Carlos Ibanez Lab @ PKU & CIBR
McGovern Institute at Peking University & Chinese Institute for Brain Research
Together these results uncover a relation between sphingomyelin abundance and fine-tuning of UCP1-mediated non-shivering thermogenesis, and pave the way for studies of Peri Renal Adipose Tissue physiology and mechanisms controlling the plasticity of brown/white adipocyte phenotypes.
The papers have been published in The Journal Of Lipid Research and eLife
Sphingomyelin Is Involved in Regulating UCP1-Mediated Non-Shivering Thermogenesis
Detian Hu, Houyu Zhang, Zhen Liu, Carlos F Ibáñez, Cai Tie, Meng Xie
Journal of Lipid Research (2024) 10.1016/j.jlr.2024.100559
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Perirenal adipose tissue contains a subpopulation of cold-inducible adipocytes derived from brown-to-white conversion
Houyu Zhang, Yan Li, Carlos F Ibáñez, Meng Xie
eLife (2024) 10.7554/elife.93151.3
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Genome-wide studies have identified three missense variants in the human gene ACVR1C, encoding the TGF-β superfamily receptor ALK7, that correlate with altered waist-to-hip ratio adjusted for body mass index (WHR/BMI), a measure of body fat distribution.
In our latest paper, to move from correlation to causation and understand the effects of these variants on fat accumulation and adipose tissue function, we introduced each of the variants in the mouse Acvr1c locus and investigated metabolic phenotypes in comparison with a null mutation.
Mice carrying the I195T variant showed resistance to high fat diet (HFD)-induced obesity, increased catecholamine-induced adipose tissue lipolysis and impaired ALK7 signaling, phenocopying the null mutants. Mice with the I482V variant displayed an intermediate phenotype, with partial resistance to HFD-induced obesity, reduction in subcutaneous, but not visceral, fat mass, decreased systemic lipolysis and reduced ALK7 signaling. Surprisingly, mice carrying the N150H variant were metabolically indistinguishable from wild type under HFD, although ALK7 signaling was reduced at low ligand concentrations.
Together, these results validate ALK7 as an attractive drug target in human obesity and suggest a lower threshold for ALK7 function in humans compared to mice.
The paper has been published in Molecular Metabolism
Read the full paper HERE
Human ACVR1C missense variants that correlate with altered body fat distribution produce metabolic alterations of graded severity in knock-in mutant mice
Pawanrat Tangseefa , Hong Jin, Houyu Zhang, Meng Xie & Carlos F. Ibáñez
Molecular Metabolism (2024) 10.1016/j.molmet.2024.101890
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PhD student
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RhoGDI phosphorylation by PKC promotes its interaction with death receptor p75 NTR to gate axon growth and neuron survival
Ajeena Ramanujan , Zhen Li, Yanchen Ma, Zhi Lin & Carlos F. Ibáñez (2024)
EMBO Reports doi.org/10.1038/s44319-024-00064-2
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How receptors juggle their interactions with multiple downstream effectors remains poorly understood.
In our latest paper, we report that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation.
These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways.
The paper has been published in EMBO Reports
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Postdoc
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Adipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the role of ALK4, the canonical pan-activin receptor, in adipose tissue is unknown.
In our latest paper, we report that, unlike ALK7, ALK4 is preferentially expressed in adipocyte precursors, where it suppresses differentiation, allowing proliferation and adipose tissue expansion. ALK4 expression in adipose tissue increases upon nutrient overload and positively correlates with fat depot mass and body weight, suggesting a role in adipose tissue hyperplasia during obesity. Mechanistically, ALK4 signaling suppresses expression of CEBPα and PPARγ, two master regulators of adipocyte differentiation. Conversely, ALK4 deletion enhances CEBPα/PPARγ expression and induces premature adipocyte differentiation, which can be rescued by CEBPα knockdown.
These results clarify the function of ALK4 in adipose tissue and highlight the contrasting roles of the two activin receptors in the regulation of adipocyte hyperplasia and hypertrophy during obesity.
The paper has been published in The Journal Of Biological Chemistry
Read the full paper HERE