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Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI184636.
Abstract
Bardet-Biedl Syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in BBS genes. More exacerbated symptoms occur with mutations in genes encoding the BBSome, a complex regulating primary cilia function. We investigated the mechanisms underlying BBS-induced obesity using a novel BBS5 knockout (BBS5-/-) mouse model. BBS5-/- mice displayed hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. They displayed an unique immunophenotype in white adipose tissue with increased proinflammatory macrophages and dysfunctional regulatory T cells, suggesting a distinct mechanism for adiposity compared to typical obesity models. Additionally, BBS5-/- mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulated endocrine signaling pathways with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signalling, while preserving glucagon-like peptide-1 receptor (GLP-1R) responsiveness. Notably, treatment with a GLP-1R agonist effectively alleviated hyperphagia, body weight gain, improved glucose tolerance, and circulating metabolic hormones in BBS5-/- mice. This study establishes BBS5-/- mice as a valuable translational model of BBS to understand the pathogenesis and develop novel treatments. Our findings highlight the therapeutic potential of GLP-1R agonists for managing BBS-associated metabolic dysregulation, warranting further investigation for clinical application.
Authors
Arashdeep Singh, Naila Haq, Mingxin Yang, Shelby Luckey, Samira Mansouri, Martha Campbell-Thompson, Lei Jin, Sofia Christou-Savina, Guillaume de Lartigue
Abstract
BACKGROUND. Microglia-mediated brain immune changes play a role in the pathogenesis of Parkinson’s disease (PD) but imaging microglia in living people with PD has relied on positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. We aimed to develop imaging of colony stimulating factor 1 receptor (CSF1R) as a microglial-sensitive marker of innate immunity. METHODS. Immunohistochemistry using a CSF1R antibody evaluated colocalization with Iba-1 in PD (n = 4) and control (n = 4) human brain samples. Autoradiography using a CSF1R tritiated ligand in PD (n = 5) and controls (n = 4) human brain samples was performed to obtain Bmax. PET imaging using a CSF1R radioligand was performed in 10 controls and 12 people with PD and VT was compared between groups and correlated with disease severity. RESULTS. Immunohistochemistry of CSF1R in human brain shows colocalization with Iba-1 and is significantly increased in PD compared to controls. Autoradiography revealed significantly increased CSF1R ligand binding in the inferior parietal cortex of PD patients. [11C]CPPC PET showed higher binding in people with moderate PD compared to controls and correlated with more severe motor disability and poorer verbal fluency. CONCLUSION. This study underscores the significance of CSF1R imaging as a promising biomarker for brain immune function in Parkinson's disease, which may be associated with cognitive and motor disease severity FUNDING. PET imaging: the Michael J. Fox Foundation and the RMS Family Foundation. Radiotracer development: NIH (R01AG066464 and P41 EB024495). Postmortem brain tissues: NIH P30 AG066507 and BIOCARD study NIH U19 AG033655.
Authors
Kelly A. Mills, Yong Du, Jennifer M. Coughlin, Catherine A. Foss, Andrew G. Horti, Katelyn R. Jenkins, Yana Skorobogatova, Ergi Spiro, Chelsie S. Motley, Robert F. Dannals, Wojciech G. Lesniak, Jae-Jin Song, Yu Ree Choi, Javier Redding-Ochoa, Juan C. Troncoso, Valina L. Dawson, Tae-In Kam, Martin G. Pomper, Ted M. Dawson
Abstract
The Fanconi anemia (FA)/BRCA DNA repair network promotes the removal of DNA interstrand crosslinks (ICLs) to counteract their devastating consequences, including oncogenesis. Network signaling is initiated by the FA core complex, which consists of seven authentic FA proteins and an FA-associated protein, FAAP100, with incompletely characterized roles and unknown disease associations. Upon activation, the FA core complex functions as a multiprotein E3 ubiquitin ligase centered on its catalytic module, the FANCB-FANCL-FAAP100 (BLP100) subcomplex, for FANCD2 and FANCI monoubiquitylation. Here, we identified a homozygous variant in FAAP100, c.1642A>C, predicting p.(T542P), in a fetus with malformations suggestive of FA. The mutation causes sensitivity to ICL-inducing agents in cells from the affected individual and genetically engineered, FAAP100-inactivated human, avian, zebrafish, and mouse cells. All FAAP100-deficient cell types were rescued by ectopic expression of wild-type FAAP100, but not FAAP100T542P. In a confirmatory animal model, customized Faap100–/– mice exhibit embryonic lethality, microsomia, malformations, and gonadal atrophy resembling mice with established FA subtypes. Mechanistically, FAAP100T542P impairs ligase activity by preventing BLP100 subcomplex formation, resulting in defective FAAP100T542P nuclear translocation and chromatin recruitment. FAAP100 dysfunction that disrupts the FA pathway and impairs genomic maintenance, together with FAconsistent human manifestations, recommends FAAP100 as a legitimate FA gene, FANCX.
