Acid-sensing ion channel 3 mediates pain hypersensitivity associated with high-fat diet consumption in mice.

ABSTRACT: Lipid-rich diet is the major cause of obesity, affecting 13% of the worldwide adult population. Obesity is a major risk factor for metabolic syndrome that includes hyperlipidemia and diabetes mellitus. The early phases of metabolic syndrome are often associated with hyperexcitability of peripheral small diameter sensory fibers and painful diabetic neuropathy. Here, we investigated the effect of high-fat diet-induced obesity on the activity of dorsal root ganglion (DRG) sensory neurons and pain perception. We deciphered the underlying cellular mechanisms involving the acid-sensing ion channel 3 (ASIC3). We show that mice made obese through consuming high-fat diet developed the metabolic syndrome and prediabetes that was associated with heat pain hypersensitivity, whereas mechanical sensitivity was not affected. Concurrently, the slow conducting C fibers in the skin of obese mice showed increased activity on heating, whereas their mechanosensitivity was not altered. Although ASIC3 knockout mice fed with high-fat diet became obese, and showed signs of metabolic syndrome and prediabetes, genetic deletion, and in vivo pharmacological inhibition of ASIC3, protected mice from obesity-induced thermal hypersensitivity. We then deciphered the mechanisms involved in the heat hypersensitivity of mice and found that serum from high-fat diet-fed mice was enriched in lysophosphatidylcholine (LPC16:0, LPC18:0, and LPC18:1). These enriched lipid species directly increased the activity of DRG neurons through activating the lipid sensitive ASIC3 channel. Our results identify ASIC3 channel in DRG neurons and circulating lipid species as a mechanism contributing to the hyperexcitability of nociceptive neurons that can cause pain associated with lipid-rich diet consumption and obesity.

Lipid exchange at ER-trans-Golgi contact sites governs polarized cargo sorting.

Oxysterol binding protein (OSBP) extracts cholesterol from the ER to deliver it to the TGN via counter exchange and subsequent hydrolysis of the phosphoinositide PI(4)P. Here, we show that this pathway is essential in polarized epithelial cells where it contributes not only to the proper subcellular distribution of cholesterol but also to the trans-Golgi sorting and trafficking of numerous plasma membrane cargo proteins with apical or basolateral localization. Reducing the expression of OSBP, blocking its activity, or inhibiting a PI4Kinase that fuels OSBP with PI(4)P abolishes the epithelial phenotype. Waves of cargo enrichment in the TGN in phase with OSBP and PI(4)P dynamics suggest that OSBP promotes the formation of lipid gradients along the TGN, which helps cargo sorting. During their transient passage through the trans-Golgi, polarized plasma membrane proteins get close to OSBP but fail to be sorted when OSBP is silenced. Thus, OSBP lipid exchange activity is decisive for polarized cargo sorting and distribution in epithelial cells.

Oxidative Phosphorylation Fueled by Fatty Acid Oxidation Sensitizes Leukemic Stem Cells to Cold.

Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSC) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells. Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyses showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C. SIGNIFICANCE: Mitochondrial metabolism fueled by FAO alters the membrane composition and introduces membrane fragility upon cold exposure in OxPhos-driven AML and in LSCs. See related commentary by Jones, p. 2441.

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites.

Membrane contact sites (MCSs) are heterogeneous in shape, composition, and dynamics. Despite this diversity, VAP proteins act as receptors for multiple FFAT motif-containing proteins and drive the formation of most MCSs that involve the endoplasmic reticulum (ER). Although the VAP-FFAT interaction is well characterized, no model explains how VAP adapts to its partners in various MCSs. We report that VAP-A localization to different MCSs depends on its intrinsically disordered regions (IDRs) in human cells. VAP-A interaction with PTPIP51 and VPS13A at ER-mitochondria MCS conditions mitochondria fusion by promoting lipid transfer and cardiolipin buildup. VAP-A also enables lipid exchange at ER-Golgi MCS by interacting with oxysterol-binding protein (OSBP) and CERT. However, removing IDRs from VAP-A restricts its distribution and function to ER-mitochondria MCS. Our data suggest that IDRs do not modulate VAP-A preference toward specific partners but do adjust their geometry to MCS organization and lifetime constraints. Thus, IDR-mediated VAP-A conformational flexibility ensures membrane tethering plasticity and efficiency.

