Endocrinology
Abstract
Obesity and type 2 diabetes (T2D) are metabolic diseases with increasing prevalence worldwide. Obesity often leads to T2D. Insulin resistance and impaired β cell function contribute to the onset of hyperglycemia. Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improved pancreatic β cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation had systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, and glucose intolerance; lower nonesterified fatty acids and triglycerides; and augment glucose uptake in skeletal muscle and adipose in male mice fed a high-fat diet. Interestingly, weight loss in Gc-ablated mice resulted from selective fat mass loss with preserved lean mass. Moreover, acute Gc inhibition prevented glucose intolerance caused by high-fat feeding. The data suggest that Gc inhibition can increase insulin production in β cells and insulin action in peripheral tissues, while reducing fat mass.
Authors
Richard Gill, Taiyi Kuo
Abstract
Autoimmune diabetes encompasses rapidly progressive type 1 diabetes mellitus (T1D) and indolent latent autoimmune diabetes in adults (LADA), representing distinct inflammatory set points along a shared autoimmune spectrum. Yet the immunological mechanisms that determine these divergent inflammatory states remain unresolved. We performed single-cell RNA sequencing with paired T and B cell receptor profiling on over 400,000 peripheral blood mononuclear cells (PBMCs) from patients with LADA, newly diagnosed T1D, and healthy controls. PBMC composition was comparable across cohorts, indicating that qualitative rather than quantitative immune differences underlie disease heterogeneity. In T1D, pan-lineage activation of NF-κB, EGFR, MAPK, and hypoxia pathways, coupled with a TNF-centered communication hub, enhanced MHC signaling, and disrupted adhesion, promoted systemic inflammation. LADA, by contrast, exhibited global suppression of NF-κB/EGFR activity, retention of moderate JAK/STAT tone, reinforced natural killer cell inhibitory checkpoints via HLA-C–KIR2DL3/3DL1 interaction, and stabilized CD8⁺ T cell synapses through HLA-C–CD8 binding, collectively restraining effector activation. Single-cell V(D)J analysis revealed multiclonal, patient-unique adaptive repertoires, emphasizing the primacy of signaling context over receptor convergence. These findings define autoimmune diabetes as an inflammatory–inhibitory set-point continuum, positioning the NF-κB/EGFR–JAK/STAT gradient and HLA-C–KIR axis as potential therapeutic targets to preserve residual β-cell function.
Authors
Ivan I. Golodnikov, Elizaveta S. Podshivalova, Vadim I. Chechekhin, Anatoliy V. Zubritskiy, Alina A. Matrosova, Nikita A. Sergeev, Margarita D. Samsonova, Yaroslav V. Dvoryanchikov, Tatiana V. Nikonova, Ekaterina V. Bondarenko, Marina Yu. Loguinova, Yulia A. Medvedeva, Dmitry N. Laptev, Rita I. Khusainova, Ildar R. Minniakhmetov, Marina V. Shestakova, Natalia G. Mokrysheva, Ivan I. Dedov
Abstract
Saturated fatty acids impose lipotoxic stress on pancreatic β-cells, leading to β-cell failure and diabetes. In this study, we investigate the critical role of organellar Ca2+ disturbance on defective autophagy and β-cell lipotoxicity. Palmitate, a saturated fatty acid, induced perilysosomal Ca2+ elevation, sustained mTORC1 activation on the lysosomal membrane, suppression of the lysosomal transient receptor potential mucolipin 1 (TRPML1) channel, and accumulation of undigested autophagosomes in β-cells. These Ca2+ aberrations with autophagy defects by palmitate were prevented by an mTORC1 inhibitor or a mitochondrial superoxide scavenger. To alleviate perilysosomal Ca2+ overload, strategies such as lowering extracellular Ca2+, employing voltage-gated Ca2+ channel blocker or ATP-sensitive K+ channel opener effectively abrogated mTORC1 activation and preserved autophagy. Furthermore, redirecting perilysosomal Ca2+ into the endoplasmic reticulum (ER) with an ER Ca2+ ATPase activator, restores TRPML1 activity, promotes autophagic flux, and improves survival of β-cells exposed to palmitate-induced lipotoxicity. Our findings suggest oxidative stress-Ca2+ overload-mTORC1 pathway involvement in TRPML1 suppression and defective autophagy during β-cell lipotoxicity. Restoring perilysosomal Ca2+ homeostasis emerges as a promising therapeutic strategy for metabolic diseases.
