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| Open AccessPaternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring
The dietary factors causing varying intergenerational responses are not fully identified. Here, the authors show that the relative proportion of protein, fats, and carbohydrates in paternal diets before conception differentially influences the phenotype of the next-generation offspring on energy metabolism and behaviour.
- Angela Jane Crean
- , Alistair McNair Senior
- & Stephen James Simpson
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Article
| Open AccessTM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction
Adipose tissue adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Here, the authors show that the deletion of TM4SF19 expressed in lipid-associated macrophages, enhances the clearance of dying adipocytes, thereby improving local and systemic insulin sensitivity as well as energy expenditure.
- Cheoljun Choi
- , Yujin L. Jeong
- & Yun-Hee Lee
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Article
| Open AccessSNX8 enables lysosome reformation and reverses lysosomal storage disorder
Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.
- Xinran Li
- , Cong Xiang
- & Xin-Hua Feng
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Article
| Open AccessDiindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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Article
| Open AccessSonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice
The mechanistic involvement of sonic hedgehog signaling in nonalcoholic steatohepatitis is not clear. Here, the authors show that sonic hedgehog protein regulates the stability of HSP90β, enabling hepatocytes to secrete exosomes containing miR-28-5-p to promote NASH development.
- Weitao Zhang
- , Junfeng Lu
- & Xiaojun Xu
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Article
| Open AccessMyeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation in male mice
The mechanism by which the cross-talk between bone and adipose tissue regulates metabolic homeostasis is unknown. Here, the authors show a mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, showing how GCA targeting could potentially treat metainflammation.
- Tian Su
- , Yue He
- & Xianghang Luo
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Article
| Open AccessSurplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy
The physiological significance of low fatty acid synthesis in adipocytes remains unclear. Here, the authors show a protective role of this phenomenon by demonstrating that overproduction of fatty acids increases ROS production and results in adipocyte necroptosis and lipodystrophy.
- Li Weng
- , Wen-Shuai Tang
- & Tong-Jin Zhao
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Article
| Open AccessMic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
The molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, authors uncover a role for the EMC2- SLC25A46-Mic19 axis in mitochondrial lipid metabolism and liver disease
- Jun Dong
- , Li Chen
- & He He
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Article
| Open AccessMtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis
Excessive lipid accumulation in hepatocytes causes fatty liver disease and liver failure. Here the authors show that ablation of Mitochondrial Fission Process 1 in hepatocytes in mice protects fatty liver disease and dysfunction caused by high fat diet.
- Cecilia Patitucci
- , Juan Diego Hernández-Camacho
- & Timothy Wai
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Article
| Open AccessCdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
The role of Cdo1 in exercise-mediated metabolic health and NAFLD is not clear. Here, the authors show that hepatic Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling to blunt hepatosteatosis and to promote exercise-mediated alleviation of NAFLD in mice.
- Min Chen
- , Jie-Ying Zhu
- & Liang Guo
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Article
| Open AccessA phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.
- Linong Ji
- , Hongwei Jiang
- & Lei Qian
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Article
| Open AccessFructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal
Manganese is an essential trace element for the activity of arginase in the process of urea generation and ammonia disposal in the liver. Here, the authors show that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice.
- Jian-Hui Shi
- , Yu-Xia Chen
- & Weiping J. Zhang
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Article
| Open AccessDevelopment and validation of an age-sex-ethnicity-specific metabolic syndrome score in the Chinese adults
Metabolic syndrome (MetS) could predict future risk for cardiovascular diseases (CVDs), but the traditionally defined dichotomous MetS cannot reflect MetS severity and demographic variations. Here, the authors develop a continuous, age-sex-ethnicity-specific MetS score to better identify CVD risk in a Chinese population.
- Shujuan Yang
- , Bin Yu
- & Peng Jia
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Article
| Open AccessZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production
Insulin receptor levels are closely related to insulin sensitivity. Here, the authors show that ZFYVE28 is involved in insulin resistance by promoting the degradation of phosphorylated insulin receptor and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.
- Liang Yu
- , Mengchen Xu
- & Yibo Wang
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Article
| Open AccessTripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation
Nonalcoholic steatohepatitis (NASH) is a heterogeneous disease with complicated pathogenesis. Here the authors identify that the E3 ligase TRIM26 confers protection against NASH development via suppression of CCAAT/enhancer binding protein delta (C/EBPδ).
- Minxuan Xu
- , Jun Tan
- & Lianyi Han
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Article
| Open AccessPhage-microbe dynamics after sterile faecal filtrate transplantation in individuals with metabolic syndrome: a double-blind, randomised, placebo-controlled clinical trial assessing efficacy and safety
Bacteriophages (phages) can modify the gut microbiome to benefit human health. Here, the authors report the results of a double blind, randomized, placebo-controlled trial, showing that faecal filtrate transplantation (FFT), containing phages from lean healthy donors, is safe and improves glycemic variability in patients with metabolic syndrome, while shifting the gut phage composition.
