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| Open AccessB3galt5 functions as a PXR target gene and regulates obesity and insulin resistance by maintaining intestinal integrity
PXR regulates glycolipid metabolism, but the role of intestinal PXR in metabolic diseases remains unknown. Here, the authors show the intestinal-selective PXR activation regulates B3galt5 expression and maintains metabolic homeostasis via regulating the intestinal mucus barrier.
- Jinhang Zhang
- , Ya Huang
- & Yanping Li
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Article
| Open AccessUnraveling the molecular architecture of autoimmune thyroid diseases at spatial resolution
Autoimmune thyroid diseases (AITD) are complex conditions involving multiple cellular components of the thyroid tissue. In this study, the authors use spatial transcriptomics data to examine thyroid tissue, identifying distinct subsets of damaged thyroid follicular cells, myofibroblasts and capillaries in AITD.
- Rebeca Martínez-Hernández
- , Nuria Sánchez de la Blanca
- & Mónica Marazuela
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Article
| Open AccessThe reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes
Diabetes complications are attributed to reactive by-products of glycolysis, but cells consuming lactate and pyruvate are not spared. Here, the authors show that the reactive dicarbonyl dimethylglyoxal is formed from pyruvate, rises in diabetes, and potentially causes neurological complications of diabetes.
- Sina Rhein
- , Riccardo Costalunga
- & Markus Schwaninger
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Article
| Open AccessStart codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease
Here, the authors conduct a GWAS for autoimmune thyroid disease, finding 225 loci including a start codon variant in LAG3 that confers a 3.4-fold risk of autoimmune thyroid disease and reduces expression and plasma levels of LAG−3.
- Saedis Saevarsdottir
- , Kristbjörg Bjarnadottir
- & Kari Stefansson
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Article
| Open AccessSystematic review and meta-analysis of birth outcomes in women with polycystic ovary syndrome
This systematic review and meta-analysis provides evidence that polycystic ovary syndrome (PCOS) is a risk factor for adverse birth outcomes such as preterm birth, fetal growth restriction and low birth weight. Early screening for PCOS and pregnancy complications could improve birth outcomes and long-term health in offspring.
- Mahnaz Bahri Khomami
- , Somayeh Hashemi
- & Helena J. Teede
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Article
| Open AccessSystematic review and meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome
This meta-analysis demonstrates that polycystic ovary syndrome (PCOS) is a risk factor for adverse pregnancy outcomes such as miscarriage, gestational diabetes, hypertensive disorders of pregnancy and cesarean section, independent of age and BMI. Early screening for PCOS can improve pregnancy outcomes and long-term health in women.
- Mahnaz Bahri Khomami
- , Soulmaz Shorakae
- & Aya Mousa
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Review Article
| Open AccessMolecular insights into Sertoli cell function: how do metabolic disorders in childhood and adolescence affect spermatogonial fate?
Pediatric obesity is increasing worldwide and its contribution to the decline is sperm count has been questioned. By comprehensively reviewing the literature, the authors herein report molecular mechanisms that may suggest the causality of this association.
- Rossella Cannarella
- , Roberto Curto
- & Aldo E. Calogero
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Article
| Open AccessIdentification of unique cell type responses in pancreatic islets to stress
Endoplasmic reticulum and inflammatory stress are associated with diabetes. Maestas et al. use single-cell sequencing to profile primary human islets under stress and identified tissue and cell-type responses.
- Marlie M. Maestas
- , Matthew Ishahak
- & Jeffrey R. Millman
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Article
| Open AccessTotal and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans
GDF15 is secreted my mitochondria and promotes weight loss in animals, but its effect in humans remain unclear. Here, they authors show that in humans, GDG15 is increase in females with chronic caloric deficit, independent of leptin levels, and that it’s positively correlated with triglyceride-rich particiles.
