Featured
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| Open Access11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. Here the authors show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.
- Nantia Othonos
- , Riccardo Pofi
- & Jeremy W. Tomlinson
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Article
| Open AccessSugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts
Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.
- Pei Ying Ng
- , Amy B. P. Ribet
- & Nathan J. Pavlos
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Article
| Open AccessDirected self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes
Cell therapy for diabetes requires the combination of bioengineering and new sources of beta cells. Here, the authors report a self-assembly platform based on neonatal pig islets, human endothelial cells and native organ extracellular matrix, which improves ex vivo islet maturation and in vivo function in a mouse model of diabetes.
- Antonio Citro
- , Alessia Neroni
- & Lorenzo Piemonti
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Article
| Open AccessCryo-EM structure supports a role of AQP7 as a junction protein
Glycerol flux across the plasma membrane is critical to metabolism and linked to disease. Here, authors present the cryo-EM structure of the glycerol channel AQP7 composed of two adhering tetramers and displaying well-defined densities in the central pore.
- Peng Huang
- , Raminta Venskutonytė
- & Karin Lindkvist-Petersson
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Article
| Open AccessAdipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice
Adipose tissue inflammation contributes to the pathogenesis of obesity-related metabolic disorders. Here the authors report that adipocyte-specific genetic deficiency or pharmacological inhibition of TRPM7, a cation channel, attenuates adipose tissue inflammation, improves glucose homeostasis, and suppresses weight gain in obese male mice.
- Weiting Zhong
- , Mingming Ma
- & Min Gao
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Article
| Open AccessLong-term statins administration exacerbates diabetic nephropathy via ectopic fat deposition in diabetic mice
Huang et al. investigated the effects of long-term statins administration in a mouse model for diabetes and found that it can worsen insulin resistance, renal inflammation and fibrosis. Statins increased renal lipid uptake and inhibited fatty acid oxidation, contributing to diabetic nephropathy.
- Tong-sheng Huang
- , Teng Wu
- & Wei-bin Cai
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Article
| Open AccessA natural biological adhesive from snail mucus for wound repair
Natural adhesives have received a lot of attention recently. Here, the authors develop a natural biological adhesive from snail mucus that can adhere to wet tissue and be used to accelerate healing of skin wounds.
- Tuo Deng
- , Dongxiu Gao
- & Mingyi Wu
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Article
| Open AccessGenome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure
Otosclerosis is a common form of hearing loss, with an unclear genetic etiology. Here, the authors perform a genome-wide association study meta-analysis of otosclerosis identifying 27 genetic loci, pointing to genes involved in bone remodeling, skeletal disorders and transforming growth factor β signaling.
- Joel T. Rämö
- , Tuomo Kiiskinen
- & Aarno Palotie
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Article
| Open AccessBMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases
Different location of adipose tissue may have different consequences to cardiometabolic risk. Here the authors report that deep learning enabled accurate prediction of specific adipose tissue volumes, and that after adjustment for BMI, visceral adiposity was associated with increased risk of cardiometabolic disease, while gluteofemoral adiposity was associated with reduced risk.
- Saaket Agrawal
- , Marcus D. R. Klarqvist
- & Amit V. Khera
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Article
| Open AccessHyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
- Yulong Gong
- , Bingyuan Yang
- & Wenbiao Chen
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Article
| Open AccessEffect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial
β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents. Here the authors report that two-weeks of treatment with the β2-agonist clenbuterol improves insulin-stimulated glucose disposal in healthy young men in a double-blinded, randomized cross-over trial.
- Sten M. M. van Beek
- , Yvonne M. H. Bruls
- & Joris Hoeks
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Article
| Open AccessTGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice
Age-related osteoporosis is known to be dependent on TGFβ1 signalling. Here the authors show that a subset of neutrophils (identified by TGFβ1+CCR5+) increase during aging in mouse bone marrow resulting in bone loss, while a CCR5 antagonist can reduce the neutrophil numbers and increase bone mass in aged mice.
- Jinbo Li
- , Zhenqiang Yao
- & Brendan F. Boyce
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Article
| Open AccessIncreased adipose catecholamine levels and protection from obesity with loss of Allograft Inflammatory Factor-1
Macrophages have been reported to regulate thermogenic, sympathetic neuron-mediated norepinephrine signaling in adipose tissues. Here the authors report that male mice lacking the allograft inflammatory factor-1 protein are resistant to diet-induced obesity, in association with higher adipose norepinephrine levels and lower expression of the norepinephrine catabolic enzyme monoamine oxidase A.
