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| Open AccessSingle cell tracing of Pomc neurons reveals recruitment of ‘Ghost’ subtypes with atypical identity in a mouse model of obesity
Whether and how hypothalamic neurons can lose or change their identity in adulthood has remained elusive. Here, the authors show that mature pro-opiomelanocortin (Pomc) neurons contain invisible ‘Ghost’ subsets with atypical identities that are recruited in response to obesogenic stimuli.
- Stéphane Leon
- , Vincent Simon
- & Carmelo Quarta
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Article
| Open AccessAn estrogen receptor α-derived peptide improves glucose homeostasis during obesity
Type 2 diabetes mellitus is an increasing global health issue, which is caused by systemic insulin resistance. Here, the authors show a ligand-independent effect of hepatic ERα in regulating insulin sensitivity and identify an ERα-derived peptide that functions as an insulin sensitizer.
- Wanbao Yang
- , Wen Jiang
- & Shaodong Guo
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| Open AccessAZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation
The hypothalamus is essential for energy regulation, with POMC neurons crucial for controlling food intake and energy balance. Here, the authors show that AZGP1 improves leptin sensitivity in POMC neurons, aiding in weight loss and energy use by altering leptin-JAK2-STAT3 signalling.
- Sheng Qiu
- , Qinan Wu
- & Mengliu Yang
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Article
| Open AccessObesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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Article
| Open AccessA negative feedback loop between TET2 and leptin in adipocyte regulates body weight
The epigenetic regulation in adipocytes during obesity remains poorly understood. Here, the authors demonstrate a negative feedback loop between TET2, a DNA demethylation enzyme, and leptin, an adipokine, in adipocytes, unveiling a compensatory mechanism by which the body counteracts the metabolic dysfunction induced by obesity.
- Qin Zeng
- , Jianfeng Song
- & Tuo Deng
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| 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 AccessMaternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice
Maternal high fat diet during lactation predisposes offspring to develop obesity in males more than females. Here, authors show expansion of key metabolic related hypothalamic neuron populations in male but not female mice, in response to maternal fat intake.
- Yi Huang
- , Anyongqi Wang
- & John R. Speakman
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Article
| Open AccessHypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
The cellular levels of the critical coenzyme nicotinamide adenine dinucleotide (NAD)+ depend on its salvage pathway. Here, the authors show that the NAD+ salvage pathway in hypothalamic astrocytes is activated to promote obesity in high fat diet-fed mice.
- Jae Woo Park
- , Se Eun Park
- & Min-Seon Kim
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Article
| Open AccessM2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1
Adipose beiging is a positive biological change, which is often thought to be primarily sympathetically induced. Here, the authors show that M2 macrophages can independently promote beige adipogenesis, further revealing the adipocyte transcription factor Ets1 as a negative regulator of this process.
- Suyang Wu
- , Chen Qiu
- & Xiao Han
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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| Open AccessProtection against overfeeding-induced weight gain is preserved in obesity but does not require FGF21 or MC4R
Overfeeding triggers a mechanistically ill-defined compensatory response that counteracts weight gain. Here, the authors show that the defence against overfeeding is preserved in obesity, and that it is independent from FGF21 and MC4R.
- Camilla Lund
- , Pablo Ranea-Robles
- & Christoffer Clemmensen
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Article
| Open AccessGlucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages
Glucocorticoids, potent anti-inflammatory drugs, can cause or exacerbate obesity, yet the underlying molecular mechanisms remain largely unknown. Here, the authors show KLF9 in macrophages integrates the beneficial anti-inflammatory and adverse metabolic effects of glucocorticoids.
- Yinliang Zhang
- , Chunyuan Du
- & Yongsheng Chang
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Article
| Open AccessArtesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis
Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.
- Xuanming Guo
- , Pallavi Asthana
- & Hoi Leong Xavier Wong
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| Open AccessAmyloid beta 42 alters cardiac metabolism and impairs cardiac function in male mice with obesity
Epidemiological evidence has identified associations among obesity, Alzheimer’s disease, and cardiovascular disease. Here, the authors report that adipose tissue releases amyloid beta 42 (Aβ42) and that antagonizing Aβ42 protects cardiac function in obesity murine models.
