Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

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Abstract

Pro-inflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the anti-inflammatory adenoviral RIDα/β protein complex in a cell type-specific manner. Suppression of adipocyte inflammation (“RIDad mice”) in a mammary tumor model driven by MMTV-PyMT (“PyMT-RIDad mice”) led to an elevated number of tumor-associated macrophages (TAMs) and upregulation of immunoregulatory molecules in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (“RIDMMTV mice”) decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.

Authors

Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer

E3 ubiquitin ligase Listerin regulates macrophage cholesterol efflux and atherosclerosis by targeting ABCA1

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Abstract

Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.

Authors

Lei Cao, Jie Zhang, Liwen Yu, Wei Yang, Wenqian Qi, Ruiqing Ren, Yapeng Liu, Yonghao Hou, Yu Cao, Qian Li, Xiaohong Wang, Zhengguo zhang, Bo Li, Wenhai Sui, Yun Zhang, Chengjiang Gao, Cheng Zhang, Meng Zhang

β-cell Gɑs signaling is critical for physiological and pharmacological enhancement of insulin secretion

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Abstract

The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors coordinate β-cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gɑs protein and generation of intracellular cyclic adenosine monophosphate (cAMP). However, recent reports have highlighted the importance of additional signaling nodes engaged by incretin receptors, including other G-proteins and β-arrestin proteins. Here, the importance of Gɑs signaling was tested in mice with conditional, post-developmental β-cell deletion of Gnas (encoding Gɑs) under physiological and pharmacological conditions. Deletion of Gɑs/cAMP signaling induced immediate and profound hyperglycemia that responded minimally to incretin receptor agonists, a sulfonylurea, or bethanechol. While islet area and insulin content were not affected in Gnasβcell-/-, perifusion of isolated islets demonstrated impaired responses to glucose, incretins, acetylcholine and IBMX. In the absence of Gɑs, incretin-stimulated insulin secretion was impaired but not absent, with some contribution from Gɑq signaling. Collectively, these findings validate a central role for cAMP to mediate incretin signaling, but also demonstrate broad impairment of insulin secretion in the absence of Gɑs that causes both fasting hyperglycemia and glucose intolerance.

Authors

Megan E. Capozzi, David Bouslov, Ashot Sargsyan, Michelle Y. Chan, Sarah M. Gray, Katrina Viloria, Akshay Bareja, Jonathan D. Douros, Sophie L. Lewandowski, Jason C.L. Tong, Annie Hasib, Federica Cuozzo, Elizabeth C. Ross, Matthew W. Foster, Lee S. Weinstein, Mehboob A. Hussain, Matthew J. Merrins, Francis S. Willard, Mark O. Huising, Kyle W. Sloop, David J. Hodson, David A. D'Alessio, Jonathan E. Campbell

TNFα impairs platelet function by inhibiting autophagy and disrupting metabolism via Syntaxin-17 downregulation

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Abstract

Platelets play a dual role in hemostasis and inflammation-associated thrombosis and hemorrhage. While the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNFα alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNFα impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism. Using human and murine models of TNFα-driven diseases, including myeloproliferative neoplasms and rheumatoid arthritis, we found that TNFα downregulates STX17, a key mediator of autophagosome–lysosome fusion. This disruption inhibited autophagy, leading to the accumulation of dysfunctional mitochondria and reduced mitochondrial respiration. These metabolic alterations compromised platelet-driven clot contraction, a process linked to thrombotic and hemorrhagic complications. Our findings reveal a mechanism by which TNFα disrupts hemostasis through autophagy inhibition, highlighting TNFα as a critical regulator of platelet metabolism and function. This study provides new insights into inflammation-associated pathologies and suggests autophagy-targeting strategies as potential therapeutic avenues to restore hemostatic balance.

Authors

Guadalupe Rojas-Sanchez, Jorge Calzada-Martinez, Brandon McMahon, Aaron C. Petrey, Gabriela Dveksler, Gerardo P. Espino-Solis, Orlando Esparza, Giovanny Hernandez, Dennis Le, Eric P. Wartchow, Ken Jones, Lucas H. Ting, Catherine Jankowski, Marguerite R. Kelher, Marilyn Manco-Johnson, Marie L. Feser, Kevin D. Deane, Travis Nemkov, Angelo D'Alessandro, Andrew Thorburn, Paola Maycotte, José A. López, Pavel Davizon-Castillo

Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice

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Abstract

Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to vascular endothelial cell growth factor A (VEGF-A) and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet (CD) refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical protein kinase C (aPKC) under both WD and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and blunted VEGF-A triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.

