Paternal obesity increases metabolic risk in offspring, but whether this risk can be reduced by restoring paternal health before conception remains unresolved. We developed a within-sire induction-and-reversal model in outbred CD1 mice in which high-fat diet (HFD)-exposed males generated offspring before and after transition to an ingredient-matched control diet with voluntary exercise. HFD caused obesity, glucose intolerance, insulin resistance, and extensive remodeling of sperm mRNA, lncRNA, and sncRNA profiles, together with transcriptomic changes in metabolic tissues. Diet and exercise reversal normalized paternal metabolic indices and broadly restored tissue RNA profiles, although sperm retained a limited transcriptional memory of prior HFD exposure. Offspring sired before reversal developed sex-dependent metabolic dysfunction despite control-diet rearing, whereas offspring sired after reversal showed substantial improvement. These findings show that paternal metabolic risk is modifiable before conception and that this reversibility is linked to remodeling of sperm RNA. ( 140 words ). Highlights:Paternal HFD-Ex induces obesity, glucose intolerance and insulin resistance in CD1 malesSperm shows much stronger RNA response than four metabolic organs profiledDiet and exercise reversal restores metabolism and RNA profiles in sperm and four metabolic organs analyzedOffspring metabolic risk is reduced when sires conceive after reversal through diet and exercise intervention. eTOC Blurb:Chen, Magalhaes, et al. show that paternal metabolic recovery before conception remodels sperm RNA and reduces transmission of HFD-associated metabolic risk to offspring in a within-sire mouse model.

Microplastics (MPs) are increasingly recognized as an urgent global health concern, with mounting evidence linking their bioaccumulation to chronic disease risks. The liver, as a central organ for metabolic homeostasis and detoxification, is particularly sensitive to sustained MP exposure. However, the mechanisms underlying hepatic responses to polyethylene (PE), the most prevalent yet relatively understudied plastic type, remain poorly defined. By performing combined bulk and spatial transcriptomic analyses, we observed that PE resulted in hepatic dysfunction in mice fed on standard or metabolic dysfunction-associated steatohepatitis (MASH)-inducing diets, driving both globally and spatially distinct transcriptional alterations, including a nuclear receptor (NR), Ppara. Spatial transcriptomics uncovered the cell type heterogeneity and gene expression patterns masked in bulk analyses. Spatial clustering uncovered inflammatory hotspots characterized by reduced cellular diversity and distinct PE-responsive gene signatures. Among these, NR signaling emerged as a key regulatory axis, with Ppara identified as a modulator. We further demonstrated that Ppara regulates Anxa2, a gene involved in damage response and tissue recovery, through enhancer and promoter binding. These findings offer insights into how PE disrupts hepatic homeostasis and underscores the value of spatial transcriptomics in elucidating environmental impacts on tissue organization and gene expression regulation. This study provides a molecular framework for understanding MP-associated disruption of liver pathophysiology and highlights potential targets for therapeutic intervention.

In both type 1 and type 2 diabetes (T1D and T2D), insulin-producing β cells undergo progressive dysfunction due to inflammation, leading to impaired glucose responsiveness, dedifferentiation, and cell loss. While bile acid (BA) dysregulation under diabetic conditions is known to influence metabolic and inflammatory pathways, its mechanistic role in β cell regulation remains incompletely defined1-3. Here we show that bile acid sensor Farnesoid X receptor (FXR) and Bromodomain and Extra-Terminal motif (BET) signaling cooperatively regulates β cell inflammatory response and β cell identity. We identified the physiological protein-protein interaction between FXR and the bromodomain-containing protein 4 (BRD4) as a regulatory axis that protects against β cell dysfunction. We show that FXR activation by Fexaramine (Fex) together with BRD4 inhibition by JQ1 synergistically suppressed IL-1β-induced inflammation while also improving β cell identity and insulin secretion in both db/db model and high-fat diet (HFD) plus multi low-dose streptozotocin (MLD-STZ) model of diabetes. Importantly, this cooperative effect is abolished in β cell-specific FXR knockout (βFXRKO) mice, establishing that FXR is required for the functional synergy between these pathways in vivo. Mechanistically, structure-guided modeling and mutational analyses identified a direct interaction between FXR and the BD2 domain of BRD4, depending on specific lysine acetylation sites. Additionally, inhibition of the BD2 domain of BET combined with FXR activation markedly improved β cell survival in human T1D and T2D models established from human pluripotent stem cell (hPSC)-derived islet-like organoids (HILOs). Collectively, these findings establish a BA-bromodomain axis as a transcriptional interface linking metabolic signaling and chromatin regulation, and highlight FXR-BET targeting as a promising strategy to counter progressive β cell failure in diabetes.

