Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

Obesity and type 2 diabetes are associated with cognitive dysfunction. Because the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggest that pregnenolone’s effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically unhealthy patients with obesity. Our data reveal an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders.This work was supported by the Swiss National Science Foundation (no.176206; NCCR Synapsy grant no.185897) to C.S.; the European Research Council (ERC) advanced grant SYNEME to J.C.B.; Instituto de Salud Carlos III (ISCIII)—Fondo Europeo de Desarrollo Regional (FEDER) (PI17/00296), RETICs Oftared (RD16/0008/0014), and Generalitat de Catalunya (2017SGR737) to X.G.; Ministerio de Ciencia e Innovación (BFU2017-83317-P) to D.S.; Ministerio de Economia, Industria y Competitividad, Maria de Maeztu (MDM-2017-0729) to Institut de Neurociencies, Universitat de Barcelona; ISCIII-FEDER (PI14/01126, PI17/01019), the National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, and R01AG061566), Fundació La Marató de TV3 (20141210), and Generalitat de Catalunya (SLT006/17/00119) to J.F.; ISCIII-FEDER (PI17/00279 and PI20/0042), Fundació La Marató de TV3 (201614.31), and Generalitat de Catalunya (SLT008/18/00127) to A.J.; Plan Nacional de I+D funded by the Agencia Estatal de Investigación (AEI) and FEDER (PID2019-111669RB-I00 and PID2020-115055RB-I00), CIBEREHD, the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, Generalitat de Catalunya (SGR-2017-1112), the European Cooperation in Science & Technology (COST) ACTION CA17112, FUNDACIÓN BBVA (“ER stress-mitochondrial cholesterol axis in obesity-associated insulin resistance and comorbidities”), and Red Nacional 2018-102799-T de Enfermedades Metabólicas y Cáncer and Fundació La Marató de TV3 (201916/31) to J.C.F.-C.; and ERC consolidator grant MITOSENSING (725004), ISCIII-FEDER (PI16/00963), “la Caixa” Foundation (ID100010434) under agreement LCF/PR/HR19/52160016, and CERCA Programme/Generalitat de Catalunya to M.C. D.A. is supported by ISCIII (INT19/00016) and Generalitat de Catalunya PERIS program (SLT006/17/125), A.P. is supported by Hospital Clínic de Barcelona (“Ajut Josep Font”), A.O. is supported by a Miguel Servet contract (CP19/00083) from ISCIII-FEDER, and R.H.-T. is supported by a Marie Skłodowska-Curie Action fellowship (H2020-MSCA-IF) and NEUROPREG (891247). S.R. is a recipient of Juan de la Cierva Formación (FJCI-2016-28911) and Incorporación (IJC2018-037341-I) programs from the Spanish Ministry of Science and Innovation. This work was carried out in part at Esther Koplowitz Centre.Peer reviewe

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

© 2021 The Authors.Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.This work was supported by Agencia Estatal de Investigación y Fondo Social Europeo, Proyecto BFU2016-76973-R FEDER (C.V.A.); AG052005, AG052986, AG051459, DK111178 from NIH and NKFI-KKP-126998 from Hungarian National Research, Development and Innovation Office (T.L.H.); MR/P009824/2 from Medical Research Council UK (G.D.); and Ayudas Fundación BBVA a Investigadores y Creadores Culturales (2015), European Research Council (ERC) under the European Union’s Horizon 2020 Research And Innovation Program (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). A.O. is supported by a Miguel Servet contract (CP19/00083) from Instituto de Salud Carlos III and co-financed by FEDER

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

Obesity and type-2 diabetes are associated with cognitive dysfunction. Since the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid-precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggested that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically-unhealthy obese patients. Our data reveals an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders

Angiocrine polyamine production regulates adiposity.

