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| Open AccessRegulation of substrate utilization and adiposity by Agrp neurons
Agouti-related peptide (AgRP) producing neurons regulate food intake and metabolic processes in peripheral organs. Here, the authors show that hypothalamic AgRP neurons alter whole body substrate utilization to favour carbohydrate usage and lipid storage.
- João Paulo Cavalcanti-de-Albuquerque
- , Jeremy Bober
- & Marcelo O. Dietrich
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| Open AccessIntergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila
Animal studies have shown that the nutritional status of parents can predispose the offspring to obesity and obesity-related diseases. Here the authors show that cardiac dysfunction induced by a high-fat diet persists for two generations in Drosophila, and that targeted expression of ATGL/bmm in the offspring, as well as inhibition of H3K27 trimethylation, is cardioprotective.
- Maria Clara Guida
- , Ryan Tyge Birse
- & Rolf Bodmer
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Article
| Open AccessEffective weight control via an implanted self-powered vagus nerve stimulation device
Developing new technologies for the neuromodulation of the vagus nerve can enable therapeutic strategies for body weight control in obese patients. Here, the authors present a battery-free self-powered implantable vagus nerve stimulation system that electrically responds to stomach movement.
- Guang Yao
- , Lei Kang
- & Xudong Wang
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| Open AccessAn inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.
- Hanyong Sun
- , Weiqin Yang
- & Alfred S. L. Cheng
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Article
| Open AccessDiet-induced adaptive thermogenesis requires neuropeptide FF receptor-2 signalling
Excess caloric intake leads to increased thermogenesis in brown adipose tissue, to limit weight gain. Here, the authors show that neuropeptide FF receptor-2 signalling promotes thermogenesis via control of NPY expression in the arcuate nucleus, and that it absence in mice leads to a failure of activation of diet-induced thermogenesis and the development of exacerbated obesity.
- Lei Zhang
- , Chi Kin Ip
- & Herbert Herzog
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Article
| Open AccessLong term but not short term exposure to obesity related microbiota promotes host insulin resistance
Gut microbiota impact host metabolism and gut microbiome composition reflects dietary habits. Here the authors show that, in animals fed obesogenic diets, changes in gut microbiota precede changes in glucose homeostasis. Importantly, long term exposure of the host to the changed microbiota is required to impair glucose homeostasis.
- Kevin P. Foley
- , Soumaya Zlitni
- & Jonathan D. Schertzer
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| Open AccessThe gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD
Infants born to obese mothers have altered microbiome and increased risk of obesity and NAFLD. Here the authors establish causality by showing that maternal obesity-shaped infant gut microbiome induces macrophage dysfunction, inflammation, and diet-induced metabolic disease in germ-free mice.
- Taylor K. Soderborg
- , Sarah E. Clark
- & Jacob E. Friedman
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Article
| Open AccessER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes
HRD1 is an E3 ligase known to play a role in targeting degradation of misfolded proteins in the ER. Here the authors show that HRD1 interacts with metabolic enzymes and its liver specific deficiency results in lower body weight, blood glucose and plasma lipids during high fat diet in mice.
- Juncheng Wei
- , Yanzhi Yuan
- & Deyu Fang
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Article
| Open Accessp53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
Emerging studies suggest that p53 is an important regulator of energy metabolism, yet there is little known about the metabolic function of this tumor suppressor in the hypothalamus. Here, authors illustrate that p53, specifically in AgRP neurons, is required for adaptation to diet-induced obesity.
- Mar Quiñones
- , Omar Al-Massadi
- & Ruben Nogueiras
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Article
| Open AccessLoss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
AMPK activation has been suggested as treatment for obesity and its complications. Here the authors show that the ubiquitin ligase MKRN1 binds to AMPK and mediates its ubiquitination and degradation. Loss of MKRN1 leads to AMPK activation, increased glucose consumption and decreased lipid accumulation.
- Min-Sik Lee
- , Hyun-Ji Han
- & Jaewhan Song
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Article
| Open AccessReduced oxidative capacity in macrophages results in systemic insulin resistance
M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.
- Saet-Byel Jung
- , Min Jeong Choi
- & Minho Shong
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Article
| Open AccessTAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis
Sexual dimorphism exists in a number of physiological processes, including energy homeostasis. Here, the authors show that pro-opiomelanocortin neurons in female mice fire more rapidly than males, and that deletion of the transcription TAp63 leads to a reduced neuronal firing rate and a male-like susceptibility to diet-induced obesity.