- Pavlina Chrysafi
- , Laura Valenzuela-Vallejo
- & Christos S. Mantzoros
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Article
| Open AccessIntra-islet α-cell Gs signaling promotes glucagon release
Glucagon plays a key role in regulating blood glucose levels. Here, Liu et al. show that
activation of α-cell Gs signaling promotes the release of glucagon from pancreatic islets and ensures the synthesis of sufficient amounts of glucagon.
- Liu Liu
- , E. I. Kimberley
- & Jürgen Wess
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Article
| Open AccessMitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption
Bone and blood lineage cells communicate with each other to maintain skeletal homeostasis. Here, the authors show that MIRO1-mediated mitochondrial transfer from osteolineage to myeloid lineage cells regulates bone resorption by altering glutathione metabolism.
- Peng Ding
- , Chuan Gao
- & Junjie Gao
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Article
| Open AccessSmooth muscle NF90 deficiency ameliorates diabetic atherosclerotic calcification in male mice via FBXW7-AGER1-AGEs axis
The accumulation of AGEs is closely related to the atherosclerotic calcification in diabetic patients. Here, the authors find that VSMC NF90 knockout attenuates diabetic atherosclerotic calcification by mediating the metabolic imbalance of AGEs.
- Fei Xie
- , Bin Liu
- & Ming-xiang Zhang
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Article
| Open AccessPancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis
IL-22RA1 is highly expressed on pancreatic islets and absent on immune cells. Here, the authors investigate its role by generating animals that lack IL-22RA1 on beta cells and reveal IL22RA1 signalling is critical for insulin biosynthesis and beta-cell health, evidenced by its regulation of MHC II expression and its suppressive effect on inflammation and cellular stress.
- Haressh Sajiir
- , Kuan Yau Wong
- & Sumaira Z. Hasnain
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Article
| Open AccessA nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila
Amplification of glucose stimulated insulin secretion by lipids is not fully understood due to complex inter organ communication in glycemic regulation. Here the authors show Vaha, a Drosophila lipase synthesized in the gut, concentrates in insulin producing cells in the brain to regulate insulin like peptide release.
- Alka Singh
- , Kandahalli Venkataranganayaka Abhilasha
- & Usha R. Acharya
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Article
| Open AccessProduction of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism
Secondary bile acids are microbially produced metabolites linked to metabolic diseases. A challenge in microbiota research is to understand how bacteria collaborate to produce such bioactive molecules. Here, the authors show that adding a single low-abundance bacterial species to a community can significantly affect the metabolic output and host physiology.
- Annika Wahlström
- , Ariel Brumbaugh
- & Fredrik Bäckhed
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Article
| Open AccessSpatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity
Hepatocytes are central for maintaining metabolic homeostasis during nutritional transitions. Here, we show that the structural remodelling of hepatic organelles is part of hepatocytes’ metabolic plasticity to adapt to cycles of fasting/feeding and this process is zonated in the liver.
- Güneş Parlakgül
- , Song Pang
- & Ana Paula Arruda
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Article
| Open AccessDistinct cellular immune responses in children en route to type 1 diabetes with different first-appearing autoantibodies
Previous studies have reported heterogeneity in the progression to clinical type 1 diabetes in children who develop either insulin- or glutamic acid decarboxylase-specific antibodies as their first autoantibodies. Here, the authors show that children who later develop disease have distinct characteristics in early immune responses, which are dependent on the type of autoantibodies that appear first.
- Inna Starskaia
- , Milla Valta
- & Riitta Lahesmaa
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Article
| Open AccessGalectin-3 impairs calcium transients and β-cell function
Galectin-3, mainly produced and secreted by macrophages, is elevated in diabetes. Here, the authors show that galectin-3 directly interacts with voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and blocks calcium transients and subsequent insulin secretion.
- Qian Jiang
- , Qijin Zhao
- & Pingping Li
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Article
| Open AccessLSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice
Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.
- Qingshuang Cai
- , Rajesh Sahu
- & Delphine Duteil
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Article
| Open AccessA cluster-randomized trial of water, sanitation, handwashing and nutritional interventions on stress and epigenetic programming
A regulated stress response is essential for healthy child growth and development. Here, the authors show that a nutrition, water, sanitation, and hygiene intervention enhanced adaptive responses of the physiological stress system in early childhood.