- Koen Wortelboer
- , Patrick A. de Jonge
- & Hilde Herrema
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Article
| Open AccessDeficiency of endothelial sirtuin1 in mice stimulates skeletal muscle insulin sensitivity by modifying the secretome
Endothelial Sirtuin1 downregulation in metabolic disorders causes vascular dysfunction and inflammation. Here, the authors show that deficiency of endothelial Sirtuin1, while having deleterious effects on the vasculature, stimulates skeletal muscle insulin sensitivity and improves glucose disposal.
- Qiuxia Li
- , Quanjiang Zhang
- & Kaikobad Irani
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Article
| Open AccessThe interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis
Here, Schoeler et al. investigate how interaction between dietary lipids and the gut microbiota affect hepatic steatosis and host metabolism, showing that dietary lipids impact the gut microbiota composition independent on fiber intake in humans and mice.
- Marc Schoeler
- , Sandrine Ellero-Simatos
- & Robert Caesar
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Article
| Open AccessGut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome
Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes.
- Lixiang Zhai
- , Haitao Xiao
- & Zhao-Xiang Bian
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Article
| Open AccessREPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
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Article
| Open AccessCullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality, and there is no specific drug to treat it. Here, the authors show that the AR-CAND1-ACAA2 axis regulates the development of NAFLD, and enhancing the function of CAND1 is a promising strategy for the development of a therapeutic agent for NAFLD.
- Xiang Huang
- , Xin Liu
- & Zhenwei Pan
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Article
| Open AccessDetermining the metabolic effects of dietary fat, sugars and fat-sugar interaction using nutritional geometry in a dietary challenge study with male mice
The role of dietary fat vs sugar in the global obesity epidemic remains controversial. Using Nutritional Geometry methodology, the authors show that, in mice, both fats and sugars could lead to adverse metabolic outcomes, depending on the dietary context.
- Jibran A. Wali
- , Duan Ni
- & Stephen J. Simpson
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Article
| Open AccessThe muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice
Interorgan communications play key roles in the regulation of whole-body energy metabolism. Here, the authors report the myokine Musclin as a negative regulator of beige adipose thermogenesis and systemic energy homeostasis through Tfr1/PKA signalling mediated muscle fat crosstalk.
- Lu Jin
- , Shuang Han
- & Zhuo-Xian Meng
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Article
| Open AccessModeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages
Hepatic insulin resistance is an established driver of type 2 diabetes but is difficult to model in vitro. Here researchers use co-culture of hepatocytes and macrophages derived from the same human iPSC line to show how inflammation disrupts insulin-mediated regulation of hepatic glucose metabolism and identify targets for therapy of hepatic insulin resistance.
- Marko Groeger
- , Koji Matsuo
- & Holger Willenbring
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Article
| Open AccessSenescent immune cells accumulation promotes brown adipose tissue dysfunction during aging
With increasing age, brown adipose tissue (BAT) becomes characterized by increased adiposity and immune cell infiltration but reduced thermogenic capacity. Here the authors report that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells accumulate in BAT of male rats and mice during aging and contribute to BAT dysfunction.
- Xu Feng
- , Liwen Wang
- & Haiyan Zhou
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Article
| Open AccessAn integrated single cell and spatial transcriptomic map of human white adipose tissue
Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue.
- Lucas Massier
- , Jutta Jalkanen
- & Niklas Mejhert
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Article
| Open AccessSAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice
Inhibition of AMPK leads to metabolic perturbations yet how AMPK is inactivated is not fully understood. Here the authors show protein phosphatase 6 subunit SAPS3 is a negative regulator of AMPK and loss of SAPS3 activates AMPK and protects male mice against overnutrition.
- Ying Yang
- , Michael A. Reid
- & Mei Kong
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Article
| 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 AccessChronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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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 AccessAdipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2.
- Tianshi Feng
- , Xuemei Zhao
- & Xiaoyan Hui
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Article
| Open AccessSpermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression
Spermidine, a polyamine reported to extend lifespan and reduce the risk of age-related diseases, serves as a substrate for the post-translational modification hypusination. Here the authors report that EIF5A hypusination, which regulates mitochondrial protein synthesis, is reduced during non-alcoholic steatohepatitis (NASH), which can be prevented by spermidine to inhibit the progression of NASH in mice.
- Jin Zhou
- , Jeremy Pang
- & Paul Michael Yen
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Article
| Open AccessProhormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing
Defective insulin secretion is observed early in the development of diabetes. Here the authors report that β cell-specific deficiency of the insulin prohormone convertase 1/3 (PC1/3) leads not only to hyperglycemia, but also to hyperphagic obesity in mice.
