Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans.

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFβ signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity.AW and AVP were supported by FP7 – BetaBAT, BBSRC (BB/J009865/1), the British Heart Foundation (PG/12/53/29714) and MDU MRC. MJ and HB were supported by Japan Health and Labour Sciences Research grant (H22-rinkensui-ippan-001) and Grants-in–aid for Scientific Research from Japanese Ministry of Education, Culture, Sports, Science and Technology (24390231 and 24790907). VP was supported by Wellcome Trust and the Cambridge Overseas Trust. JR was supported by Ministerio de Educación, through “Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de I-D+i 2008-2011 (Subprograma de Estancias de Movilidad en el Extranjero “José Castillejo” para jóvenes Doctores, ref: JC2011-0248). SV was supported by MRC. WJS was supported by the Austrian Science Fund (FWF P-20218 and P-20455). Animal work was performed at the MDU DMC Core facilities.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ncomms995

Soluble LR11/SorLA represses thermogenesis in adipose tissue and correlates with BMI in humans

Thermogenesis in brown adipose tissue (BAT) is an important component of energy expenditure in mammals. Recent studies have confirmed its presence and metabolic role in humans. Defining the physiological regulation of BAT is therefore of great importance for developing strategies to treat metabolic diseases. Here we show that the soluble form of the low-density lipoprotein receptor relative, LR11/SorLA (sLR11), suppresses thermogenesis in adipose tissue in a cell-autonomous manner. Mice lacking LR11 are protected from diet-induced obesity associated with an increased browning of white adipose tissue and hypermetabolism. Treatment of adipocytes with sLR11 inhibits thermogenesis via the bone morphogenetic protein/TGFb signalling pathway and reduces Smad phosphorylation. In addition, sLR11 levels in humans are shown to positively correlate with body mass index and adiposity. Given the need for tight regulation of a tissue with a high capacity for energy wastage, we propose that LR11 plays an energy conserving role that is exaggerated in states of obesity

Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis

© 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.This work is supported by the Wellcome strategic award (100574/Z/12/Z); MRC MDU: MC_UU_12012/2 and MC_UU_12012/5 (The Disease Model Core, Biochemistry Assay Lab, Histology Core, and the Genomics and Transcriptomics Core); the Wellcome grant 10953/Z/15/Z (I.S.); the Wellcome Cambridge Trust scholarship (E.F.-J.); the Spanish Ministry of Economy and Competitiveness (SAF2017-88908-R) and PT17/0009/0006 from the ISCIII (C.Ç. and J.D.B.); the Academy of Finland (grants 259926, 265204, 292839, 314456, and 335446), the Paulo Foundation, the Finnish Cultural Foundation Southwest Finland Regional Fund, the Turku University Hospital Research Funds, and the European Union (EUFP7 project 278373; DIABAT) (K.A.V. and M.U.-D.); the Fundación Ramón Areces (BEVP32P01S10090) and subsequently by a Sir Henry Wellcome postdoctoral fellowship (222748/Z/21/Z) (S.R.-F.); We thank the Wellcome-Trust Sanger Institute Mouse Genetics Project (Sanger MGP) and its funders for providing the mutant mouse line (Pepd<tm1a[KOMP]Wtsi). Funding and associated primary phenotypic information may be found at www.sanger.ac.uk/mouseportal.Peer reviewe

Cost-minimisation model of magnetic resonance-guided focussed ultrasound therapy compared to unilateral deep brain stimulation for essential tremor treatment in Japan.

