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.
PhD students, postdoctoral fellows and lab technicians are being recruited for the new laboratories at Peking University and Chinese Institute For Brain Research.
Work in the unit will focus on understanding the functions and signaling mechanisms of neuronal growth factors and their receptors in neuronal function and connectivity, neurodegeneration and in metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolic disorders.
Candidates with expertise in cellular, molecular or structural biology, drug development, neurobiology, metabolism, adipose tissue and mouse genetics are encouraged to apply.
Applications, including CV, list of publications and statement of research interests should be sent by email to Prof. Carlos Ibanez: Applicants should arrange to have at least two confidential letters of reference sent independently by referees to this email address.
Starting in January 2020, new laboratories dedicated to studies of growth factor receptor signaling and physiology will be established at the McGovern Institute of the School of Life Sciences in Peking University, and the Chinese Institute for Brain Research in Beijing, China. The research activities of the PKU and CIBR labs will run in parallel to and complement with those ongoing at the laboratories in Karolinska Institute and National University of Singapore. The initial focus of the Beijing labs will be on studies of death receptor signaling in neurodegeneation, metabolic regulation by activin receptors, control of brain microvasculature integrity and function by neurotrophin receptors, and a drug discovery program targeted to these receptors. PhD students, postdoctoral fellows and lab technicians are being recruited for the new Beijing laboratories. For details and how to apply, visit the Open Positions page.