Authors

Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren

Panose prevents acute-on-chronic liver failure by reducing bacterial infection in mice

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Abstract

Acute-on-chronic liver failure (ACLF) is a leading cause of global liver-related mortality. Bacterial infection, especially in patients with decompensated cirrhosis (DC), commonly triggers ACLF and is difficult to treat with antibiotics. Therefore, finding alternative strategies for preventing and managing bacterial infection is an urgent priority. Here, we observed that infected DC patients and ACLF mice exhibited lower fecal panose levels than uninfected controls. Megamonas funiformis (M. funiformis), with 4α-glucanosyltransferase (4αGT) as a key enzyme for panose production, was identified as a potential panose producer. Animal experiments demonstrated that panose efficiently reduced liver injury and extended survival in ACLF mice by mitigating bacterial infection. Further results revealed that panose enhanced resistance to bacterial infection by inhibiting oxidative stress-induced gut barrier disruption, thereby limiting bacterial dissemination. Mechanistically, panose interacted with the solute carrier family 7 member 11 (SLC7A11, also known as xCT) protein to boost antioxidant glutathione (GSH) levels in intestinal epithelial cells. These findings highlight panose's potential in preventing bacterial infection, offering a valuable insight into mitigating ACLF progression.

Authors

Jiaxin Li, Shihao Xie, Meiling Chen, Changze Hong, Yuqi Chen, Fengyuan Lyu, Niexin Tang, Tianqi Chen, Lingyan Zhao, Weihao Zou, Hongjuan Peng, Jingna Bao, Peng Gu, Bernd Schnabl, Jinjun Chen, Peng Chen

The microRNA miR-30a blocks adipose tissue fibrosis accumulation in obesity

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Abstract

White adipose tissue (WAT) fibrosis occurring in obesity contributes to the inflammatory and metabolic co-morbidities of insulin resistance and type 2 diabetes, yet the mechanisms involved remain poorly understood. Here, we report a role for the broadly conserved microRNA miR-30a as a regulator of WAT fibrosis and systemic glucose metabolism. Mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced fatty liver disease when fed high fat diet. These effects were attributable to cell-autonomous functions of miR-30a that potently increase expression of adipocyte-specific genes. Proteomic screening revealed miR-30a limits pro-fibrotic programs in subcutaneous WAT, at least in part, by repressing PAI-1, a dominant regulator of fibrinolysis and biomarker of insulin resistance. Conversely, mouse adipocytes lacking miR-30a exhibited greater expression of fibrosis markers with disrupted cellular metabolism. Lastly, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT from people with obesity, further supporting an anti-fibrotic role for miR-30a. Together, these findings uncover miR-30a as a critical regulator of adipose tissue fibrosis that predicts metabolically healthy obesity in people and mice.

Authors

Pradip K. Saha, Robert Sharp, Aaron R. Cox, Rabie Habib, Michael J. Bolt, Jessica B. Felix, Claudia E. Ramirez Bustamante, Xin Li, Sung Yun Jung, Kang Ho Kim, Kai Sun, Huaizhu Wu, Samuel Klein, Sean M. Hartig

Hepatic glycogen directly regulates gluconeogenesis through an AMPK/CRTC2 axis in mice

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Abstract

Glycogenolysis and gluconeogenesis ensure sufficient hepatic glucose production during energy shortages. Here, we report that hepatic glycogen levels control the phosphorylation of a transcriptional coactivator to determine the amplitude of gluconeogenesis. Decreased liver glycogen during fasting promotes gluconeogenic gene expression, while feeding-induced glycogen accumulation suppresses it. Liver-specific deletion of the glycogen scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels, increases the expression of gluconeogenic genes, and promotes glucose production in primary hepatocytes. In contrast, liver glycogen phosphorylase (PYGL) knockdown or inhibition increases glycogen levels and represses gluconeogenic gene expression. These changes in hepatic glycogen levels are sensed by AMP-activated protein kinase (AMPK). AMPK activity is increased when glycogen levels decline, resulting in the phosphorylation and stabilization of CREB-regulated transcriptional coactivator 2 (CRTC2), which is crucial for the full activation of the cAMP-responsive transcriptional factor CREB. High glycogen allosterically inhibits AMPK, leading to CRTC2 degradation and reduced CREB transcriptional activity. Hepatocytes with low glycogen levels or high AMPK activity show higher CRTC2 protein levels, priming the cell for gluconeogenesis through transcriptional regulation. Thus, glycogen plays a regulatory role in controlling hepatic glucose metabolism through the glycogen/AMPK/CRTC2 signaling axis, safeguarding efficient glucose output during fasting and suppressing it during feeding.

Authors

Bichen Zhang, Morgan M. Johnson, Timothy Yuan, Tammy-Nhu Nguyen, Junichi Okada, Fajun Yang, Alus M. Xiaoli, Liana H. Melikian, Songran Xu, Benyamin Dadpey, Jeffrey E. Pessin, Alan R. Saltiel

Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity

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Abstract

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

Authors

Brian I. Park, Andrew R. Reeves, Ying Zhu, Robin A. Wilson, Sophia C. Fernandes, Kimberly K. Buhman, Kelli A. Lytle, Michael D. Jensen, Andrew S. Greenberg

Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis

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Abstract

Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.

Authors

Xin Li, Jingxin Hu, Yumeng Huang, Hai Zhang, Ning Xu, Yang Liu, Xuan Liu, Yuanyuan Ye, Xinxin Zhang, Xiaoxi Xu, Yuxin Fan, Ziyue Zhang, Weiping J. Zhang, Shusen Wang, Wenli Feng, Peter Arvan, Ming Liu