Pancreatic α-cells can be redirected along a metabolic road toward an insulin-producing β-cell-like identity. A study reveals that an epigenetic–metabolic axis centered on PRC2 and androgen receptor signaling governs endocrine cell fate and charts a tractable route to β-cell regeneration.

Human pancreatic islets regulate organ development and metabolic homeostasis, with dysfunction leading to diabetes. Human pluripotent stem cells (hPSCs) provide a potential alternative source to cadaveric human pancreatic islets for replacement therapy in diabetes. However, human islet-like organoids (HILOs) generated from hPSCs in vitro often exhibit heterogeneous immature phenotypes such as aberrant gene expression and inadequate insulin secretion in response to glucose. Here we show that FXYD Domain Containing Ion Transport Regulator 2 (FXYD2) marks and regulates functional maturation and heterogeneity of generated HILOs, by controlling the β cell transcriptome necessary for glucose-stimulated insulin secretion (GSIS). Despite its presence in mature β cells, FXYD2 is diminished in hPSC-derived β-like cells. Mechanistically, we find that FXYD2 physically interacts with SRC proto-oncogene, non-receptor tyrosine kinase (SRC) protein to regulate FXYD2-SRC-TEAD1 signaling to modulate β cell transcriptome. We demonstrate that FXYD2High HILOs significantly outperform FXYD2Low counterparts to improve hyperglycemia in STZ-induced diabetic immune deficient mice. These results suggest that FXYD2 marks and regulates human β cell maturation via channel-sensing signal transduction and that it can be used as a selection marker for functional heterogeneity of stem cell derived human islet organoids.

Pancreatic (3-cells play a critical role in glucose homeostasis by secreting insulin. Chronic oxidative stress causes (3-cell dysfunction, including (3-cell loss; however, the underlying mechanisms remain unclear. Here, we demonstrate the critical role of the regulated in development and DNA damage response 2 (REDD2/DDiT4L/Rtp801L) in (3-cell dysfunction. In INS-1 (3-cells, Redd2 was induced by high glucose/palmitate or streptozotocin (STZ) exposure. Knockdown of Redd2 attenuated STZ-induced loss of cell viability, while REDD2 over-expression reduced cell viability and p70S6K phosphorylation, suggesting the involvement of suppression of mTORC1 activation. STZ also activated the transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and p53, and over-expression of these transcription factors synergistically induced Redd2 expression. Reporter assays using the Redd2 promoter (-2328/-1) and chromatin immunoprecipitation identified the functional binding sites for Nrf2 (EpRE2, -349/-340) and p53 (p53RE1,-90/-81) on the Redd2 promoter. Purified recombinant p53 and Nrf2 bound directly. There were no noticeable changes in male global Redd2-knockout mice (C57BL/6J background), except for inguinal adipose tissue decrease when the mice were fed a standard diet. In contrast, when the mice were fed a high-fat diet (HFD), Redd2-knockout mice exhibited improved glucose tolerance relative to littermate controls. Redd2-knockout in HFD-fed mice increased (3-cell mass due to reduced (3-cell apoptosis and elevated plasma insulin concentrations, whereas insulin sensitivity remained unaffected. In both STZ-induced male and female and HFD-fed male models, (3-cell-specific Redd2-knockout improved glucose tolerance without affecting insulin sensitivity. Our results identify REDD2 as a novel regulator of (3-cell dysfunction under oxidative stress.