Reciprocal interactions between endothelial cells (ECs) and adipocytes are fundamental to maintain white adipose tissue (WAT) homeostasis, as illustrated by the activation of angiogenesis upon WAT expansion, a process that is impaired in obesity. However, the molecular mechanisms underlying the crosstalk between ECs and adipocytes remain poorly understood. Here, we show that local production of polyamines in ECs stimulates adipocyte lipolysis and regulates WAT homeostasis in mice. We promote enhanced cell-autonomous angiogenesis by deleting Pten in the murine endothelium. Endothelial Pten loss leads to a WAT-selective phenotype, characterized by reduced body weight and adiposity in pathophysiological conditions. This phenotype stems from enhanced fatty acid β-oxidation in ECs concomitant with a paracrine lipolytic action on adipocytes, accounting for reduced adiposity. Combined analysis of murine models, isolated ECs and human specimens reveals that WAT lipolysis is mediated by mTORC1-dependent production of polyamines by ECs. Our results indicate that angiocrine metabolic signals are important for WAT homeostasis and organismal metabolism.We thank members of the Endothelial Pathobiology and Microenvironment Group for helpful discussions. We thank the CERCA Program/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. The research leading to these results has received funding from la Fundación BBVA (Ayuda Fundacion BBVA a Equipos de Investigación Científica 2019, PR19BIOMET0061) and from SAF2017-82072-ERC from Ministerio de Ciencia, Innovación y Universidades (MCIU) (Spain). The laboratory of M.G. is also supported by the research grants SAF2017-89116R-P (FEDER/EU) co-funded by European Regional Developmental Fund (ERDF), a Way to Build Europe and PID2020-116184RB-I00 from MCEI; by the Catalan Government through the project 2017-SGR; PTEN Research Foundation (BRR-17-001); La Caixa Foundation (HR19-00120 and HR21-00046); by la Asociación Española contra el Cancer-Grupos Traslacionales (GCTRA18006CARR, also to A.C.); European Foundation for the Study of Diabetes/Lilly research grant, also to M.C.); and by the People Programme (Marie Curie Actions; grant agreement 317250) of the European Union’s Seventh Framework Programme FP7/2007-2013 and the Marie Skłodowska-Curie (grant agreement 675392) of the European Union’s Horizon 2020 research. The laboratory of A.C. is supported by the Basque Department of Industry, Tourism and Trade (Elkartek) and the department of education (IKERTALDE IT1106-16), the MCIU (PID2019-108787RB-I00 (FEDER/ EU); Severo Ochoa Excellence Accreditation SEV-2016-0644; Excellence Networks SAF2016-81975-REDT), La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17, the Vencer el Cancer foundation and the European Research Council (ERC) (consolidator grant 819242). CIBERONC was co-funded with FEDER funds and funded by Instituto de Salud Carlos III (ISCIII). The laboratory of M.C. is supported by the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). The laboratory of D.S. is supported by research grants from MINECO (SAF2017- 83813-C3-1-R, also to L.H., cofounded by the ERDF), CIBEROBN (CB06/03/0001), Government of Catalonia (2017SGR278) and Fundació La Marató de TV3 (201627- 30). The laboratory of R.N. is supported by FEDER/Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (RTI2018-099413-B-I00 and and RED2018-102379-T), Xunta de Galicia (2016-PG057 and 2020-PG015), ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement 810331), Fundación BBVA, Fundacion Atresmedia and CIBEROBN, which is an initiative of the ISCIII of Spain, which is supported by FEDER funds. The laboratory of J.A.V. is supported by research grants from MICINN (RTI2018-099250-B100) and by La Caixa Foundation (ID 100010434, LCF/PR/HR17/52150009). P.M.G.-R. is supported by ISCIII grant PI15/00701 cofinanced by the ERDF, A Way to Build Europe. Personal support was from Marie Curie ITN Actions (E.M.), Juan de la Cierva (IJCI-2015-23455, P.V.), CONICYT fellowship from Chile (S.Z.), Vetenskapsradet (Swedish Research Council, 2018-06591, L.G.) and NCI K99/R00 Pathway to Independence Award (K99CA245122, P. Castel).S

Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans.

Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.Postdoctoral fellowships were from EMBO (A LTF 165-2013) to S.D.C, EU Marie Curie (MEIF-CT-2005-010264) to E.T. and EU Marie Curie (PIIF-GA-2009-252846) to I.M.B. M.Z.-T. is supported by the EPSRC Early Career Fellowship of T.L.K. (EP/L006472/1). D.J.S. is a BHF Intermediate Basic Science Research Fellow (FS/15/33/31608). A.L.D is supported by the UK NIHR Joint UCL/University College London Hospitals Biomedical Research Centre. V.E.R.P. was supported by the Wellcome Trust (097721/Z/11/Z). R.K.S. is supported by the Wellcome Trust (WT098498), the Medical Research Council (M RC_MC_UU_12012/5). R.G.K. is supported by the NIHR Rare Diseases Translational Research Collaboration. V.W. is supported by the European FPVI Integrated Project ‘Eurostemcell’. M.F.L. and A.B. are supported by the King’s College London and UCL Comprehensive Cancer Imaging Centre CR-UK and EPSRC, in association with the MRC and DoH (England). W.A.P. is supported by funding from the National Health and Medical Research Council (NHMRC) of Australia. Work in the laboratory of M.G. is supported by research grants SAF2013-46542-P and SAF2014-59950-P from MICINN (Spain), 2014-SGR-725 from the Catalan Government, the People Programme (Marie Curie Actions) from the European Union's Seventh Framework Programme FP7/2007-2013/ (REA grant agreement 317250), the Institute of Health Carlos III (ISC III) and the European Regional Development Fund (ERDF) under the integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE). Work in the laboratory of B.V. is supported by Cancer Research UK (C23338/A15965) and the UK NIHR University College London Hospitals Biomedical Research Centre.This is the author accepted manuscript. The final version is available from the American Association for the Advancement of Science via http://dx.doi.org/10.1126/scitranslmed.aad998