Combining affinity purification and mass spectrometry to define the network of the nuclear proteins interacting with the N-terminal region of FMRP.

Fragile X-Syndrome (FXS) represents the most common inherited form of intellectual disability and the leading monogenic cause of Autism Spectrum Disorders. In most cases, this disease results from the absence of expression of the protein FMRP encoded by the FMR1 gene (Fragile X messenger ribonucleoprotein 1). FMRP is mainly defined as a cytoplasmic RNA-binding protein regulating the local translation of thousands of target mRNAs. Interestingly, FMRP is also able to shuttle between the nucleus and the cytoplasm. However, to date, its roles in the nucleus of mammalian neurons are just emerging. To broaden our insight into the contribution of nuclear FMRP in mammalian neuronal physiology, we identified here a nuclear interactome of the protein by combining subcellular fractionation of rat forebrains with pull- down affinity purification and mass spectrometry analysis. By this approach, we listed 55 candidate nuclear partners. This interactome includes known nuclear FMRP-binding proteins as Adar or Rbm14 as well as several novel candidates, notably Ddx41, Poldip3, or Hnrnpa3 that we further validated by target-specific approaches. Through our approach, we identified factors involved in different steps of mRNA biogenesis, as transcription, splicing, editing or nuclear export, revealing a potential central regulatory function of FMRP in the biogenesis of its target mRNAs. Therefore, our work considerably enlarges the nuclear proteins interaction network of FMRP in mammalian neurons and lays the basis for exciting future mechanistic studies deepening the roles of nuclear FMRP in neuronal physiology and the etiology of the FXS.

Tumor protein D54 binds intracellular nanovesicles via an extended amphipathic region.

Tumor protein D54 (TPD54) is an abundant cytosolic protein that belongs to the TPD52 family, a family of four proteins (TPD52, 53, 54, and 55) that are overexpressed in several cancer cells. Even though the functions of these proteins remain elusive, recent investigations indicate that TPD54 binds to very small cytosolic vesicles with a diameter of ca. 30 nm, half the size of classical (e.g., COPI and COPII) transport vesicles. Here, we investigated the mechanism of intracellular nanovesicle capture by TPD54. Bioinformatical analysis suggests that TPD54 contains a small coiled-coil followed by four amphipathic helices (AH1-4), which could fold upon binding to lipid membranes. Limited proteolysis, CD spectroscopy, tryptophan fluorescence, and cysteine mutagenesis coupled to covalent binding of a membrane-sensitive probe showed that binding of TPD54 to small liposomes is accompanied by large structural changes in the amphipathic helix region. Furthermore, site-directed mutagenesis indicated that AH2 and AH3 have a predominant role in TPD54 binding to membranes both in cells and using model liposomes. We found that AH3 has the physicochemical features of an amphipathic lipid packing sensor (ALPS) motif, which, in other proteins, enables membrane binding in a curvature-dependent manner. Accordingly, we observed that binding of TPD54 to liposomes is very sensitive to membrane curvature and lipid unsaturation. We conclude that TPD54 recognizes nanovesicles through a combination of ALPS-dependent and ALPS-independent mechanisms.

Proteomics datasets of developing rat brain: Synaptic proteome and SUMO2/3-ylome.