Authors
Ha Thu Nguyen, Luong Dai Ly, Thuy Thi Thanh Ngo, Soo Kyung Lee, Carlos Noriega Polo, Subo Lee, Taesic Lee, Seung-Kuy Cha, Xaviera Riani Yasasilka, Kae Won Cho, Myung-Shik Lee, Andreas Wiederkehr, Claes B. Wollheim, Kyu-Sang Park
Abstract
Reproductive disorders can result from a defective action of the neuropeptide gonadotropin-releasing hormone (GnRH), the master regulator of reproduction. We have previously shown that SELENOT, a newly-described thioredoxin-like selenoprotein highly expressed in endocrine and neuroendocrine cells, plays a role in hormone secretion and neuroprotection. However, whether SELENOT is involved in neuro-endocrine regulations in vivo is totally unknown. We found that SELENOT deficiency in the brain impaired sexual behavior, leading to a decline in fertility in both male and female mice. Biochemical and histological analyses of the gonadotrope axis of these mice revealed a higher expression of GnRH, which is associated with circulating luteinizing hormone (LH) excess, and elevated steroid hormones in males and a polycystic ovary syndrome (PCOS)-like phenotype in females. In addition, SELENOT deficiency impaired LH pulse secretion in both male and female mice. These alterations are reverted after administration of a GnRH antagonist. Together, our data demonstrate for the first time the role of a selenoprotein in the central control of sexual behavior and reproduction, and identify a new redox effector of GnRH neuron activity impacting both male and female reproductive function.
Authors
Ben Yamine Mallouki, Loubna Boukhzar, Ludovic Dumont, Azénor Abgrall, Marjorie Gras, Agathe Prieur, David Alexandre, David Godefroy, Yves Tillet, Luca Grumolato, Nathalie Rives, Fatiha Chigr, Youssef Anouar
Abstract
The present study aims to explore the role and possible underlying mechanisms of histone lactylation modifications in diabetes-associated cognitive impairment (DACD). In this study, behavioral tests, Hematoxylin & Eosin (HE) staining, and immunohistochemistry were used to evaluate cognitive function and the extent of cerebral tissue injury. We quantified the levels of lactic acid and Pan-lysine lactylation (Pan Kla) in the brains of type 2 diabetes mellitus (T2DM) mice and in high glucose–treated microglia. We also identified all Kla sites in isolated microglia. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were subsequently conducted to identify the functions and pathways that were enriched at the differentially expressed modification sites. cleavage under targets and tagmentation (CUT&Tag) technology was used to identify candidate genes that are regulated by H3K18la. Small interfering RNA (siRNA) and H3K18R mutant sequences were used to knock down crucial components in key signaling pathways to assess the effects of histone lactylation on microglial polarization. We found that lactic acid levels were significantly greater in the brains of T2DM mice and high glucose-treated microglia than in those of their corresponding controls, which increased the level of Pan-Kla. We discovered that lactate can directly stimulate an increase in H3K18la. The global landscape of the lactylome reveals information about modification sites, indicating a correlation between the upregulation of H3K18la and protein lactylation and Toll-like receptor signaling. CUT&Tag demonstrated that enhanced H3K18la directly stimulates the nuclear factor kappa-B (NF-κB) signaling pathway by increasing binding to the promoter of Toll Like Receptor 4 (TLR4), thereby promoting M1 microglial polarization. The present study demonstrated that enhanced H3K18la directly stimulates TLR4 signaling to promote M1 microglial polarization, thereby facilitating DACD phenotypes. Targeting such loop may be a potential therapeutic approach for the treatment of DACD.