- Liam G. Hall
- , Juliane K. Czeczor
- & Sean L. McGee
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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 AccessApoL6 associates with lipid droplets and disrupts Perilipin1-HSL interaction to inhibit lipolysis
Lipolysis in adipose tissue releases fatty acids during fasting. Here, authors show that ApoL6, a lipid droplet-associated protein, is specifically expressed in adipocytes upon feeding to inhibit lipolysis by directly interacting with Perilipin 1 to competitively inhibit Perilipin 1-HSL interaction.
- Yuhui Wang
- , Hai P. Nguyen
- & Hei S. Sul
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| 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 AccessEffects of accelerometer-based sedentary time and physical activity on DEXA-measured fat mass in 6059 children
Childhood obesity remains a global epidemic. Here, using objective measurements, the authors show that sedentary time increased from 6 h/day in childhood to 9 h/day in young adulthood, and was cumulatively associated with increased total and trunk fat mass. Both light or moderate-to-vigorous physical activity similarly partly reversed risk.
- Andrew O. Agbaje
- , Wei Perng
- & Tomi-Pekka Tuomainen
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Article
| Open AccessSkeletal muscle-secreted DLPC orchestrates systemic energy homeostasis by enhancing adipose browning
MyoD is a transcription factor expressed in skeletal muscle that plays a critical role in determining myogenic cell fate. Here, Hu et al. reveal a metabolic role of MyoD in orchestrating systemic energy homeostasis by mediating muscle-fat crosstalk through the muscle-secreted lipokine DLPC.
- Xiaodi Hu
- , Mingwei Sun
- & Dahai Zhu
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| Open AccessCerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Ceramides in peripheral tissues contribute to obesity-related metabolic dysfunction. This study reveals that CerS6-derived ceramides induce hypothalamic lipotoxicity in mice via altered ER/mitochondrial homeostasis.
- Philipp Hammerschmidt
- , Sophie M. Steculorum
- & Jens C. Brüning
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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 AccessA common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators
A common East Asian-specific defect of an alcohol metabolizing enzyme (ALDH2) causes glucose abnormality, obesity, and fatty liver. Here, the authors show an ALDH2 activator can treat these metabolic disorders in mice.
- Yi-Cheng Chang
- , Hsiao-Lin Lee
- & Lee-Ming Chuang
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Article
| Open AccessImpaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence
Plakophilin-2 is a key component of desmosomes required to maintain cardiac tissue cohesion. Here the authors uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired Plakophilin-2 in subjects with obesity.
- Aina Lluch
- , Jessica Latorre
- & Francisco J. Ortega
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| 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 AccessMitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons
SHLP2 is a mitochondrial-derived peptide that plays an important role in energy homeostasis. Here, the authors show SHLP2’s protective effect against obesity and its mechanisms of action by binding to CXCR7 and activating hypothalamic neurons that regulate food intake, energy expenditure, and glucose homeostasis.
- Seul Ki Kim
- , Le Trung Tran
- & Ki Woo Kim
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| 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 AccessIncreased body mass index is linked to systemic inflammation through altered chromatin co-accessibility in human preadipocytes
Preadipocytes contribute to the pro-inflammatory environment in obesity, via unknown mechanisms. Here, comparing monozygotic twin pairs, the authors show that co-accessibility of chromatin in preadipocytes is altered in siblings with higher compared to lower BMI, and that variants in these regions contribute to systemic inflammation via interactions with BMI.
- Kristina M. Garske
- , Asha Kar
- & Päivi Pajukanta
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| Open AccessDynamic chromatin architecture of the porcine adipose tissues with weight gain and loss
Here the authors study diet-induced weight gain/loss to identify chromatin architectures in adipose tissue (AT) associated obesity in a pig model. They found parallels and species-specific regulatory elements in humans and pigs that underpin AT specialization.