- Prameladevi Chinnasamy
- , Isabel Casimiro
- & Nicholas E. S. Sibinga
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| Open AccessThe urban built environment and adult BMI, obesity, and diabetes in Latin American cities
Latin America is the world’s most urbanized region and its heterogeneous urban development may impact chronic diseases. In this study, the authors evaluate the association of built environment characteristics with body mass index, obesity, and type 2 diabetes.
- Cecilia Anza-Ramirez
- , Mariana Lazo
- & J. Jaime Miranda
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Article
| Open AccessGenomics and phenomics of body mass index reveals a complex disease network
Elevated body mass index is heritable and associated with many health conditions that impact morbidity and mortality. Here, the authors identify greater than 900 genetic loci for body mass index (BMI) and find over 300 diagnoses associated with increasing BMI.
- Jie Huang
- , Jennifer E. Huffman
- & Christopher J. O’Donnell
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Article
| Open AccessImplantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats
Islet transplantation for type 1 diabetes management is hindered by the life-long need for immunosuppressive medications. Here, the authors report an islet encapsulation device with local anti-rejection drug release that achieves long-term diabetes reversal in male rats and reduces drug-related toxicity.
- Jesus Paez-Mayorga
- , Jocelyn Nikita Campa-Carranza
- & Alessandro Grattoni
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| Open AccessA randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes
Based on preclinical studies, gamma aminobutyric acid (GABA) and immunization for the enzyme that produces GABA glutamate decarboxylase (GAD) could be a potential therapy for type 1 diabetes. Here the authors report that in a placebo-controlled, double blind trial in children with new onset type 1 diabetes oral GABA plus GAD did not preserve beta-cell function measured as fasting/meal-stimulated c-peptide levels.
- Alexandra Martin
- , Gail J. Mick
- & Kenneth L. McCormick
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Article
| Open AccessAdipose-targeted triiodothyronine therapy counteracts obesity-related metabolic complications and atherosclerosis with negligible side effects
Although thyroid hormone (TH) has anti-obesity potential, systemic administration of TH causes severe adverse effects without obvious weight loss. Here, the authors show that adipose tissue-targeted delivery of TH with liposomes is a safe and efficient strategy to treat obesity and its related complications in mice.
- Kang Chen
- , Lai Yee Cheong
- & Aimin Xu
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Article
| Open AccessUpper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis
High-fat diet (HFD) increases the risk of insulin resistance and non-alcoholic steatohepatitis (NASH). Here the authors report that the heat shock proteins HSP70 and GRP78 are increased in the jejunum of rats on HFD, and their continuous infusion leads insulin resistance and NASH, while in rats on a high-fat diet infused with monoclonal antibodies against HSP70 and GRP78 these phenotypes are reversed.
- Giulia Angelini
- , Lidia Castagneto-Gissey
- & Geltrude Mingrone
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Article
| Open AccessSIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice
Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.
- Tatsuya Yoshizawa
- , Yoshifumi Sato
- & Kazuya Yamagata
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| Open AccessA brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis
The signaling mechanisms regulating adipose thermogenesis have not been fully elucidated. Here, the authors show that a brown fat-enriched adipokine ADISSP promotes adipose thermogenesis and improves metabolic health independently of b-adrenergic receptor.
- Qingbo Chen
- , Lei Huang
- & Yong-Xu Wang
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Article
| Open AccessDifferential IL18 signaling via IL18 receptor and Na-Cl co-transporter discriminating thermogenesis and glucose metabolism regulation
Interleukin-18 (IL18) has a pivotal role in interferon signalling and T cell development, but increasingly recognized as an adipokine that regulates energy metabolism in fat tissue. Authors here dissect the function of IL18 signalling in the adipose compartment by targeted genomic deletion of its two receptors individually and in combination in brown and white adipose tissues.
- Xian Zhang
- , Songyuan Luo
- & Guo-Ping Shi
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Article
| Open AccessThe dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.
- Alessandra Dall’Agnese
- , Jesse M. Platt
- & Richard A. Young
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Article
| Open AccessSecreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice
Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.
