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| 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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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 AccessEndothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Estrogen has anti-diabetic effects via estrogen receptor alpha (ERα). Here, authors show that via coupled nuclear and non-nuclear actions, ERα in endothelial cells promotes insulin transport to skeletal muscle to foster normal glucose homeostasis.
- Anastasia Sacharidou
- , Ken Chambliss
- & Philip W. Shaul
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| Open AccessDeterminants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes
In early type 2 diabetes, “induction” with short-term insulin therapy followed by “maintenance” with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization.
- Ravi Retnakaran
- , Jiajie Pu
- & Bernard Zinman
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| Open AccessEffect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes
A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.
- Doris R. Pierce
- , Malcolm McDonald
- & Paul R. Giacomin
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| Open AccessA gut feeling for drugs that have metabolic benefits
Resveratrol (REV) is a natural polyphenol with anti-obesity effects. However, the mechanisms remain unclear due to its low bioavailability and the lack of defined membrane-bound or nuclear receptors. Pang and colleagues reported that REV intervention (REV-I) alters gut microbiota and bile acid profile, leading to the inhibition of farnesoid X receptor (FXR) and attenuation of scavenger receptor class B type 1 (SR-B1)-mediated chylomicron secretion. This highlights a therapeutic potential of targeting gut microbiome and intestinal SR-B1 for obesity and diabetes treatment.
- Eryun Zhang
- , Alon Agua
- & Wendong Huang
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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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| Open AccessPrevalence of diabetic retinopathy and vision-threatening diabetic retinopathy in adults with diabetes in China
Current data on the national distribution of diabetic retinopathy (DR) is lacking. Here, the authors show the national distribution, associated multi-level factors, and visual impairment of DR and vision-threatening DR in Chinese adults with diabetes.
- Xuhong Hou
- , Limin Wang
- & Weiping Jia
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Article
| Open AccessRestoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
Type 2 diabetes (T2D) is characterized by pancreatic beta-cell failure. Here, the authors show restoration of Phosphatidylinositol transfer protein alpha (PITPNA), a mediator of PtdIns-4-phosphate synthesis in the trans-Golgi network, in human T2D islets reverses impaired insulin granule maturation, exocytosis, and ER stress.
- Yu-Te Yeh
- , Chandan Sona
- & Matthew N. Poy
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Article
| Open AccessOpportunistic detection of type 2 diabetes using deep learning from frontal chest radiographs
Traditional type 2 diabetes (T2D) screening methods often depend on age, BMI guidelines and glucose measurements. Here, authors use a deep learning model that leverages chest radiographs and electronic health record data to screen for T2D, highlighting potential for early detection and intervention.
- Ayis Pyrros
- , Stephen M. Borstelmann
- & William Galanter
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Article
| Open AccessLinker histone variant H1.2 is a brake on white adipose tissue browning
Thermogenic adipocytes are ideal targets to counteract obesity and associated metabolic disorders. Here, the authors show a regulatory role of linker histone variant H1.2 on iWAT browning and thermogenesis through an H1.2-IL10rα axis.
- Yangmian Yuan
- , Yu Fan
- & Ling Zheng
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Article
| Open AccessUBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis
The authors identify UBAP2 as a novel osteoporosis susceptibility gene by performing association studies focusing on coding regions of the genome, and report that it plays a role in bone homeostasis through the regulation of bone remodelling.
- Jeonghyun Kim
- , Bo-Young Kim
- & Seon-Yong Jeong
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Article
| Open AccessVariants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
The SART3 gene encodes an RNA-binding protein critical for spliceosome function. Here, the authors find that bi-allelic variants in SART3 underlie a congenital condition characterised by neuro-developmental defects and 46,XY gonadal dysgenesis.
- Katie L. Ayers
- , Stefanie Eggers
- & Andrew H. Sinclair
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Article
| Open AccessResistance to thyroid hormone induced tachycardia in RTHα syndrome
Patients with a mutant thyroid hormone receptor α1 are treated with high-dose thyroxine, but their heart rate remains low. Here, the authors show that the mutant receptor triggers cardiac reprogramming in the embryo, which prevents the response of specific ion channels and heart rate to the hormone.
- Riccardo Dore
- , Laura Watson
- & Jens Mittag
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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 AccessA versatile bioelectronic interface programmed for hormone sensing
Ultrasensitive, real-time profiling of bio-analytes is a prerequisite for precision medicine. Here, the authors present a versatile bio-electronic interface (VIBE) to sense signaling cascade-guided receptor-ligand interactions and show that it can detect hormone levels in blood samples and differentiate individual metabolic conditions.
- Preetam Guha Ray
- , Debasis Maity
- & Martin Fussenegger
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Article
| Open AccessTranscriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice
Glucocorticoids are known to induce insulin resistance via transcriptional activation of genes related to liver gluconeogenesis and insulin resistance. Here the authors report that in male mice treated with glucocorticoids, the transcriptional co-regulator EHMT2 is involved in the induction of Irs2 (a gene promoting insulin action) to restrict the extent of insulin resistance in the liver.