- Chunmei Wang
- , Yanlin He
- & Yong Xu
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Article
| Open AccessIntegration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS
GWAS have identified numerous genetic loci for BMI and related traits. Here, Pan et al. generate Promoter Capture Hi-C data for human white adipocytes and integrate these with data of transcription factor motifs, RNA-seq and GWAS to identify eQTL-eGene relationships mediated by chromosomal interactions.
- David Z. Pan
- , Kristina M. Garske
- & Arthur Ko
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Article
| Open AccessCDK6 inhibits white to beige fat transition by suppressing RUNX1
Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.
- Xiaoli Hou
- , Yongzhao Zhang
- & Miaofen G. Hu
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Article
| Open AccessDe novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity
Adipocyte hyperplasia is thought to have beneficial metabolic effects in obesity, but definitive evidence is lacking. Here, Shao et al. promote de novo formation of adipocytes in visceral white adipose tissue (WAT) of adult mice through inducible overexpression of Pparg in Pdgfrβ+ preadipocytes and show that this protects from pathological WAT remodeling.
- Mengle Shao
- , Lavanya Vishvanath
- & Rana K. Gupta
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Article
| Open AccessBone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4
Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
- Ailing Liu
- , Minhui Chen
- & Lisa Borghesi
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Article
| Open AccessEpigenetic modulation of Fgf21 in the perinatal mouse liver ameliorates diet-induced obesity in adulthood
FGF21 exerts beneficial metabolic effects on multiple tissues. Here the authors show that the Fgf21 gene is demethylated during the postnatal suckling period, creating an epigenetic memory that determines the responsiveness of the Fgf21 gene to inducers such as PPARα activators or fasting in adulthood.
- Xunmei Yuan
- , Kazutaka Tsujimoto
- & Yoshihiro Ogawa
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Article
| Open AccessFibroblast growth factor 21 increases insulin sensitivity through specific expansion of subcutaneous fat
FGF21 has a number of beneficial metabolic effects. Here, Li et al. show that FGF21 promotes the healthy expansion of subcutaneous white adipose tissue, promoting the healthy expansion of fat tissue as a regulatory mechanism to maintain systemic insulin sensitivity during nutrient excess.
- Huating Li
- , Guangyu Wu
- & Weiping Jia
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Article
| Open AccessTGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue
White adipose tissue can undergo a process of beiging and acquire functional characteristics similar to brown adipose tissue, including the ability to dissipate energy via uncoupled respiration. Here, Velazquez-Villegas et al. show that activation of the bile acid membrane receptor, TGR5, leads to white adipocyte beiging by promoting mitochondrial fission.
- Laura A. Velazquez-Villegas
- , Alessia Perino
- & Kristina Schoonjans
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Article
| Open AccessGLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose
The sweetener D-allulose has beneficial metabolic effects in animal models, but its mechanism of action was unclear. Here the authors report that D-allulose triggers GLP-1 release in the gut and GLP-1R signaling on vagal afferents, counteracting arrhythmic overeating, obesity and diabetes.
- Yusaku Iwasaki
- , Mio Sendo
- & Toshihiko Yada
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Article
| Open AccessA miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning
White adipocytes can be stimulated to express thermogenic genes in a process known as beiging. Here, the authors show that miR-327 is downregulated during beiging, which releases FGF10 from inhibition and supports beige adipocyte formation via signaling through FGFR2.
- Carina Fischer
- , Takahiro Seki
- & Yihai Cao
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Article
| Open AccessProtein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator
Although many genetic variants are known for obesity, their function remains largely unknown. Here, in a weight-loss intervention cohort, the authors identify protein quantitative trait loci associated with BMI at baseline and after weight loss and find FAM46A to be a regulator of leptin in adipocytes.
- Jérôme Carayol
- , Christian Chabert
- & Jörg Hager
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Article
| Open AccessAncestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice
Early life exposure to endocrine disrupting chemicals has been linked to increased adiposity during adulthood. Here Chamorro-García et al. show that ancestral exposure to the obesogen tributyltin causes obesity in untreated F4 generation male descendants by inducing heritable changes in genome architecture that promote a thrifty phenotype.
- Raquel Chamorro-Garcia
- , Carlos Diaz-Castillo
- & Bruce Blumberg
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Article
| Open AccessNeuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism
Neuronal signals, in particular those transmitted via the vagal nerve, regulate both β-cell function and proliferation. Here, Yamamoto et al. show that the forkhead box M1 pathway is required for vagal signal-mediated induction of β-cell proliferation during obesity.