PTEN mediates Notch-dependent stalk cell arrest in angiogenesis

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch-PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis.We thank Ramon Parsons (The Mount Sinai Hospital, NY, US) for pGL3 PTEN HindIII-NotI construct and Lluis Espinosa (IMIM, Barcelona), Alba Martinez (Research Laboratory, Catalan Institute of Oncology, IDIBELL, Barcelona) and Magali Castells (Vascular Signalling laboratory, IDIBELL) for support with experiments. This work was supported by research grants SAF2010-15661 and SAF2013-46542-P from MICINN (Spain), 2014-SGR-725 from the Catalan Government, from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/(REA grant agreement 317250) and Ajuts Joves Investigadors from IDIBELL to M.G., and SAF2013-40922 and RD12/0036/0054 to A.B. Personal support was from FPI of the Spanish Ministry of Education (A.S.), IDIBELL (H.S.) and Ramon y Cajal fellow of the Spanish Ministry of Education (M.G. and O.C.). The work of A.C. is supported by the Ramon y Cajal award, the Basque Department of Industry, Tourism and Trade (Etortek), health (2012111086) and education (PI2012-03), Marie Curie (277043), Movember, ISCIII (PI10/01484, PI13/00031) and ERC (336343). The work of M.P. is supported by the Max Planck Society, the Deutsche Forschungsgemeinschaft (SFB 834) and an ERC Starting Grant (ANGIOMET). H.G. is supported by Cancer Research UK, the Lister Institute of Preventive Medicine, the Leducq Network Grant ARTEMIS, BIRAX and an ERC starting grant Reshape 311719.S

PTEN mediates Notch-dependent stalk cell arrest in angiogenesis

Coordinated activity of VEGF and Notch signals guides the endothelial cell (EC) specification into tip and stalk cells during angiogenesis. Notch activation in stalk cells leads to proliferation arrest via an unknown mechanism. By using gain- and loss-of-function gene-targeting approaches, here we show that PTEN is crucial for blocking stalk cell proliferation downstream of Notch, and this is critical for mouse vessel development. Endothelial deletion of PTEN results in vascular hyperplasia due to a failure to mediate Notch-induced proliferation arrest. Conversely, overexpression of PTEN reduces vascular density and abrogates the increase in EC proliferation induced by Notch blockade. PTEN is a lipid/protein phosphatase that also has nuclear phosphatase-independent functions. We show that both the catalytic and non-catalytic APC/C-Fzr1/Cdh1-mediated activities of PTEN are required for stalk cells' proliferative arrest. These findings define a Notch–PTEN signalling axis as an orchestrator of vessel density and implicate the PTEN-APC/C-Fzr1/Cdh1 hub in angiogenesis

Bringing rehabilitation home with an e-health platform to treat stroke patients: study protocol of a randomized clinical trial (RGS@home)

International audienceAbstract Background There is a pressing need for scalable healthcare solutions and a shift in the rehabilitation paradigm from hospitals to homes to tackle the increase in stroke incidence while reducing the practical and economic burden for patients, hospitals, and society. Digital health technologies can contribute to addressing this challenge; however, little is known about their effectiveness in at-home settings. In response, we have designed the RGS@home study to investigate the effectiveness, acceptance, and cost of a deep tech solution called the Rehabilitation Gaming System (RGS). RGS is a cloud-based system for delivering AI-enhanced rehabilitation using virtual reality, motion capture, and wearables that can be used in the hospital and at home. The core principles of the brain theory-based RGS intervention are to deliver rehabilitation exercises in the form of embodied, goal-oriented, and task-specific action. Methods The RGS@home study is a randomized longitudinal clinical trial designed to assess whether the combination of the RGS intervention with standard care is superior to standard care alone for the functional recovery of stroke patients at the hospital and at home. The study is conducted in collaboration with hospitals in Spain, Sweden, and France and includes inpatients and outpatients at subacute and chronic stages post-stroke. The intervention duration is 3 months with assessment at baseline and after 3, 6, and 12 months. The impact of RGS is evaluated in terms of quality of life measurements, usability, and acceptance using standardized clinical scales, together with health economic analysis. So far, one-third of the patients expected to participate in the study have been recruited ( N = 90, mean age 60, days after stroke ≥ 30 days). The trial will end in July 2023. Discussion We predict an improvement in the patients’ recovery, high acceptance, and reduced costs due to a soft landing from the clinic to home rehabilitation. In addition, the data provided will allow us to assess whether the prescription of therapy at home can counteract deterioration and improve quality of life while also identifying new standards for online and remote assessment, diagnostics, and intervention across European hospitals. Trial registration C linicalTrials.gov NCT04620707. Registered on November 3, 202

Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release