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AZGP1 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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Illuminating 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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Deficiency 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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Involution 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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A 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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TM4SF19-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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Diindoles 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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Trimethylamine N-oxide impairs β-cell function and glucose tolerance
β-Cell dysfunction is a hallmark of type 2 diabetes. Here, the authors show that trimethylamine N-oxide (TMAO (a microbiota metabolite)) induces β-cell dysfunction and type 2 diabetes in mice through NLRP3 inflammasome activation and calcium transients.
- Lijuan Kong
- , Qijin Zhao
- & Pingping Li
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Heterozygous missense variant in GLI2 impairs human endocrine pancreas development
Mutations in the Hedgehog signaling have not been previously associated to diabetes. Here, authors identify a missense variant of GLI2 in a family with early-onset diabetes and report an essential role of this gene during human iPSC-based pancreatic differentiation.
- Laura M. Mueller
- , Abigail Isaacson
- & Francesca M. Spagnoli
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Epigenetic 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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Hypothalamic 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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M2 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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Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src
The authors of this manuscript identify that Gpr54 activation by its natural ligand Kisspeptin-10 can abrogate bone resorption. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase, which causes Dusp18 to dephosphorylate Src at Tyr 416.
- Zhenxi Li
- , Xinghai Yang
- & Jianru Xiao
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Sonic 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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Palmitic 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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Glucocorticoids 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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Protection 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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Unraveling 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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Artesunate 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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Programmed microalgae-gel promotes chronic wound healing in diabetes
The treatment of infected diabetic wounds faces obstacles of bacterial infection, hypoxia, hyperexpression of reactive oxygen species, and inflammation. Here, the authors address these issues by developing a programmed treatment strategy that utilizes live Haematococcus to promote healing of diabetic wounds in a comprehensive manner.
- Yong Kang
- , Lingling Xu
- & Xiaoyuan Ji
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Multi-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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Rescuing 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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Sox9 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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Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
The mechanisms underlying diabetic neuropathy remain elusive. Here, the authors identify that UCHL1 deubiquitinase positively regulates insulin signaling and its loss leads to axonal degeneration of sensory neurons.
- Daewon Lee
- , Eunju Yoon
- & Jongkyeong Chung
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Autonomous 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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A 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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Myeloid-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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Fatty 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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Surplus fatty acid synthesis increases oxidative stress in adipocytes and induces lipodystrophy
The physiological significance of low fatty acid synthesis in adipocytes remains unclear. Here, the authors show a protective role of this phenomenon by demonstrating that overproduction of fatty acids increases ROS production and results in adipocyte necroptosis and lipodystrophy.
- Li Weng
- , Wen-Shuai Tang
- & Tong-Jin Zhao
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ApoL6 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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Mic19 depletion impairs endoplasmic reticulum-mitochondrial contacts and mitochondrial lipid metabolism and triggers liver disease
The molecular mechanism and physiological function of endoplasmic reticulum-mitochondrial contacts remain unclear. Here, authors uncover a role for the EMC2- SLC25A46-Mic19 axis in mitochondrial lipid metabolism and liver disease
- Jun Dong
- , Li Chen
- & He He
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Cdo1-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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A 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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Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Red blood cells (RBC) carry the majority of sphingosine-1-phosphate (S1P). Here, the authors show that RBC dynamically regulate S1P levels in response to metabolic stress and employ them to regulate glucose uptake, glycolysis and the pentose phosphate pathway as protection against lipid peroxidation.
- Nadine Thomas
- , Nathalie H. Schröder
- & Bodo Levkau
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Effects 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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Genes 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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Astrocytic 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
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The NERP-4–SNAT2 axis regulates pancreatic β-cell maintenance and function
Amino acids modulate insulin secretion via amino acid transporters expressed on β cells. Here, the authors show a VGF-derived peptide NERP-4 acts as a positive allosteric modulator on the amino acid transporter SNAT2/SLC38A2, thereby contributing to β-cell maintenance and function.
- Weidong Zhang
- , Ayako Miura
- & Masamitsu Nakazato
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Myeloid cells interact with a subset of thyrocytes to promote their migration and follicle formation through NF-κB
The mechanism underlying thyroid follicle formation is not well understood. Here, the authors show that a subgroup of NF-κB-activated thyrocytes, through interactions with myeloid cells, exhibit increased migration capacity to generate new follicles.
- Yang Rui-Meng
- , Song Shi-Yang
- & Song Huai-Dong
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| Open Access
Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal
Manganese is an essential trace element for the activity of arginase in the process of urea generation and ammonia disposal in the liver. Here, the authors show that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice.
- Jian-Hui Shi
- , Yu-Xia Chen
- & Weiping J. Zhang
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Article
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Skeletal 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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Article
| Open Access
Parabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a
Here, the authors show that the gut commensal Parabacteroides distasonis alleviates insulin resistance via nicotinic acid-intestinal GPR109a axis activation, a process promoted by Dendrobium officinale polysaccharide.
- Yonggan Sun
- , Qixing Nie
- & Shaoping Nie
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A standardized metric to enhance clinical trial design and outcome interpretation in type 1 diabetes
The use of a standardized outcome metric enhances clinical trial interpretation and cross-trial comparison. Here, the authors show the implementation of such a metric using type 1 diabetes trial data, reassess and compare results from these trials, and extend its use to define response to therapy.
- Alyssa Ylescupidez
- , Henry T. Bahnson
- & Carla J. Greenbaum
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Poor sleep and shift work associate with increased blood pressure and inflammation in UK Biobank participants
Circadian disruption is linked to increased blood pressure and heart disease risk. Here, the authors show a positive association between circadian disruption and blood pressure (SBP/DBP) regulation in males and females irrespective of age, weight and inflammatory status.
- Monica Kanki
- , Artika P. Nath
- & Morag J. Young
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Article
| Open Access
Development and validation of an age-sex-ethnicity-specific metabolic syndrome score in the Chinese adults
Metabolic syndrome (MetS) could predict future risk for cardiovascular diseases (CVDs), but the traditionally defined dichotomous MetS cannot reflect MetS severity and demographic variations. Here, the authors develop a continuous, age-sex-ethnicity-specific MetS score to better identify CVD risk in a Chinese population.
- Shujuan Yang
- , Bin Yu
- & Peng Jia
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Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets
Follicle-stimulating hormone (FSH) is involved in mammalian reproduction, but several studies have suggested a role of FSH and its receptor in extragonadal tissue. Here, the authors show that FSH orchestrates glucose-stimulated insulin secretion (GSIS) via its receptor on pancreatic β-cells, with pre-menopausal FSH levels dose-dependently promoting GSIS and postmenopausal FSH levels inhibiting this effect.
- Yi Cheng
- , Hong Zhu
- & He-Feng Huang
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eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Fetal development plays an important role in defining adult diabetes risk. Here, authors identified a genetic link between fetal pancreatic gene expression, obesity, and diabetes risk through eQTL mapping of iPSC-derived pancreatic progenitor cells.
- Jennifer P. Nguyen
- , Timothy D. Arthur
- & Kelly A. Frazer
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| Open Access
Gut microbiota impacts bone via Bacteroides vulgatus-valeric acid-related pathways
Gut microbiota has been reported to influence osteoporosis risk, but the individual species, and underlying mechanisms, remain largely unknown. Here, the authors identify Bacteroides vulgatus and serum valeric acid as potential targets for osteoporosis prevention/treatment.
- Xu Lin
- , Hong-Mei Xiao
- & Hong-Wen Deng
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ZFYVE28 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
An estrogen receptor α-derived peptide improves glucose homeostasis during obesity