- Long Jin
- , Danyang Wang
- & Mingzhou Li
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Article
| Open AccessIntegrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
DNA methylation variation is associated with human obesity but a whether it plays a causal role in disease pathogenesis is unclear. Here, the authors perfom an integrative genomic study in human adipocytes to show that DNA methylation variations contribute to obesity and type 2 diabetes susceptibility, revealing underlying genomic and molecular mechanisms.
- Liam McAllan
- , Damir Baranasic
- & William R. Scott
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Article
| Open AccessLysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice
Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence, but the underlying mechanism remains poorly understood. Here, the authors show LAPTM5 expression ameliorates NASH and can potentially serve as a biological marker indicative of NASH progression.
- Lang Jiang
- , Jing Zhao
- & Jiahong Xia
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Article
| Open AccessMale reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity
We know that nutrition and obesity can impact male fertility, but specific dietary guidelines for men trying to conceive don’t exist. Here the authors show that diet composition is likely more important than body fat in influencing reproductive traits and each macronutrient has different impacts.
- A. J. Crean
- , S. Afrin
- & T. Pini
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Article
| Open AccessThe melanocortin action is biased toward protection from weight loss in mice
Melanocortin action is known to regulate body weight. Here the authors report that while inhibition of the hypothalamic melanocortin action leads to obesity in mice, chronic activation of melanocortin action is not sufficient to cause weight loss.
- Hongli Li
- , Yuanzhong Xu
- & Qingchun Tong
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Article
| Open AccessCirculating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure
Nicotinamide phosphoribosyl transferase (NAMPT) is a critical regulator of cellular nicotinamide adenine dinucleotide (NAD)+ levels. Here, the authors show that blood NAMPT contributes to the circadian rhythm generation of locomotor activity and energy expenditure by regulating hypothalamic NAD+ levels.
- Jae Woo Park
- , Eun Roh
- & Min-Seon Kim
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Article
| Open AccessTime-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice
The timing of NAD + supply determines its efficacy to treat metabolic disease. Here, the authors show that increasing NAD + at the early active phase maximizes weight loss and glucose regulation in mice. NAD + can displace the phase of the liver clock which can cause circadian misalignment.
- Quetzalcoatl Escalante-Covarrubias
- , Lucía Mendoza-Viveros
- & Lorena Aguilar-Arnal
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| 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 AccessAdipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice
Activation of white adipose tissue (WAT) thermogenesis alleviates obesity-associated metabolic disorders in rodents. Here the authors report that the m6 A RNA modification reader YTHDF1 promotes WAT thermogenesis in a study with male mice, and may be a potential target for the treatment of obesity.
- Sujun Yan
- , Xiaoling Zhou
- & Xiangwei Gao
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Article
| Open AccessN-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model
Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.
- Stefano Suzzi
- , Tommaso Croese
- & Michal Schwartz
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Article
| Open AccessFibroblastic reticular cells in lymph node potentiate white adipose tissue beiging through neuro-immune crosstalk in male mice
Beiging and thermogenesis in white adipose tissue (WAT) is an important adaptive response to cold exposure, but how the brain senses cold and subsequently induces beiging remains unclear. Here, the authors show that sympathetic nerves stimulate lymph nodes to release IL-33, thereby mediating cold-induced beiging of WAT.
- Lai Yee Cheong
- , Baile Wang
- & Aimin Xu
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Article
| Open AccessTime-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models
Time-restricted feeding (TRF) can prevent muscle function decline from obesogenic challenges. Here, the authors reveal that TRF improves muscle function through modulations of common and distinct pathways in diet- and genetic-induced obesity models.
- Christopher Livelo
- , Yiming Guo
- & Girish C. Melkani
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Article
| Open AccessA method for an unbiased estimate of cross-ancestry genetic correlation using individual-level data
Cross-ancestry genetic correlation can reveal differences in the genetic basis of traits between populations, but methods can be biased by ancestry-specific genetic architecture. Here, the authors present a method to for estimating cross-ancestry genetic correlations, accounting for ancestry-specific genetic architecture.
- Md. Moksedul Momin
- , Jisu Shin
- & S. Hong Lee
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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 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 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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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 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 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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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 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 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