Authors
Julia Kuehl, Yutong Xue, Fenghua Yuan, Ramanagouda Ramanagoudr-Bhojappa, Simone Pickel, Reinhard Kalb, Settara C. Chandrasekharappa, Weidong Wang, Yanbin Zhang, Detlev Schindler
Abstract
Weight loss medications are emerging candidates for pharmacotherapy of sleep disordered breathing (SDB). A melanocortin receptor 4 (MC4R) agonist, setmelanotide (SET), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that SET can treat SDB in diet induced obese mice. We performed a proof-of-concept randomized crossover trial of a single dose of SET vs vehicle and a two-week daily SET vs vehicle trial, examined co-localization of Mc4r mRNAs with markers of CO2 sensing neurons Phox2b and neuromedin-B in the brainstem, and expressed Cre-dependent designer receptors exclusively activated by designer drugs or caspase in obese Mc4r-Cre mice. SET increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR) and abolished apneas during sleep. Phox2b+ neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R+ neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R+ neurons abolished effects of SET on HCVR. Parafacial MC4R+ neurons projected to the respiratory pre-motor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R+ neurons.
Authors
Mateus R. Amorim, Noah R. Williams, O Aung, Melanie Alexis Ruiz, Frederick Anokye-Danso, Junia Lara de Deus, Jiali Xiong, Olga Dergacheva, Shannon Bevans-Fonti, Sean M. Lee, Jeffrey S Berger, Mark N. Wu, Rexford S. Ahima, David Mendelowitz, Vsevolod Y. Polotsky
Abstract
BACKGROUND. Decoding the clinical impact of genetic variants is particularly important for precision medicine in cancer. Genetic screening of mainly breast and ovarian cancer patients has identified numerous BRCA1/BRCA2 ‘variants of uncertain significance’ (VUS) that remain unclassified due to a lack of pedigrees and functional data. METHODS. Here, we used CRISPR-Select — a technology that exploits unique inbuilt controls at the endogenous locus — to assess 54 rare ClinVar VUS located in the PALB2-binding domain (PBD) of BRCA2. Variant deleteriousness was examined in the absence and presence of PARPi, Cisplatin, or Mitomycin C. RESULTS. Marked functional deficiency was observed for variants in the exon 2-donor splice region (A22 = (c.66A>C), A22 = (c.66A>G), A22 = (c.66A>T), and D23H) and Trp31 amino acid (W31G, W31L, and W31C), both critical for BRCA2 function. Moreover, T10K and G25R resulted in an intermediate phenotype, suggesting these variants are hypomorphic in nature. Combining our functional results with the latest ClinGen BRCA1/2 Variant Curation Expert Panel recommendations, we could classify 49 of the 54 VUS as either likely benign (n = 45) or likely pathogenic (n = 4). CONCLUSION. Hence, CRISPR-Select is an important tool for efficient variant clinical classification. Application of this technology in the future will ultimately improve patient care. FUNDING. Danish Cancer Society, Novo Nordisk Foundation, Sygeforsikring Danmark, Børnecancerfonden, Neye-Fonden, Roche, Novartis, Pfizer, AstraZeneca, MSD, and Daiichi Sankyo Europe GmbH.
Authors
Muthiah Bose, Manika Indrajit Singh, Morten Frödin, Bent Ejlertsen, Claus S. Sørensen, Maria Rossing
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI178806.
Abstract
Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross-sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild type (WT) mice, or mice with genetic deletion of the central complement component 3 (C3–/– mice). Compared to WT mice, C3–/– mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation is contributory to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.
Authors
Andrew C. D'Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI183343.
Abstract
In the kidney, cells of thick ascending limb of the loop of Henle (TAL) are resistant to ischemic injury, despite high energy demands. This adaptive metabolic response is not fully understood even though the integrity of TAL cells is essential for recovery from acute kidney injury (AKI). TAL cells uniquely express uromodulin, the most abundant protein secreted in healthy urine. Here, we demonstrate that alternative splicing generates a conserved intracellular isoform of uromodulin, which contributes to metabolic adaptation of TAL cells. This splice variant was induced by oxidative stress and was up-regulated by AKI that is associated with recovery, but not by severe AKI and chronic kidney disease (CKD). This intracellular variant was targeted to the mitochondria, increased NAD+ and ATP levels, and protected TAL cells from hypoxic injury. Augmentation of this variant using antisense oligonucleotides after severe AKI improved the course of injury. These findings underscore an important role of condition-specific alternative splicing in adaptive energy metabolism to hypoxic stress. Enhancing this protective splice variant in TAL cells could become a novel therapeutic intervention for AKI.