- Junpei Yamamoto
- , Junta Imai
- & Hideki Katagiri
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Article
| Open AccessStress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function
Stress is recognized as risk factor for the development of type 2 diabetes. Here Balsevich et al. show that the stress responsive co-chaperone FKBP5 regulates glucose metabolism in mice by modulating AS160 phosphorylation, glucose transporter expression and muscle glucose uptake.
- Georgia Balsevich
- , Alexander S. Häusl
- & Mathias V. Schmidt
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Article
| Open AccessMacrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
VLDLR regulates cellular lipoprotein uptake and storage. Here, the authors show that VLDLR, expressed on adipose tissue macrophages, is upregulated in obesity and promotes adipose tissue inflammation by upregulating ceramide production and facilitating M1-like macrophage polarization.
- Kyung Cheul Shin
- , Injae Hwang
- & Jae Bum Kim
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Article
| Open AccessMANF regulates hypothalamic control of food intake and body weight
MANF is a neurotrophic factor that is secreted but also mediates the unfolded protein response acting intracellularly. Here, the authors show that MANF expression in the brain is influenced by nutritional cues, and hypothalamic MANF influences food intake and systemic energy homeostasis.
- Su Yang
- , Huiming Yang
- & Xiao-Jiang Li
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Article
| Open AccessCD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors
Adipose tissue contains macrophages that can influence both local and systemic metabolism via the secretion of cytokines. Here, Nawaz et al. report that M2-like macrophages, present in adipose tissue, create a microenvironment that inhibits proliferation of adipocyte progenitors due to the secretion of TGF-β1
- Allah Nawaz
- , Aminuddin Aminuddin
- & Kazuyuki Tobe
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Article
| Open AccessRETRACTED ARTICLE:Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives
Harmful chemicals that disrupt the endocrine system and hormone regulation have been associated with obesity. Here the authors apply a human pluripotent stem cell-based platform to study the effects of such compounds on developing gut endocrine and neuroendocrine systems.
- Uthra Rajamani
- , Andrew R. Gross
- & Dhruv Sareen
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Article
| Open AccessEndotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
- Jia Cao
- , Jinghua Peng
- & Ling He
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Article
| Open AccessHDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning
Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
- Alessandra Ferrari
- , Raffaella Longo
- & Maurizio Crestani
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Article
| Open AccessCentral insulin modulates food valuation via mesolimbic pathways
The influence of insulin on food preference and the corresponding underlying neural circuits are unknown in humans. Here, the authors show that increasing insulin changes food preference by modulating mesolimbic neural circuits, and that this pattern is changed in insulin-resistant individuals.
- Lena J. Tiedemann
- , Sebastian M. Schmid
- & Stefanie Brassen
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Article
| Open AccessAdipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells
Obesity is associated with inflammation in adipose tissue, characterized by a shift in local T cell subsets. Here the authors show that loss of MHCII expression on adipocytes increases levels of immunosuppressive regulatory T cells in adipose tissue, which enhances insulin sensitivity.
- Tuo Deng
- , Joey Liu
- & Willa A. Hsueh
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Article
| Open AccessCaffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice
The mechanism by which caffeine, an antagonist of adenosine receptors, regulates metabolism is not clear. Here the authors show that adenosine A1R receptor expression is increased in the hypothalamus of diet-induced obesity mice, and that body weight can be alleviated by central administration of caffeine via its action on hypothalamic oxytocin neurons.
- Liufeng Wu
- , Jia Meng
- & Guo Zhang
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Article
| Open AccessTNFα drives mitochondrial stress in POMC neurons in obesity
Long-term consumption of a calorie-rich diet persistently activates brain microglia. Here, the authors show that microglial activity in mouse brains oscillates daily in conjunction with feeding, and that TNFα, secreted by activated microglia, induces mitochondrial stress in satiety-promoting POMC neurons.
- Chun-Xia Yi
- , Marc Walter
- & Matthias H. Tschöp
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Article
| Open AccessTemporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance
Interleukin-6 (IL-6) is increased in obesity and activates T cells to promote inflammation. Here, Xuet al. use mice that lack IL-6 receptors on T cells to uncover the temporal and tissue-specific effects of classic and trans IL-6 signalling on inflammation and insulin resistance on a high-fat diet.
- Elaine Xu
- , Mafalda M. A. Pereira
- & Jens C. Brüning
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Article
| Open AccessGenome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits
Genome-wide association studies (GWAS) have become a key tool to discover genetic markers for complex traits; however, environmental factors that interact with genes are rarely considered. Here, the authors conduct a GWAS of obesity traits, and find that smoking may alter genetic susceptibilities.