- Xuanchun Wang
- , Yanliang Li
- & Chong Wee Liew
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Article
| Open AccessTargeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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Article
| Open AccessGPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages
G-protein-signaling modulator 1 (GPSM1), an accessory protein which activates heterotrimeric G-protein signaling, exhibits a genetic association with type 2 diabetes. Here the authors show that myeloid GPSM1 ablation in mice inhibits inflammation and metabolic dysfunction upon high fat diet.
- Jing Yan
- , Yuemei Zhang
- & Cheng Hu
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| Open AccessReduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity
Adipose tissue is an important secretory organ, but less is known about the secretory activity of perivascular fat. Here the authors use proteomics analysis on secretomes from perivascular fat to identify neuronal growth regulator 1 as an adipocyte-derived neurotrophic factor, whose decreased secretion in obesity results in a loss of sympathetic innervation of adipose depots in mice.
- Elisa Duregotti
- , Christina M. Reumiller
- & Manuel Mayr
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Article
| Open AccessMetabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population
Four T2D subtypes were previously identified: severe insulin deficient, severe insulin resistant, mild obesity-related, and mild age-related diabetes. Here, the authors show that these subtypes can be translated to an Arabic population and identify distinct subtype-specific metabolic and proteomic signatures.
- Shaza B. Zaghlool
- , Anna Halama
- & Karsten Suhre
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| Open AccessCausal deep learning reveals the comparative effectiveness of antihyperglycemic treatments in poorly controlled diabetes
Current treatment guidelines for Type-2 diabetes endorse a massive number of potential anti-hyper-glycemic treatment options in various permutations and combinations. Here, the authors present a causal deep learning approach for more personalized recommendations of treatment selection.
- Chinmay Belthangady
- , Stefanos Giampanis
- & Beau Norgeot
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| Open AccessParkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes
Parkin plays a role in mitophagy and has been shown to control adipose tissue browning and thermogenesis. Here the authors report that Parkin coordinates mitophagy with Pgc1α-mediated mitochondrial biogenesis in white adipocytes to regulate adiposity.
- Timothy M. Moore
- , Lijing Cheng
- & Zhenqi Zhou
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Article
| Open AccessThe contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians
Metabolic traits are heritable intermediate phenotypes widely used in assessing the risk of various diseases. By conducting a genome-wide meta-analysis for metabolic traits in 288,137 East Asians, the authors highlight the interplay of common and rare variants on inherited risk of metabolic traits.
- Young Jin Kim
- , Sanghoon Moon
- & Bong-Jo Kim
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| Open AccessUse of a glycomics array to establish the anti-carbohydrate antibody repertoire in type 1 diabetes
Type I diabetes is characterized by autoantibodies directed against protein or non-protein self-antigens. Here the authors profile glycan reactive anti-carbohydrate antibodies (ACA) in a longitudinal and cross-sectional childhood diabetes cohort and associate clusters of ACA with disease progression.
- Paul M. H. Tran
- , Fran Dong
- & Sharad Purohit
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Article
| Open AccessStructural mechanism of SGLT1 inhibitors
SGLT1 is essential for glucose, galactose and water uptake from the intestine, and its inhibitors have broad therapeutic potential. Here, the authors describe the cryo-EM structure of human SGLT1 in complex with an inhibitor.
- Yange Niu
- , Wenhao Cui
- & Lei Chen
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Article
| Open AccessHepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
- Ying Yan
- , Zhoumin Niu
- & Hao Ying
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| Open AccessThe type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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Article
| Open AccessFunctional and metabolic alterations of gut microbiota in children with new-onset type 1 diabetes
Here, by performing multi-omics microbiome analyses in a cohort of children with new-onset T1D, the authors characterize altered microbial functional and metabolic traits involved in T1D, which they validate in animal experiments, together providing potential avenues for microbiome-based interventions.
- Xiaoxiao Yuan
- , Ruirui Wang
- & Feihong Luo
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Article
| Open AccessREDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation
The stress response protein REDD1 is regulates inflammation and energy metabolism. Here the authors report that global or adipocyte-specific deletion of REDD1 inhibits diet induced obesity, insulin resistance, liver steatosis and inflammation in mice, at least in part via reduced atypical NF-κB activation.