During brain development, synapses undergo structural rearrangements and functional changes mediated by many molecular processes including post-translational modifications by the Small Ubiquitin-like MOdifier (SUMO). To get an overview of the endogenous SUMO-modified proteins in the developing rat brain synapses, our first aim was to characterize the synaptic proteome from rat at 14 postnatal days (PND14), a period that combines intense synaptogenesis, neurotransmission and high levels of SUMO2/3-ylation. In this purpose, we isolated the synaptosomal fraction by differential centrifugation on sucrose percoll gradient and characterized the synaptosomal proteome by nanoLC-MS/MS. Our second aim was to provide a comprehensive list of the SUMO2/3-modified protein in this compartment. We thus performed an enrichment in SUMO2/3-ylated proteins from the synaptosomal fraction by denaturing immunoprecipitation using specific anti-SUMO2/3 antibodies prior to proteomics analysis. The information presented in this article complement the publication "Proteomic Identification of an Endogenous Synaptic SUMOylome in the Developing Rat Brain" [1], by focusing on the characterization of the synaptic proteome of PND14 rat brain. Altogether, these data can inform future experiments focused on studying the functional consequences of synaptic SUMOylation regarding synapses structure and function. In addition, they can provide the basis for future mechanistic studies investigating brain pathologies involving altered SUMOylation levels.

CLEC12B Decreases Melanoma Proliferation by Repressing Signal Transducer and Activator of Transcription 3.

The potential role of CLEC12B, a gene predominantly expressed by skin melanocytes discovered through transcriptomic analysis, in melanoma is unknown. In this study, we show that CLEC12B expression is lower in melanoma and melanoma metastases than in melanocytes and benign melanocytic lesions and that its decrease correlates with poor prognosis. We further show that CLEC12B recruits SHP2 phosphatase through its immunoreceptor tyrosine-based inhibition motif domain, inactivates signal transducer and activator of transcription 1/3/5, increases p53/p21/p27 expression/activity, and modulates melanoma cell proliferation. The growth of human melanoma cells overexpressing CLEC12B in nude mice after subcutaneous injection is significantly decreased compared with that in the vehicle control group and is associated with decreased signal transducer and activator of transcription 3 phosphorylation and increased p53 levels in the tumors. Reducing the level of CLEC12B had the opposite effect. We show that CLEC12B represses the activation of the signal transducer and activator of transcription pathway and negatively regulates the cell cycle, providing a proliferative asset to melanoma cells.

DHA-containing phospholipids control membrane fusion and transcellular tunnel dynamics.

Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (DHA-PLs) in physiology. Here, we investigated the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) triggered by RhoA inhibition-associated cell spreading. Lipidomic analyses showed that human umbilical vein endothelial cells (HUVECs) subjected to a DHA diet undergo a 6-fold enrichment in DHA-PLs at the plasma membrane (PM) at the expense of monounsaturated oleic acid-containing PLs (OA-PLs). Consequently, DHA-PL enrichment at the PM induces a reduction in cell thickness and shifts cellular membranes towards a permissive mode of membrane fusion for transcellular tunnel initiation. We provide evidence that a global homeostatic control of membrane tension and cell cortex rigidity minimizes overall changes of TEM area through a decrease of TEM size and lifetime. Conversely, low DHA-PL levels at the PM lead to the opening of unstable and wider TEMs. Together, this provides evidence that variations of DHA-PL levels in membranes affect cell biomechanical properties.

CLEC12B Is a Melanocytic Gene Regulating the Color of the Skin.

Pigmentation of the human skin is a complex process regulated by many genes. However, only a few have a profound impact on melanogenesis. Transcriptome analysis of pigmented skin compared with analysis of vitiligo skin devoid of melanocytes allowed us to unravel CLEC12B as a melanocytic gene. We showed that CLEC12B, a C-type lectin receptor, is highly expressed in melanocytes and that its expression is decreased in dark skin compared with that in white skin. CLEC12B directly recruits and activates SHP1 and SHP2 through its immunoreceptor tyrosine-based inhibitory motif domain and promotes CRE-binding protein degradation, leading to the downregulation of the downstream MITF pathway. CLEC12B ultimately controls melanin production and pigmentation in vitro and in a model of reconstructed human epidermis. The identification of CLEC12B in melanocytes shows that C-type lectin receptors exert function beyond immunity and inflammation. It also provides insights into the understanding of melanocyte biology and regulation of melanogenesis.

Proteomic Identification of an Endogenous Synaptic SUMOylome in the Developing Rat Brain.