Authors
Ying Yang, Fei Chen, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang
Abstract
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may protect from cardiovascular disease. ANGPTL3 oligomerizes with ANGPTL8 to inhibit lipoprotein lipase (LPL), the enzyme responsible for plasma triglyceride hydrolysis. Independent of ANGPTL8, oligomers of ANGPTL3 can inhibit endothelial lipase (EL), which regulates circulating HDL-C and LDL-C levels through the hydrolysis of lipoprotein phospholipids. The N-terminal region of ANGPTL3 is necessary for both oligomerization and lipase inhibition. However, our understanding of the specific residues that contribute to these functions is incomplete. In this study, we performed mutagenesis of the N-terminal region to identify residues important for EL inhibition and oligomerization. We also assessed the presence of different ANGPTL3 species in human plasma. We identified a motif important for lipase inhibition, and protein structure prediction suggested that this region interacted directly with EL. We also found that recombinant ANGPTL3 formed a homotrimer and was unable to inhibit EL activity when trimerization was disrupted. Surprisingly, we observed that human plasma contained more monomeric ANGPTL3 than trimeric ANGPTL3. An important implication of these findings is that previous correlations between circulating ANGPTL3 and circulating triglyceride-rich lipoproteins need to be revisited.
Authors
Sydney G. Walker, Yan Q. Chen, Kelli L. Sylvers-Davie, Alex Dou, Eugene Y. Zhen, Yuewei Qian, Yi Wen, Mariam E. Ehsani, Sydney A. Smith, Rakshya Thapa, Maxwell J. Mercer, Lucy Langmack, Bharat Raj Bhattarai, Michael Ploug, Robert J. Konrad, Brandon S.J. Davies
Abstract
A distinguishing feature of older mesenchymal stem cells (MSCs) from bone marrow (BM) is the transition in their differentiation capabilities from osteoblasts to adipocytes. However, the mechanisms underlying these cellular events during the aging process remain unclear. We identified Angiopoietin-like protein 8 (ANGPTL8), a newly found adipokine implicated in lipid metabolism, that influences the fate of MSCs in BM during skeletal aging. Our studies revealed that ANGPTL8 steered MSCs towards adipogenic differentiation, overshadowing osteoblastogenesis. Mice with overexpressed ANGPTL8 exhibited reduced bone mass and increased bone marrow adiposity, while those with transgenic depletion of ANGPTL8 showed lowered bone loss and less accumulation of bone marrow fat. ANGPTL8 influenced the bone marrow niche of MSCs by inhibiting the Wnt/β-catenin signaling pathway. Partial inhibition of PPARγ rescued some aspects of the phenotype in MSCs with ANGPTL8 overexpression. Furthermore, treatment with Angptl8-Antisense Oligonucleotide (Angptl8-ASO) improved the phenotype of aging mice. The research proposes that ANGPTL8 is a critical regulator of senesence-related changes in the BM niche and the cell fate switch of MSCs.
Authors
Yaming Guo, Zeqing Zhang, Junyu He, Peiqiong Luo, Zhihan Wang, Yurong Zhu, Xiaoyu Meng, Limeng Pan, Ranran Kan, Yuxi Xiang, Beibei Mao, Yi He, Siyi Wang, Yan Yang, Fengjing Guo, Hongbo You, Feng Li, Danpei Li, Yong Chen, Xuefeng Yu
Abstract
Fibroblast Growth Factor Receptors (FGFRs) are tyrosine kinase receptors critical for organogenesis and tissue maintenance, including in the adrenal gland. Here we delineate the role of FGFR2 in the morphogenesis, maintenance and function of the adrenal cortex with a focus on the zona Glomerulosa (zG). zG-specific Fgfr2 deletion (Fgfr2-cKO) resulted in impaired zG cell identity, proliferation and transdifferentiation into zona Fasciculata (zF) cells during postnatal development. In adult mice, induced deletion of Fgfr2 led to loss of mature zG cell identity, highlighting the importance of FGFR2 for the maintenance of a differentiated zG state. Strikingly, Fgfr2-cKO was sufficient to fully abrogate β-Catenin-induced zG hyperplasia and to reduce aldosterone levels. Finally, short-term treatment with pan-FGFR small molecule inhibitors suppressed aldosterone production in both wild-type and β-Catenin gain-of-function mice. These results demonstrate a critical role for FGFR signaling in adrenal morphogenesis, maintenance and function and suggest that targeting FGFR signaling may benefit patients with aldosterone excess and/or adrenal hyperplasia.