- Rebecca A. Lee
- , Maggie Chang
- & Jen-Chywan Wang
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Article
| Open AccessDax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice
Estrogen controls female fertility in part via restraining or promoting kisspeptin (Kiss1)-neuron activity in the arcuate hypothalamic nucleus and the AVPV hypothalamic nucleus, respectively. Here the authors report that estrogen receptor alpha (ERα) interacts with the genome and the nuclear receptor co-repressor NR0B1 (DAX1) to manifest region-specific actions on Kiss1 expression.
- Jose M. Ramos-Pittol
- , Isabel Fernandes-Freitas
- & Bryn M. Owen
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Article
| Open AccessDNA methylation markers for kidney function and progression of diabetic kidney disease
Epigenetic markers are potential biomarkers for diabetes and related complications. Here, the authors identify CpG sites associated with kidney function and its subsequent decline using both single-site and multisite analyses, which are shown to have functional significance in the kidney.
- Kelly Yichen Li
- , Claudia Ha Ting Tam
- & Ronald C. W. Ma
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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 AccessEndothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes
Although it is known that cellular crosstalk between endothelial cells and brown adipocytes is essential, it remains poorly understood. Here the authors show that SCF derived from the surrounding endothelial cells promotes lipid accumulation in BAT by enhancing lipogenic enzymes in through c-Kit activation.
- Hyuek Jong Lee
- , Jueun Lee
- & Gou Young Koh
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Article
| Open AccessResveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1
Resveratrol intervention improves lipid homeostasis, but how it can target multiple organs with very low bioavailability remains elusive. Here, the authors report that gut microbiota-bile acids are linked to the hypolipidemic effect of resveratrol via inhibiting the intestinal FXR/SR-B1 signalling pathway.
- Juan Pang
- , Fitore Raka
- & Tianru Jin
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Article
| Open AccessReduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice
Adipose tissue thermogenesis plays a role in appropriate response to cold exposure through incompletely understood mechanisms. Here the authors report that acute cold exposure increases the serum levels of bradykinin, which induces brown adipose tissue thermogenesis and white adipose tissue browning in male mice.
- Fei Xiao
- , Haizhou Jiang
- & Feifan Guo
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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 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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| Open AccessA rare human variant that disrupts GPR10 signalling causes weight gain in mice
The brain-expressed receptor GPR10 is involved in energy homeostasis in mice. Here the authors identify rare loss of function variants in GPR10 in people with severe obesity and showed that one of these variants causes obesity when modelled in mice, suggesting that future studies could explore GPR10 as a potential target for weight-loss therapy.
- Fleur Talbot
- , Claire H. Feetham
- & I. Sadaf Farooqi
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| Open AccessA phase I open-label clinical trial to study drug-drug interactions of Dorzagliatin and Sitagliptin in patients with type 2 diabetes and obesity
Dorzagliatin, which acts on the glucose sensor glucokinase, is a new class of anti-diabetic medicine. Here the authors report that in a phase I open-label trial co-administration of dorzagliatin and sitagliptin (a different class of anti-diabetic medicine) does not significantly change the pharmacokinetics of either medicine in patients with type 2 diabetes and obesity.
- Li Chen
- , Jiayi Zhang
- & Gregory J. Tracey
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Article
| Open AccessLoss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage
Thyroid hormones have an important role in fostering tumour progression, however their upstream regulators are less clear. Here, the authors identify the thyroid hormone activating enzyme type 2 deiodinase as a p53 target gene and demonstrate its contribution to tumour progression in p53 mutant squamous cell carcinoma.
- Annarita Nappi
- , Caterina Miro
- & Monica Dentice
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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 AccessGenomic and immune landscape Of metastatic pheochromocytoma and paraganglioma
The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.
- Bruna Calsina
- , Elena Piñeiro-Yáñez
- & Mercedes Robledo
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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 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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| 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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| 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 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 AccessAnalysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma
Puberty is an important developmental period marked by hormonal, metabolic and immunological changes. Here the authors report gene expression changes in immune cells associated with age and puberty, and that may be relevant for sex differences in susceptibility to asthma, in a longitudinal cohort of 251 children with asthma.
- Justyna A. Resztak
- , Jane Choe
- & Francesca Luca
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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 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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Article
| 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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Article
| 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 AccessDeconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice
The role of non-neuronal glial cells in the regulation of adipose tissue function are incompletely understood. Here the authors report that stimulation of mediobasal hypothalamic astrocytes promotes inguinal white adipose tissue lipolysis in mice, dependent on the activation of the pro-opiomelanocortin neurons.
- Dan Chen
- , Yong Qi
- & Yunlei Yang
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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