ObjectiveTo investigate the cost differences between magnetic resonance-guided focussed ultrasound (MRgFUS) and unilateral deep brain stimulation (DBS) for the treatment of medication-refractory essential tremor (ET) in Japan using a cost-minimisation model.MethodsA cost-minimisation model estimated total costs for MRgFUS and unilateral DBS by summing the pre-procedure, procedure, and post-procedure costs over a 12-month time horizon, using data from published sources and expert clinical opinion. The model base case considered medical costs from fee-for-service tariffs. Scenario analyses investigated the use of Diagnosis Procedure Combination tariffs, a diagnosis-related group-based fixed-payment system, and the addition of healthcare professional labour costs healthcare professionals using tariffs from the Japanese Health Insurance Federation for Surgery. One-way sensitivity analyses altered costs associated with tremor recurrence after MRgFUS, the extraction rate following unilateral DBS, the length of hospitalisation for unilateral DBS and the procedure duration for MRgFUS. The impact of uncertainty in model parameters on the model results was further explored using probabilistic sensitivity analysis.ResultsCompared to unilateral DBS, MRgFUS was cost saving in the base case and Diagnosis Procedure Combination cost scenario, with total savings of JPY400,380 and JPY414,691, respectively. The majority of savings were accrued at the procedural stage. Including labour costs further increased the cost differences between MRgFUS and unilateral DBS. Cost savings were maintained in each sensitivity analysis and the probabilistic sensitivity analysis, demonstrating that the model results are highly robust.ConclusionsIn the Japanese healthcare setting, MRgFUS could be a cost saving option versus unilateral DBS for treating medication-refractory ET. The model results may even be conservative, as the cost of multiple follow-ups for unilateral DBS and treatment costs for adverse events associated with each procedure were not included. This model is also consistent with the results of other economic analyses of MRgFUS versus DBS in various settings worldwide

Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.the American Heart Association (14EIA18860041) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center

Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity.the American Heart Association (14EIA18860041) and the University of Iowa Fraternal Order of Eagles Diabetes Research Center

Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.MV, JLG, AVP are supported by MRC programs (MRC MDU Programme Grant. PO 4050281695 “Lipotoxicity and the Metabolic Syndrome” and MRC DMC MC UU 12012/2 to AVP; Lipid Profiling and Signalling, MC UP A90 1006 to JLG) and MRC adjunct funding as part of the Cambridge Initiative in Metabolic Diseases (Lipid Dynamics and Regulation: MC_PC_13030). MV, MA and AVP are also supported by the Cambridge NIHR Biomedical Research Center (Gastroenterology); MV is recipient of the BRC Gastroenterology Pump-Priming award 2018/2019 that founded part of this study. FO is supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. JL is supported by Medical Research Council PhD studentship and a CRUK program grant (C18342/A23390). QMA, MV, AVP, VR, MA and DT are contributing members of the European NAFLD Registry. QMA is supported by the Newcastle NIHR Biomedical Research Centre (BRC). MV has been fellow of the Fondazione Umberto Veronesi in 2014. MA, AVP, and JLG received funding from the Evelyn Trust. MV, OG, DT, MA, FO, QMA, MJN DJL, and AVP are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413

Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.MV, JLG, AVP are supported by MRC programs (MRC MDU Programme Grant. PO 4050281695 “Lipotoxicity and the Metabolic Syndrome” and MRC DMC MC UU 12012/2 to AVP; Lipid Profiling and Signalling, MC UP A90 1006 to JLG) and MRC adjunct funding as part of the Cambridge Initiative in Metabolic Diseases (Lipid Dynamics and Regulation: MC_PC_13030). MV, MA and AVP are also supported by the Cambridge NIHR Biomedical Research Center (Gastroenterology); MV is recipient of the BRC Gastroenterology Pump-Priming award 2018/2019 that founded part of this study. FO is supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. JL is supported by Medical Research Council PhD studentship and a CRUK program grant (C18342/A23390). QMA, MV, AVP, VR, MA and DT are contributing members of the European NAFLD Registry. QMA is supported by the Newcastle NIHR Biomedical Research Centre (BRC). MV has been fellow of the Fondazione Umberto Veronesi in 2014. MA, AVP, and JLG received funding from the Evelyn Trust. MV, OG, DT, MA, FO, QMA, MJN DJL, and AVP are members of the EPoS (Elucidating Pathways of Steatohepatitis) consortium, which is funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413