- Audrie Lin
- , Andrew N. Mertens
- & Douglas A. Granger
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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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Article
| 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 AccessIlluminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans
The pancreatic islets of Langerhans play a pivotal role in regulating blood glucose homeostasis through the regulated secretion of the hormones insulin and glucagon. Here, the authors use deep tissue 3D imaging to re-construct the entire human pancreas at microscopic resolution and display previously unrecognized heterogeneities in the islet’s cellularity with pre-clinical and clinical implications.
- Joakim Lehrstrand
- , Wayne I. L. Davies
- & Ulf Ahlgren
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Article
| Open AccessDeficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion
The mechanisms of bifurgation, a key step in thyroid development, are largely unknown. Here, Fang et al. find that HGF/Met is indispensable for the bifurgation of the thyroid primordium during zebrafish thyroid development.
- Ya Fang
- , Jia-Ping Wan
- & Huai-Dong Song
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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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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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 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 AccessEpigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids
Parathyroid glands are crucial for balancing blood calcium levels. Here, the authors generate comprehensive maps of the chromatin landscape of human parathyroids, linking identified regulatory elements to key functions in calcium homeostasis.
- Youngsook Lucy Jung
- , Wenping Zhao
- & Michael Mannstadt
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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 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 AccessPalmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability. Here, the authors show that elevated palmitic acid levels are linked to increased atherosclerotic plaque vulnerability.
- Xiqiang Wang
- , Ling Zhu
- & Zhongwei Liu
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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 AccessUnraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses
Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.
- Seong Eun Lee
- , Seongyeol Park
- & Yea Eun Kang
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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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Article
| Open AccessMulti-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications
Thyroid dysfunction is involved in many diseases. Here, the authors provide insights into the genetics and biological pathways influencing important thyroid function parameters, showing potential causal effects on many clinical outcomes.
- Rosalie B. T. M. Sterenborg
- , Inga Steinbrenner
- & Marco Medici
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Article
| Open AccessRescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics
Here, Shao et. al attribute the reduction in bone mechano-responsiveness seen in type 2 diabetes to abnormal osteocytic calcium dynamics. They identify reduced SERCA2 pump activity as a mediator of this process and show that rescuing SERCA2 significantly improves bone mechanical adaptation in this context.
- Xi Shao
- , Yulan Tian
- & Da Jing
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Article
| Open AccessSox9 regulates alternative splicing and pancreatic beta cell function
Sox9 is a well-known transcriptional regulator of embryonic pancreas and endocrine cell development. Here, the authors show that loss of Sox9 in mature beta cells disrupts alternative splicing patterns and impairs insulin secretion, with significant implications for cellular function.
- Sapna Puri
- , Hasna Maachi
- & Matthias Hebrok
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Article
| Open AccessAutonomous artificial intelligence increases screening and follow-up for diabetic retinopathy in youth: the ACCESS randomized control trial
Diabetic retinopathy is a complication of diabetes that can be prevented through screening, yet adherence is low. Here, the authors show that autonomous AI increases diabetic eye exam completion in a diverse cohort of youth with diabetes.
- Risa M. Wolf
- , Roomasa Channa
- & Michael D. Abramoff
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Article
| Open AccessA role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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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 AccessFatty acid synthesis suppresses dietary polyunsaturated fatty acid use
Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.
- Anna Worthmann
- , Julius Ridder
- & Christian Schlein
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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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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 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 AccessGenes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
- Tina Rönn
- , Jones K. Ofori
- & Charlotte Ling
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Article
| Open AccessAstrocytic insulin receptor controls circadian behavior via dopamine signaling in a sexually dimorphic manner
Mammalian circadian clocks align with feeding and light cues. Here, the authors reveal a role for astrocytic insulin-dopaminergic signaling in sex-specific circadian behavior and energy balance regulation.
- Antía González-Vila
- , María Luengo-Mateos
- & Olga Barca-Mayo