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.
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.
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.
ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown.
In this new paper, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine.
These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.
The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown.
In this study, we used spatiotemporally controlled Cre-mediated recombination in adult mice, and found that the glial cell–derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septo-habenular and habenulo-interpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb.
These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septo-habenulo-interpeduncular pathway and attuning of anxiety and fear behaviors.
Life- style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity.
In this study, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre- existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low- fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet- switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of β3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of β3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer- lasting benefits in obesity.
Yanchen Ma obtained a PhD in Cell Biology in December 2020, from the School of Life Science, Xiamen University, China, under the supervision of Prof. Ying Chen. The title of her PhD thesis is “A GPR17-cAMP-lactate signaling axis in oligodendrocytes regulates whole-body metabolism”. She is joining the neuroscience team to unravel novel mechanisms of p75ntr subcellular localization and signaling.
Pawanrat Tangseefa, a.k.a. Queenie, obtained a PhD in Medicine/Physiology in May 2020 from the University of Adelaide, Australia, under supervision of Prof. Andrew Zannettino. The title of her PhD thesis is “The role of osteoblasts-mTORC1 in the regulation of glucose metabolism”. She is joining the metabolism team to elucidate the mechanistic basis of the metabolic effects of mutations in the ACVR1C gene found in the human population.
Meng Xie took a PhD in 2014 at McGill University, Montréal, Canada. His doctoral thesis was on studies of the regulation of lipid metabolism in the dauer larvae of Caenorhabditis elegans. With a prestigious EMBO fellowship, he then undertook postdoctoral studies at Karolinska Institute in Stockholm, Sweden, under the guidance of A/Prof. Andrei Chagin. During his postdoc tenure, he worked on several projects, including studies on the mediation of phenotypic plasticity of body size and craniofacial shape by amino acid sensing, and evolution of long bone secondary ossification center and regulation of craniofacial cartilage during development. He has an impressive research output, with articles in Cell Metabolism, PNAS, Nature and eLife. Meng will conduct research at the new units at PKU and CIBR, and assist in training of students and lab management tasks.
Yunxi Zhang has a Bachelor in Veterinary Medicine from Beijing University Of Agriculture and several internships, including the Institute of Biophysics at the Chinese Academy Of Science. She joins the CIBR unit to take care of our mouse colonies including genotyping and colony management.