Pancreatic β-cells play a critical role in glucose homeostasis by secreting insulin. Chronic oxidative stress causes β-cell dysfunction, including β-cell loss; however, the underlying mechanisms remain unclear. Here, we demonstrate the critical role of the regulated in development and DNA damage response 2 (REDD2/DDiT4L/Rtp801L) in β-cell dysfunction. In INS-1 β-cells, Redd2 was induced by high glucose/palmitate or streptozotocin (STZ) exposure. Knockdown of Redd2 attenuated STZ-induced loss of cell viability, while REDD2 overexpression reduced cell viability and p70S6K phosphorylation, suggesting the involvement of suppression of mTORC1 activation. STZ also activated the transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and p53, and overexpression of these transcription factors synergistically induced Redd2 expression. Reporter assays using the Redd2 promoter (-2328/-1) and chromatin immunoprecipitation identified the functional binding sites for Nrf2 (EpRE2, -349/-340) and p53 (p53RE1, -90/-81) on the Redd2 promoter. Purified recombinant p53 and Nrf2 bound directly. There were no noticeable changes in male global Redd2-knockout mice (C57BL/6J background), except for inguinal adipose tissue decrease when the mice were fed a standard diet. In contrast, when the mice were fed a high-fat diet (HFD), Redd2-knockout mice exhibited improved glucose tolerance relative to littermate controls. Redd2-knockout in HFD-fed mice increased β-cell mass due to reduced β-cell apoptosis and elevated plasma insulin concentrations, whereas insulin sensitivity remained unaffected. In both STZ-induced male and female and HFD-fed male models, β-cell-specific Redd2-knockout improved glucose tolerance without affecting insulin sensitivity. Our results identify REDD2 as a novel regulator of β-cell dysfunction under oxidative stress.

Recent studies have provided evidence for the direct binding of thioredoxin-1 (TRX1) to a component of inflammasome complex NLR family pyrin domain containing 1 (NLRP-1). This interaction suggests a potential role for TRX1 in the regulation of the NLRP-1 inflammasome. Furthermore, the NLRP-3 inflammasome is known to bind TRX1 and its inhibitor, TRX-binding protein-2/TRX-interacting protein/vitamin D3 upregulated protein-1 (TBP2/TXNIP/VDUP-1). This binding forms a redox-sensitive complex, termed the "Redoxisome," as described previously. However, the specific functions of NLRP-1 within the redoxisome complex remain undefined. Antioxid. Redox Signal. 40, 595-597.

Pancreatic β-cell mass is a critical determinant of insulin secretion. Severe endoplasmic reticulum (ER) stress causes β-cell apoptosis; however, the mechanisms of progression and suppression are not yet fully understood. Here, we report that the autocrine/paracrine function of insulin reduces ER stress-induced β-cell apoptosis. Insulin reduced the ER-stress inducer tunicamycin- and thapsigargin-induced cell viability loss due to apoptosis in INS-1 β-cells. Moreover, the effect of insulin was greater than that of insulin-like growth factor-1 at physiologically relevant concentrations. Insulin did not attenuate the ER stress-induced increase in unfolded protein response genes. ER stress did not induce cytochrome c release from mitochondria. Mitochondrial hyperpolarization was induced by ER stress and prevented by insulin. The protonophore/mitochondrial oxidative phosphorylation uncoupler, but not the antioxidants N-acetylcysteine and α-tocopherol, exhibited potential cytoprotection during ER stress. Both procaspase-12 and cleaved caspase-12 levels increased under ER stress. The caspase-12 inhibitor Z-ATAD-FMK decreased ER stress-induced apoptosis. Caspase-12 overexpression reduced cell viability, which was diminished in the presence of insulin. Insulin decreased caspase-12 levels at the post-translational stages. These results demonstrate that insulin protects against ER stress-induced β-cell apoptosis in this cell line. Furthermore, mitochondrial hyperpolarization and increased caspase-12 levels are involved in ER stress-induced and insulin-suppressed β-cell apoptosis.

In the quest to combat insulin-dependent diabetes mellitus (IDDM), allogenic pancreatic islet cell therapy sourced from deceased donors represents a significant therapeutic advance. However, the applicability of this approach is hampered by donor scarcity and the demand for sustained immunosuppression. Human induced pluripotent stem cells are a game-changing resource for generating synthetic functional insulin-producing β cells. In addition, novel methodologies allow the direct expansion of pancreatic progenitors and mature β cells, thereby circumventing prolonged differentiation. Nevertheless, achieving practical reproducibility and scalability presents a substantial challenge for this technology. As these innovative approaches become more prominent, it is crucial to thoroughly evaluate existing expansion techniques with an emphasis on their optimization and scalability. This manuscript delineates these cutting-edge advancements, offers a critical analysis of the prevailing strategies, and underscores pivotal challenges, including cost-efficiency and logistical issues. Our insights provide a roadmap, elucidating both the promises and the imperatives in harnessing the potential of these cellular therapies for IDDM.