- Daniel T. Meier
- , Leila Rachid
- & Marc Y. Donath
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Article
| Open AccessEGFR-mediated activation of adipose tissue macrophages promotes obesity and insulin resistance
In obesity, adipose tissue is chronically inflamed, leading to insulin resistance, and adipose tissue macrophages (ATMs) are a major source of cytokines that aggravate adipocyte dysfunction. Here, the authors show that selective deletion of the epidermal growth factor receptor in ATMs decreased obesity and development of insulin resistance.
- Shirong Cao
- , Yu Pan
- & Ming-Zhi Zhang
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Article
| Open AccessFGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice
The restriction of dietary protein or amino acid intake is well established to extend lifespan in multiple species. Here, the authors show that the endocrine hormone FGF21 is necessary for dietary protein restriction to extend lifespan and improve metabolic health in aged, male mice.
- Cristal M. Hill
- , Diana C. Albarado
- & Christopher D. Morrison
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Article
| Open AccessLong-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle
Endoplasmic Reticulum stress induces cell non-autonomous Unfolded Protein Response (UPR) activation. Here the authors show that long-chain ceramides are secreted from muscle cells in extracellular vesicles and induce cell non-autonomous UPR activation in muscle cells in response to lipotoxcity.
- Ben D. McNally
- , Dean F. Ashley
- & Lee D. Roberts
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Article
| Open AccessDeep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis.
- Magdalene K. Montgomery
- , Jacqueline Bayliss
- & Matthew J. Watt
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Article
| Open AccessSmall molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes
Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.
- Susheel K. Gunasekar
- , Litao Xie
- & Rajan Sah
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Article
| Open AccessThe mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production
Disordered hepatic glucagon response contributes to hyperglycemia in diabetes via gluconeogenesis. Here the authors report that the mitochondrial β-oxidation enzyme HADHA promotes β-hydroxybutyrate production, which negatively regulates hepatic gluconeogenesis during glucagon challenge by targeting HDAC7 in mice.
- An Pan
- , Xiao-Meng Sun
- & Lian-Wen Qi
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Article
| Open AccessGPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1
Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism.
- Lucia Balazova
- , Miroslav Balaz
- & Christian Wolfrum
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Article
| Open AccessSpatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis
How enhancers transition from a hypoacetylated primed state to a hyperacetylated-active state in response to differentiation stimuli is incompletely understood. Here the authors show that SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of master adipogenic gene enhancers, while SETD5 degradation triggers enhancer hyperacetylation and transition to active state.
- Yoshihiro Matsumura
- , Ryo Ito
- & Juro Sakai
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Article
| Open AccessAngiogenin mediates paternal inflammation-induced metabolic disorders in offspring through sperm tsRNAs
Paternal environmental inputs can influence various phenotypes in offspring, with important implications for basic biology and public health. Here the authors show that Ang-mediated biogenesis of 5′-tsRNAs in sperm contributes to paternal inflammation-induced metabolic disorders in offspring.
- Yanwen Zhang
- , Li Ren
- & Bin He
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Article
| Open AccessAGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway
AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the synthesis of all glycerolipids. Here, the authors show that AGPAT2 and CDP-DAG synthases (CDS1 and CDS2) form functional complexes that promote further conversion of PA along the CDP-DAG pathway of phospholipid synthesis.
- Hoi Yin Mak
- , Qian Ouyang
- & Hongyuan Yang
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Article
| Open AccessAdipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue
Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.
- Xin Cui
- , Jia Jing
- & Hang Shi
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Article
| Open AccessO-GlcNAcylated p53 in the liver modulates hepatic glucose production
p53 regulates signalling pathways involved in metabolic homeostasis. Here the authors show that O-GlcNAcylation of p53 in the liver plays a key role in the physiological regulation of glucose homeostasis, potentially via controlling the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase.
- Maria J. Gonzalez-Rellan
- , Marcos F. Fondevila
- & Ruben Nogueiras
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Article
| Open AccessOrphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue
The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.
- Anastasia Georgiadi
- , Valeria Lopez-Salazar
- & Stephan Herzig
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Review Article
| Open AccessEmerging concepts in intestinal immune control of obesity-related metabolic disease
At the centre of intestinal health and the fight against obesity and metabolic syndrome is the intestinal microbiota and its interaction with our immune systems. Here the authors Review the current understanding of how these systems interact and how we can capitalize on recent advances to provide better therapeutic options.
- Saad Khan
- , Helen Luck
- & Daniel A. Winer
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Article
| Open AccessHigh-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.
- Anil Kumar
- , Kumaran Sundaram
- & Huang-Ge Zhang
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Article
| Open AccessMyeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation
Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.
- David R. Sweet
- , Neelakantan T. Vasudevan
- & Mukesh K. Jain