Good news!
"Scientists have made a major breakthrough in understanding how fat cells grow in size, in response to accommodating larger droplets of fat. The findings unlock a new path in tackling obesity, by reducing the amount of fat our cells can store away. ...
Earlier ... research had identified a protein known as seipin that was critical for healthy lipid storage across organisms, including humans. But how seipin was facilitating this remained unknown, and despite some studies naming another protein – adipogenin – in the process, scientists didn't know how it was involved.
Using cryo-electron microscopy, the researchers found that adipogenin was more than a bystander in the process, reinforcing seipin's structural integrity to enhance its ability to form and deliver lipid droplets to cells. The result is adipocytes accommodating larger lipid droplets – and increasing the size of these fat cells. ..."
From the abstract of the Perspective:
"Obesity is characterized by the accumulation of triacylglycerols in lipid droplets of adipocytes (fat cells) and the expansion of adipose tissue. Adipocytes arise from stem cells through adipogenesis, a process driven by several transcription factors ... Li et al. (3) identify adipogenin as a molecular switch that shifts the emphasis from generating new lipid droplets to expanding existing ones during adipogenesis."
From the editor's summary and abstract:
"Editor’s summary
Fat storage in the body relies on specialized structures called lipid droplets (LDs). Li et al. identified the microprotein adipogenin as a regulator of adipocyte LD size ... Adipogenin interacts with the membrane protein seipin and stabilizes the assembly of seipin dodecamers by bridging adjacent subunits. Functionally, seipin-adipogenin complexes promote the formation of fewer but larger LDs. In mice, adipocyte-specific adipogenin overexpression results in increased fat mass and larger LDs, whereas adipogenin deletion reduces fat accumulation and LD size, particularly in brown adipose tissue. Thus, adipogenin represents a modulator of adipocyte lipid storage that acts through a structural and functional partnership with seipin. ...
Abstract
INTRODUCTION
Adipogenin (Adig) is an 80–amino acid microprotein that is highly expressed in adipose tissues and steatotic liver. A previous genome-wide association study suggested that human ADIG is associated with blood leptin levels, highlighting its importance in energy metabolism. At the molecular level, Adig’s function is largely unknown: No interacting proteins have been identified. ...
RATIONALE
Microproteins typically exert their functions by binding to larger proteins and regulating their activities. We pulled down Adig from adipocytes and identified its interacting proteins by mass spectrometry. Upon the identification of a seipin-Adig complex, we resolved its structure using cryo–electron microscopy (cryo-EM), enabling us to determine Adig’s effect on seipin configuration at an atomic scale. Because seipin plays a vital role in lipid droplet (LD) formation and growth, we explored the function of the seipin-Adig complex in these processes. Moreover, we generated adipocyte-specific Adig overexpression and deletion mice to investigate Adig’s effect on adipose tissue expansion and lipid metabolism in vivo.
RESULTS
We found that Adig is a highly conserved protein with a single transmembrane (TM) segment that localizes to the endoplasmic reticulum (ER). Notably, Adig and seipin can form a complex and stabilize each other.
Cryo-EM analysis revealed two distinct oligomers: an undecameric seipin-alone complex at ~3.2-Å overall resolution and a dodecameric seipin-Adig complex at ~3.0-Å overall resolution.
In the seipin-Adig complex map, extra densities, corresponding to seipin and Adig TM domains, were observed. Multiple approaches, including high-resolution imaging, gel filtration, and molecular dynamics simulations, revealed that Adig could facilitate the assembly of dodecameric seipin complexes. Seipin complexes with varying Adig contents modulated LD formation and growth. The presence of the seipin-Adig complex altered triacylglycerol (TAG) flux in the ER, leading to the formation of fewer, but larger, LDs.
Additionally, the ER-to-LD trafficking of select lipid-synthesizing enzymes was accelerated in Adig-expressing cells.
In mice, Adig overexpression in adipocytes promoted LD enlargement and adipose tissue expansion, whereas Adig deletion decreased the amount of the seipin complexes in adipocytes and impaired TAG accumulation in brown adipose tissues.
CONCLUSION
In this study, we demonstrate that Adig complexes with seipin, forming a previously unrecognized dodecameric seipin complex. Furthermore, Adig stabilizes and promotes the assembly of this complex, thereby supporting LD growth in cells. In mice, modulating the expression of seipin-Adig complexes in adipose tissues by Adig overexpression or deletion substantially affects LD formation and expansion as well as lipid absorption by adipose tissues. This study reveals Adig as a key cofactor that modulates seipin function and fat storage in adipose tissue. We conclude that the oligomerization and function of seipin complexes can be modulated by Adig expression."
Seipin-adipogenin controls lipid storage in fat cells (Perspective, no public access) "A protein complex promotes the expansion of lipid droplets during the formation of mature adipocytes"
Microprotein plays vital role in fat accumulation (original news release) "Findings from UTSW researchers, colleagues could lead to new treatments to improve metabolic health and reduce risks of obesity, diabetes"
Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex (no public access)
Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex (preprint, open access, but seems to be dated and does not match the journal article)
Seipin-Adig complex promotes the development of lipid droplets.
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