Direct conversions offer an alternative approach to generate insulin-producing cells for cell therapy in diabetes. A study reports a method to convert human stomach-derived gastric stem cells into functional insulin-producing cells through a unique differentiation path.

Since the discovery of insulin a century ago, insulin injection has been a primary treatment for both type 1 (T1D) and type 2 diabetes (T2D). T2D is a complicated disea se that is triggered by the dysfunction of insulin-producing β cells and insulin resistance in peripheral tissues. Insulin injection partially compensates for the role of endogenous insulin which promotes glucose uptake, lipid synthesis and organ growth. However, lacking the continuous, rapid, and accurate glucose regulation by endogenous functional β cells, the current insulin injection therapy is unable to treat the root causes of the disease. Thus, new technologies such as human pluripotent stem cell (hPSC)-derived islets are needed for both identifying the key molecular and genetic causes of T2D and for achieving a long-term treatment. This perspective review will provide insight into the efficacy of hPSC-derived human islets for treating and understanding T2D. We discuss the evidence that β cells should be the primary target for T2D treatment, the use of stem cells for the modeling of T2D and the potential use of hPSC-derived islet transplantation for treating T2D.

Background & AimsMitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.MethodsTwo models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts.ResultsBlocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis.ConclusionsCollectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Generation of three-dimensional (3D)-structured functional human islets is expected to be an alternative cell source for cadaveric human islet transplantation for the treatment of insulin-dependent diabetes. Human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer infinite resources for newly synthesized human islets. Recent advancements in hPSCs technology have enabled direct differentiation to human islet-like clusters, which can sense glucose and secrete insulin, and those islet clusters can ameliorate diabetes when transplanted into rodents or non-human primates (NHPs). However, the generated hPSC-derived human islet-like clusters are functionally immature compared with primary human islets. There remains a challenge to establish a technology to create fully functional human islets in vitro, which are functionally and transcriptionally indistinguishable from cadaveric human islets. Understanding the complex differentiation and maturation pathway is necessary to generate fully functional human islets for a tremendous supply of high-quality human islets with less batch-to-batch difference for millions of patients. In this review, I summarized the current progress in the generation of 3D-structured human islets from pluripotent stem cells and discussed the importance of adapting physiology for in vitro functional human islet organogenesis and possible improvements with environmental cues.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03109-3.

Insulin injection is currently the main therapy for type 1 diabetes (T1D) or late stage of severe type 2 diabetes (T2D). Human pancreatic islet transplantation confers a significant improvement in glycemic control and prevents life-threatening severe hypoglycemia in T1D patients. However, the shortage of cadaveric human islets limits their therapeutic potential. In addition, chronic immunosuppression, which is required to avoid rejection of transplanted islets, is associated with severe complications, such as an increased risk of malignancies and infections. Thus, there is a significant need for novel approaches to the large-scale generation of functional human islets protected from autoimmune rejection in order to ensure durable graft acceptance without immunosuppression. An important step in addressing this need is to strengthen our understanding of transplant immune tolerance mechanisms for both graft rejection and autoimmune rejection. Engineering of functional human pancreatic islets that can avoid attacks from host immune cells would provide an alternative safe resource for transplantation therapy. Human pluripotent stem cells (hPSCs) offer a potentially limitless supply of cells because of their self-renewal ability and pluripotency. Therefore, studying immune tolerance induction in hPSC-derived human pancreatic islets will directly contribute toward the goal of generating a functional cure for insulin-dependent diabetes. In this review, we will discuss the current progress in the immune protection of stem cell-derived islet cell therapy for treating diabetes.

Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.

Bisphenol A and its derivatives are recognized endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is not well understood. Herein, we identified novel ERβ ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ERα agonists and ERβ antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ERβ demonstrated the presence of a second ligand interaction position at the coactivator binding site in ERβ. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting a critical view point for future ER signaling-based drug development.

Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.