Authors
Vasileios Chortis, Dulanjalee Kariyawasam, Mesut Berber, Nick A. Guagliardo, Sining Leng, Betul Haykir, Claudio Ribeiro, Manasvi S. Shah, Emanuele Pignatti, Brenna Jorgensen, Lindsey Gaston, Paula Q. Barrett, Diana L. Carlone, Kleiton Silva Borges, David T. Breault
Abstract
Intracellular trafficking of secretory and membrane proteins from the endoplasmic reticulum (ER) to the cell surface, via the secretory pathway, is crucial to the differentiated function of epithelial tissues. In the thyroid gland, a prerequisite for such trafficking is proper protein folding in the ER, assisted by an array of ER molecular chaperones. One of the most abundant of these chaperones, Glucose-Regulated-Protein-170 (GRP170, encoded by Hyou1), is a noncanonical hsp70-like family member. Thyroid follicular epithelial cells abundantly express GRP170, but the role of this abundant ER chaperone in thyrocytes remains unknown. Here, we have examined the effect of inducible Pax8-specific (thyroid and kidney) deficiency of GRP170 in mice, in parallel with siRNA-treated PCCL3 (rat) thyrocytes for knockdown of GRP170. Thyrocyte-specific loss of GRP170 in vivo triggers primary hypothyroidism with a deficient thyroidal response to Thyroid-Stimulating Hormone (TSH). In addition, knockdown of GRP170 in PCCL3 thyrocytes inhibits the folding and forward trafficking of TSH receptors to the cell surface. Taken together, our findings suggest that GRP170 contributes to the conformational maturation of TSH receptors and thyroid gland responsiveness to TSH, which is required for proper regulation of thyroid hormone synthesis.
Authors
Xiaohan Zhang, Crystal Young, Xiao-Hui Liao, Samuel Refetoff, Stephanie M. Mutchler, Jeffrey L. Brodsky, Teresa M. Buck, Peter Arvan
Abstract
BACKGROUND. Active vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects that attenuate acute kidney injury (AKI) in animal models. METHODS. We conducted a phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among 150 critically ill adult patients at high-risk of moderate-to-severe AKI. The primary endpoint was a hierarchical composite of death, kidney replacement therapy (KRT), and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. Secondary endpoints included new or progressive AKI and a composite of KRT or death. Hypercalcemia was the key safety endpoint. We also performed RNA sequencing on circulating CD14+ monocytes collected immediately prior to randomization and two days later. RESULTS. The global rank score for the primary endpoint was similar among calcifediol (n = 51) vs. placebo (n = 49) treated patients (P = 0.85) and for calcitriol (n = 50) versus placebo-treated patients (P = 0.58). Secondary endpoints also occurred at similar rates across groups. Hypercalcemia occurred in one patient in the calcifediol group (1.7%), one patient in the calcitriol group (2.0%), and none of the patients in the placebo group. Compared to placebo, calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving interferon (IFN)-α, IFN-γ, oxidative phosphorylation, DNA repair, and heme metabolism. CONCLUSION. Treatment with calcifediol or calcitriol in critically ill adults upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism, but did not attenuate AKI. TRIAL REGISTRATION. ClinicalTrials.gov (NCT02962102). FUNDING. NIH/NIDDK grant K23DK106448 (Leaf) and NIH/NHLBI grant R01HL16687 (Kim)
Authors
David E. Leaf, Tushar Shenoy, Kevin Zinchuk, Shruti Gupta, Julie-Alexia Dias, Daniel Sanchez-Almanzar, Adit A. Ginde, Humra Athar, Changde Cheng, Tomoyoshi Tamura, Edy Y. Kim, Sushrut S. Waikar
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