Synapses are highly specialized structures that interconnect neurons to form functional networks dedicated to neuronal communication. During brain development, synapses undergo activity-dependent rearrangements leading to both structural and functional changes. Many molecular processes are involved in this regulation, including post-translational modifications by the Small Ubiquitin-like MOdifier SUMO. To get a wider view of the panel of endogenous synaptic SUMO-modified proteins in the mammalian brain, we combined subcellular fractionation of rat brains at the post-natal day 14 with denaturing immunoprecipitation using SUMO2/3 antibodies and tandem mass spectrometry analysis. Our screening identified 803 candidate SUMO2/3 targets, which represents about 18% of the synaptic proteome. Our dataset includes neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins as well as vesicular trafficking and cytoskeleton-associated proteins, defining SUMO2/3 as a central regulator of the synaptic organization and function.

Dipeptidyl peptidase 4 contributes to Alzheimer's disease-like defects in a mouse model and is increased in sporadic Alzheimer's disease brains.

The amyloid cascade hypothesis, which proposes a prominent role for full-length amyloid ß peptides in Alzheimer's disease, is currently being questioned. In addition to full-length amyloid ß peptide, several N-terminally truncated fragments of amyloid ß peptide could well contribute to Alzheimer's disease setting and/or progression. Among them, pyroGlu3-amyloid ß peptide appears to be one of the main components of early anatomical lesions in Alzheimer's disease-affected brains. Little is known about the proteolytic activities that could account for the N-terminal truncations of full-length amyloid ß, but they appear as the rate-limiting enzymes yielding the Glu3-amyloid ß peptide sequence that undergoes subsequent cyclization by glutaminyl cyclase, thereby yielding pyroGlu3-amyloid ß. Here, we investigated the contribution of dipeptidyl peptidase 4 in Glu3-amyloid ß peptide formation and the functional influence of its genetic depletion or pharmacological blockade on spine maturation as well as on pyroGlu3-amyloid ß peptide and amyloid ß 42-positive plaques and amyloid ß 42 load in the triple transgenic Alzheimer's disease mouse model. Furthermore, we examined whether reduction of dipeptidyl peptidase 4 could rescue learning and memory deficits displayed by these mice. Our data establish that dipeptidyl peptidase 4 reduction alleviates anatomical, biochemical, and behavioral Alzheimer's disease-related defects. Furthermore, we demonstrate that dipeptidyl peptidase 4 activity is increased early in sporadic Alzheimer's disease brains. Thus, our data demonstrate that dipeptidyl peptidase 4 participates in pyroGlu3-amyloid ß peptide formation and that targeting this peptidase could be considered as an alternative strategy to interfere with Alzheimer's disease progression.

Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer's disease (AD) mouse model and is increased at early stage in sporadic AD brain.

One of the main components of senile plaques in Alzheimer's disease (AD)-affected brain is the Aß peptide species harboring a pyroglutamate at position three pE3-Aß. Several studies indicated that pE3-Aß is toxic, prone to aggregation and serves as a seed of Aß aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aß N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aß and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aß1-40 to yield Aß2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aß-precursor protein (ßAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aß- and Aß1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aß-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aß N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling.

To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that ubiquitin domain-containing protein 1 (UBTD1) plays a crucial role in both the epidermal growth factor receptor (EGFR) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through N-acylsphingosine amidohydrolase 1 (ASAH1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of Sequestosome 1 (SQSTM1/p62) by RNF26 and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGFR-driven human cell proliferation.

FBXO32 links ubiquitination to epigenetic reprograming of melanoma cells.

Ubiquitination by serving as a major degradation signal of proteins, but also by controlling protein functioning and localization, plays critical roles in most key cellular processes. Here, we show that MITF, the master transcription factor in melanocytes, controls ubiquitination in melanoma cells. We identified FBXO32, a component of the SCF E3 ligase complex as a new MITF target gene. FBXO32 favors melanoma cell migration, proliferation, and tumor development in vivo. Transcriptomic analysis shows that FBXO32 knockdown induces a global change in melanoma gene expression profile. These include the inhibition of CDK6 in agreement with an inhibition of cell proliferation and invasion upon FBXO32 silencing. Furthermore, proteomic analysis identifies SMARC4, a component of the chromatin remodeling complexes BAF/PBAF, as a FBXO32 partner. FBXO32 and SMARCA4 co-localize at loci regulated by FBXO32, such as CDK6 suggesting that FBXO32 controls transcription through the regulation of chromatin remodeling complex activity. FBXO32 and SMARCA4 are the components of a molecular cascade, linking MITF to epigenetics, in melanoma cells.

Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice.

In humans, obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 hr of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Here, we sought to characterize the postprandial HT inflammatory response to 1, 3, and 6 hr of exposure to either a standard diet (SD) or HFD. HFD exposure increased gene expression of astrocyte and microglial markers (glial fibrillary acidic protein [GFAP] and Iba1, respectively) compared to SD-treated mice and induced morphological modifications of microglial cells in HT. This remodeling was associated with higher expression of inflammatory genes and differential regulation of hypothalamic neuropeptides involved in energy balance regulation. DREADD and PLX5622 technologies, used to modulate GFAP-positive or microglial cells activity, respectively, showed that both glial cell types are involved in hypothalamic postprandial inflammation, with their own specific kinetics and reactiveness to ingested foods. Thus, recurrent exacerbated postprandial inflammation in the brain might promote obesity and needs to be characterized to address this worldwide crisis.

Inhibition of Patched Drug Efflux Increases Vemurafenib Effectiveness against Resistant BrafV600E Melanoma.

Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma.

Osh6 requires Ist2 for localization to ER-PM contacts and efficient phosphatidylserine transport in budding yeast.

Osh6 and Osh7 are lipid transfer proteins (LTPs) that move phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM). High PS levels at the PM are key for many cellular functions. Intriguingly, Osh6 and Osh7 localize to ER-PM contact sites, although they lack membrane-targeting motifs, in contrast to multidomain LTPs that both bridge membranes and convey lipids. We show that Osh6 localization to contact sites depends on its interaction with the cytosolic tail of the ER-PM tether Ist2, a homolog of TMEM16 proteins. We identify a motif in the Ist2 tail, conserved in yeasts, as the Osh6-binding region, and we map an Ist2-binding surface on Osh6. Mutations in the Ist2 tail phenocopy osh6Δ osh7Δ deletion: they decrease cellular PS levels and block PS transport to the PM. Our study unveils an unexpected partnership between a TMEM16-like protein and a soluble LTP, which together mediate lipid transport at contact sites.This article has an associated First Person interview with the first author of the paper.

Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor.

ORPphilins are bioactive natural products that strongly and selectively inhibit the growth of some cancer cell lines and are proposed to target intracellular lipid-transfer proteins of the oxysterol-binding protein (OSBP) family. These conserved proteins exchange key lipids, such as cholesterol and phosphatidylinositol 4-phosphate (PI(4)P), between organelle membranes. Among ORPphilins, molecules of the schweinfurthin family interfere with intracellular lipid distribution and metabolism, but their functioning at the molecular level is poorly understood. We report here that cell line sensitivity to schweinfurthin G (SWG) is inversely proportional to cellular OSBP levels. By taking advantage of the intrinsic fluorescence of SWG, we followed its fate in cell cultures and show that its incorporation at the trans-Golgi network depends on cellular abundance of OSBP. Using in vitro membrane reconstitution systems and cellular imaging approaches, we also report that SWG inhibits specifically the lipid transfer activity of OSBP. As a consequence, post-Golgi trafficking, membrane cholesterol levels, and PI(4)P turnover were affected. Finally, using intermolecular FRET analysis, we demonstrate that SWG directly binds to the lipid-binding cavity of OSBP. Collectively these results describe SWG as a specific and intrinsically fluorescent pharmacological tool for dissecting OSBP properties at the cellular and molecular levels. Our findings indicate that SWG binds OSBP with nanomolar affinity, that this binding is sensitive to the membrane environment, and that SWG inhibits the OSBP-catalyzed lipid exchange cycle.

Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression.

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.