Authors
Azuma Nanamatsu, George J. Rhodes, Kaice A. LaFavers, Radmila Micanovic, Virginie Lazar, Shehnaz Khan, Daria Barwinska, Shinichi Makino, Amy Zollman, Ying-Hua Cheng, Emma H. Doud, Amber L. Mosley, Matthew J. Repass, Malgorzata M. Kamocka, Aravind Baride, Carrie L. Phillips, Katherine J. Kelly, Michael T. Eadon, Jonathan Himmelfarb, Matthias Kretzler, Robert L. Bacallao, Pierre C. Dagher, Takashi Hato, Tarek M. El-Achkar
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI169152.
Abstract
Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index and type 2 diabetes. These results suggest that IL-13 signaling-regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.
Authors
Alexandra R. Yesian, Mayer M. Chalom, Nelson H. Knudsen, Alec L. Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A. Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B. Hu, Alexander S. Banks, Chih-Hao Lee
Abstract
Aortic aneurysm is a high-risk cardiovascular disease without effective cure. Vascular Smooth Muscle Cell (VSMC) phenotypic switching is a key step in the pathogenesis of aortic aneurysm. Here, we revealed the role of histidine triad nucleotide-binding protein 1 (HINT1) in aortic aneurysm. HINT1 was upregulated both in aortic tissue from patients with aortic aneurysm and Ang II-induced aortic aneurysm mice. VSMC-specific HINT1 deletion alleviated aortic aneurysm via preventing VSMC phenotypic switching. With the stimulation of pathological factors, the increased nuclear translocation of HINT1 mediated by nucleoporin 98 (Nup98) promoted the interaction between HINT1 and transcription factor AP-2 alpha (TFAP2A) and further triggered the transcription of integrin alpha 6 (ITGA6) mediated by TFAP2A, and consequently activated the downstream focal adhesion kinase (FAK)/STAT3 signal pathway, leading to aggravation of VSMC phenotypic switching and aortic aneurysm. Importantly, Defactinib treatment was demonstrated to limit aortic aneurysm development by inhibiting the FAK signal pathway. Thus, HINT1/ITGA6/FAK axis emerges as potential therapeutic strategies in aortic aneurysm.
Authors
Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI176818.
Abstract
Acute myeloid leukemia (AML) is an aggressive and often deadly malignancy associated with proliferative immature myeloid blasts. Here, we identified CD84 as a critical survival regulator in AML. High levels of CD84 expression provided a survival advantage to leukemia cells, whereas CD84 downregulation disrupted their proliferation, clonogenicity and engraftment capabilities in both human cell lines and patient derived xenograft cells. Critically, loss of CD84 also markedly blocked leukemia engraftment and clonogenicity in MLL-AF9 and inv(16) AML mouse models, highlighting its pivotal role as survival factor across species. Mechanistically, CD84 regulated leukemia cells’ energy metabolism and mitochondrial dynamics. Depletion of CD84 altered mitochondrial ultra-structure and function of leukemia cells, and it caused down-modulation of both oxidative phosphorylation and fatty acid oxidation pathways. CD84 knockdown induced a block of Akt phosphorylation and down-modulation of nuclear factor erythroid 2-related factor 2 (NRF2), impairing AML antioxidant defense. Conversely, CD84 over-expression stabilized NRF2 and promoted its transcriptional activation, thereby supporting redox homeostasis and mitochondrial function in AML. Collectively, our findings indicated that AML cells depend on CD84 to support antioxidant pro-survival pathways, highlighting a therapeutic vulnerability of leukemia cells.
Authors
Yinghui Zhu, Mariam Murtadha, Miaomiao Liu, Enrico Caserta, Ottavio Napolitano, Le Xuan Truong Nguyen, Huafeng Wang, Milad Moloudizargari, Lokesh Nigam, Theophilus Tandoh, Xuemei Wang, Alex Pozhitkov, Rui Su, Xiangjie Lin, Marc Denisse Estepa, Raju Pillai, Joo Song, James F. Sanchez, Yu-Hsuan Fu, Lianjun Zhang, Man Li, Bin Zhang, Ling Li, Ya-Huei Kuo, Steven Rosen, Guido Marcucci, John C. Williams, Flavia Pichiorri
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