- Anne E. Justice
- , Thomas W. Winkler
- & L Adrienne Cupples
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Article
| Open AccessSex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice
Unlike males, female mice are resistant to hypothalamic inflammation and weight gain when fed a high-fat diet. Here, the authors reveal sex-specific regulation of hypothalamic microglial activation through CX3CR1 signalling, providing a potential mechanism for differential susceptibility to diet-induced obesity.
- Mauricio D. Dorfman
- , Jordan E. Krull
- & Joshua P. Thaler
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Article
| Open AccessA-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes
The protein A-FABP is secreted from adipocytes and known to regulate glucose and lipid metabolism. Here the authors show A-FABP enhances thermogenesis by promoting the conversion of thyroxine T4 to the bioactive form, T3, in brown adipocytes, and by enhancing fatty acid uptake of brown fat.
- Lingling Shu
- , Ruby L. C. Hoo
- & Aimin Xu
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Article
| Open AccessInhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity
Glycine sensing in the dorsal vagal complex (DVC) regulates hepatic glucose production in rodents. Here the authors show that pharmacological and molecular inhibition of glycine reuptake in the DVC potentiates NMDA receptors, and improves metabolic homeostasis in animal models of obesity and diabetes.
- Jessica T. Y. Yue
- , Mona A. Abraham
- & Tony K. T. Lam
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Article
| Open AccessObesity-associated NLRC4 inflammasome activation drives breast cancer progression
Obesity is associated with higher breast cancer risk and poor prognosis. Here, the authors show that obesity promotes breast cancer through the recruitment of macrophages with activated NLRC4 inflammasome, which activate IL-1β production, resulting in VEGFA expression in adipocytes and angiogenesis.
- Ryan Kolb
- , Liem Phan
- & Weizhou Zhang
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Article
| Open AccessThe obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation
Visceral and subcutaneous fat are associated with different metabolic risk, but mediators of such depot specific effects are not very well known. Here the authors identify the transcriptional regulator, TRIP-Br2, as a regulator of endoplasmic reticulum (ER) stress-induced inflammatory responses specifically in visceral fat.
- Guifen Qiang
- , Hyerim Whang Kong
- & Chong Wee Liew
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Article
| Open AccessThe Gq signalling pathway inhibits brown and beige adipose tissue
Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that Gq-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.
- Katarina Klepac
- , Ana Kilić
- & Alexander Pfeifer
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Article
| Open AccessTenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion
Expansion of visceral adipose tissue is usually associated with insulin resistance and metabolic disease. Here, the authors show that the membrane protein TNMD is upregulated in visceral fat of insulin resistant obese individuals and promotes healthy adipose tissue expansion through increasing adipogenesis.
- Ozlem Senol-Cosar
- , Rachel J. Roth Flach
- & Michael P. Czech
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Article
| Open AccessPKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications
Protein kinase R (PKR) has been suggested to act as a mediator of ER stress and inflammation in obesity. Here, Lancaster et al. find that genetic loss of PKR does not alter the development of obesity, and suggest that the use of littermate controls may explain differences in mouse knockout phenotypes.
- G. I. Lancaster
- , H. L. Kammoun
- & M. A. Febbraio
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Article
| Open AccessGenome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.
- Tuomas O. Kilpeläinen
- , Jayne F. Martin Carli
- & Ruth J. F. Loos
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Article
| Open AccessA mouse model for a partially inactive obesity-associated human MC3R variant
The melanocortin receptor, MC3R, regulates organismal energy homeostasis. Here, Lee et al. create knock-in mice with the a mutated version of the human MC3R receptor found in obese children, and show these mice have more fat and smaller bone, yet are by and large metabolically healthy.
- Bonggi Lee
- , Jashin Koo
- & Jack A. Yanovski
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Article
| Open AccessPeriprostatic adipocytes act as a driving force for prostate cancer progression in obesity
Obesity is associated with an elevated risk of prostate cancer. Here, the authors show that periprostatic adipose tissue promotes the migration and local invasion of prostate cancer cells by secreting the chemokine, CCL7, and that this process is enhanced in the context of obesity.
- Victor Laurent
- , Adrien Guérard
- & Catherine Muller
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Article
| Open AccessElevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation
Alzheimer's disease is linked to metabolic syndrome and Type-2 diabetes, but the mechanism behind this association is unclear. Here, the authors show that elevated glucose and amyloid ß work together to increase nitrosative stress, leading to aberrant mitochondrial activity and synaptic dysfunction.
- Mohd Waseem Akhtar
- , Sara Sanz-Blasco
- & Stuart A. Lipton