- Dong-Keon Lee
- , Taesam Kim
- & Young-Myeong Kim
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Article
| Open AccessSuppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery
Fibrodysplasia ossificans progressiva is an ultra-rare genetic disorder with progressive heterotopic ossification. Yang et al develop different gene therapy approaches and show their efficacy in mouse models and in human induced pluripotent stem cells.
- Yeon-Suk Yang
- , Jung-Min Kim
- & Jae-Hyuck Shim
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Article
| Open AccessThe metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial
Combining a GLP-1 receptor agonist, to increase endogenous beta cell function, with exogenous insulin is a possible therapeutic option for the treatment of type 2 diabetes. Here, the authors show adding exenatide to basal insulin in early type 2 diabetes does not further enhance underlying pancreatic beta-cell function or the capacity to achieve diabetes remission, but may yield on-treatment glycemic benefits.
- Ravi Retnakaran
- , Chang Ye
- & Bernard Zinman
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Article
| Open AccessPhosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling
The insulin signalling cascade can be inhibited by phosphatases, including Ser/Thr protein phosphatase 2A (PP2A). Here the authors show that Alpha4, a regulator of the PP2A catalytic subunit, modulates insulin receptor tyrosine phosphorylation via the YBX-1/PTP1B pathway and is involved in maintenance of adipose tissue homeostasis and systemic metabolism.
- Masaji Sakaguchi
- , Shota Okagawa
- & Eiichi Araki
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Article
| Open AccessA predictive computational platform for optimizing the design of bioartificial pancreas devices
Transplanting encapsulated insulin-producing cells may achieve a functional cure for type 1 diabetes, but efficacy is constrained by mass transfer limits. Here, the authors report a dynamic computational platform to investigate the therapeutic potency of such programmable bioartificial pancreas devices.
- Alexander U. Ernst
- , Long-Hai Wang
- & Minglin Ma
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Article
| Open AccessReducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
Retinal pigment epithelium (RPE) plays an important role in diabetic retinopathy (DR) progression. Here, the authors show AKT1 and AKT2 are reciprocally regulated in the RPE of DR donor tissue and diabetic mice, reducing Akt2 in RPE causing a compensatory increase in Akt1 and attenuating DR.
- Haitao Liu
- , Nadezda A. Stepicheva
- & Debasish Sinha
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Article
| Open AccessDeletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice
Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.
- Takayoshi Sasako
- , Toshihiro Umehara
- & Kohjiro Ueki
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Article
| Open AccessLipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion
During hypoglycemia, glucagon secretion is part of the mechanism needed to restore normal blood glucose levels. Here, Strembitska et al. report that sensing of hypoglycemia by AgRP neurons requires Agpat5, an enzyme which prevents fatty acids from entering the mitochondria for ATP production, ensuring correct neuronal activation and glucagon secretion.
- Anastasiya Strembitska
- , Gwenaël Labouèbe
- & Bernard Thorens
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Article
| Open AccessMicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans.
- Mary P. LaPierre
- , Katherine Lawler
- & Markus Stoffel
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Article
| Open AccessMYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open AccessInterferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Murine models of obesity suggest that decreases in the adipose tissue regulatory T cell compartment may contribute to insulin resistance, but how this corresponds in the human clinical context is less well understood. Here the authors propose a role for interferon gamma in shrinking the adipose tissue regulatory T cell compartment seen in human obesity and assess the alterations seen during induction of dietary changes.
- David Bradley
- , Alan J. Smith
- & Willa A. Hsueh
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Article
| Open AccessDiabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder
Patients with diabetes have an increased susceptibility to infections. Here the authors show that high glucose impairs innate immunity through reduced levels of the antimicrobial peptide psoriasin and impaired epithelial barrier function, resulting in an increased risk of urinary tract infection.
- Soumitra Mohanty
- , Witchuda Kamolvit
- & Annelie Brauner
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Article
| Open AccessLiver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis
Besides hepatocytes, resident immune cells of the liver are also contributing to the body’s energy homeostasis. Here authors show that group 2 innate lymphoid cells interact with a specific set of hepatocytes in suppressing gluconeogenesis and regulate blood glucose levels via Interleukin-13 signalling.
- Masanori Fujimoto
- , Masataka Yokoyama
- & Tomoaki Tanaka