. Here we investigated the interactions between seipin, GPAT3 and AGPAT2. We reveal that seipin and GPAT3 associate via direct interaction and that seipin can simultaneously bind GPAT3 and AGPAT2. Inhibiting the expression of seipin, AGPAT2 or GPAT3 led to impaired induction of early markers of adipocyte differentiation in cultured cells. However, consistent with normal adipose mass in GPAT3null mice, GPAT3 inhibition did not prevent the formation of mature adipocytes. Nonetheless, loss of GPAT3 in seipin-deficient preadipocytes exacerbated the failure of adipogenesis in these cells. Thus, our data indicate that GPAT3 plays a modest positive role in adipogenesis and argue against the potential of GPAT inhibitors to rescue white adipose tissue mass in CGL2. Overall, our study reveals novel mechanistic insights regarding the molecular pathogenesis of severe lipodystrophy caused by mutations in either seipin or AGPAT2.

Bscl2 Deficiency Does Not Directly Impair the Innate Immune Response in a Murine Model of Generalized Lipodystrophy

“…Seipin is known to be a critical regulator of adipogenesis, as its loss prevents adipocyte differentiation in vitro [ 3 , 4 ] and adipose tissue development in vivo [ 5 , 6 , 7 , 8 ]. More recently, it has been revealed that seipin plays an important role as a scaffold protein, capable of binding numerous proteins that play critical functions in lipid droplet organization and triglyceride synthesis [ 9 , 10 , 11 , 12 ].…”

Seipin-Mediated Contacts as Gatekeepers of Lipid Flux at the Endoplasmic Reticulum–Lipid Droplet Nexus

“…In line with this, defective adipogenesis due to seipin-depletion was partially restored by GPAT inhibition (Pagac et al., 2016; Gao et al., 2020). However, in a recent study, GPAT3 deficiency failed to rescue adipogenesis in seipin-deficient differentiating adipocytes (Sim et al., 2020). Based on these findings, the significance of seipin-GPAT interaction remains to be determined, but increasing evidence suggests that seipin can act as a scaffold for lipogenic enzymes.…”

“…Seipin might control ER PL metabolism, especially that of PA, via protein–protein interactions of major lipid synthesizing enzymes, such as AGPAT2, lipin-1, and GPATs (Sim et al., 2012; Talukder et al., 2015; Pagac et al., 2016; Gao et al., 2019b; Sim et al., 2020). Indeed, GPAT activity was altered in a number of seipin depleted systems, suggesting that seipin negatively regulates GPAT activity to inhibit aberrant expansion of LDs (Pagac et al., 2016).…”

Seipin forms a flexible cage at lipid droplet formation sites

“…This model is supported by molecular simulation experiments utilizing the lumenal domain structures that detect TG molecules binding and accumulating at seipin’s central hydrophobic helices 17,18 . Other models for seipin function include generating or transferring specific lipids to forming LDs 23,24 , or promoting calcium transport 25,26…”

“…This model is supported by molecular simulation experiments utilizing the lumenal domain structures that detect TG molecules binding and accumulating at seipin's central hydrophobic helices 17,18 . Other models for seipin function include generating or transferring specific lipids to forming LDs 23,24 , or promoting calcium transport 25,26 Nonetheless, insights into how seipin and LDACs ensure the fidelity of LD formation have been lacking. One limitation for determining seipin and LDAC function is that structural information and analyses have been restricted so far to seipin's lumenal domain 15,16 .…”