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Dissertation Defense: The impact of NOX4 deficiency on sexually dimorphic lipid handling in HFD-challenged mice

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Mary Frazier

Dissertation Defense: The impact of NOX4 deficiency on sexually dimorphic lipid handling in HFD-challenged mice

Jacob Bond

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Craige Lab, Department of Human Nutrition, Foods, & Exercise
April 30, 2025, at 8 a.m.

Steger Hall, Room 145

Visit the Craige Lab
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More About the Candidate and Project

Education

Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Virginia Tech, B.S., Biochemistry

Virginia Tech, B.S., Human Nutrition, Foods, and Exercise

Tidewater Community College, A.S., Science

Training

Graduate Research Assistant, Craige Lab, Department of Human Nutrition, Foods, & Exercise

Mentor

Sioban Craige, Ph.D., Department of Human Nutrition, Foods, & Exercise

Committee Members

  • Michaela Tencerová, Ph.D., Head of Laboratory, Department of Physiology of Bone, Institute of Physiology of the Czech Academy of Sciences
  • Elizabeth Gilbert, Ph.D., Professor, School of Neuroscience
  • Kevin Davy, Ph.D., Professor, Deaprtment of Human Nutrition, Foods, & Exercise
  • Bond J., Dzubanova M., Addington A., Najt C., Gilbert E., Tencerova M., Craige S. Sex-Specific Metabolic Responses to NOX4 Deficiency with High-Fat Diet. 2025. In Submission.
  • Craige SM, Kaur G, Bond JM, Caliz AD, Kant S, Keaney JF Jr. Endothelial Reactive Oxygen Species: Key Players in Cardiovascular Health and Disease. Antioxid Redox Signal. 2024 Sep 30. doi: 10.1089/ars.2024.0706. Epub ahead of print. PMID: 39213161.

  • Dzubanova M, Bond JM, Craige SM, Tencerova M. NOX4-reactive oxygen species axis: critical regulators of bone health and metabolism. Front Cell Dev Biol. 2024 Aug 12;12:1432668. doi: 10.3389/fcell.2024.1432668. PMID: 39188529; PMCID: PMC11345137.

  • Brisendine MH, Nichenko AS, Bandara AB, Willoughby OS, Amiri N, Weingrad Z, Specht KS, Bond JM, Addington A, Jones RG 3rd, Murach KA, Poelzing S, Craige SM, Grange RW, Drake JC. Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease. Function (Oxf). 2023 Dec 4;5(1):zqad066. doi: 10.1093/function/zqad066. PMID: 38111538; PMCID: PMC10727840.

  • Cabana-Puig X, Bond JM, Wang Z, Dai R, Lu R, Lin A, Oakes V, Rizzo A, Swartwout B, Abdelhamid L, Mao J, Prakash M, Sangmeister C, Cheung N, Cowan C, Reilly CM, Sun S, Ahmed SA, Luo XM. Phenotypic Drift in Lupus-Prone MRL/lpr Mice: Potential Roles of MicroRNAs and Gut Microbiota. Immunohorizons. 2022 Jan 17;6(1):36-46. doi: 10.4049/immunohorizons.2100082. PMID: 35039434; PMCID: PMC10984647.

  • Brisendine MH, Bond JM. A glimpse into the early window of muscle unloading. J Physiol. 2021 Sep;599(18):4249-4251. doi: 10.1113/JP282019. Epub 2021 Aug 12. PMID: 34318496.

  • Specht KS, Kant S, Addington AK, McMillan RP, Hulver MW, Learnard H, Campbell M, Donnelly SR, Caliz AD, Pei Y, Reif MM, Bond JM, DeMarco A, Craige B, Keaney JF Jr, Craige SM. Nox4 mediates skeletal muscle metabolic responses to exercise. Mol Metab. 2021 Mar;45:101160. doi: 10.1016/j.molmet.2020.101160. Epub 2021 Jan 2. PMID: 33400973; PMCID: PMC7856463.
  • 2024 Graduate Research Development Program
  • Oral presentation, abstract, poster, and online conference: Bond J, Benova A, Ferencakova M, Prakash B, Addington A, Specht K, Craige S, Tencerova M. 2021. The role of Nox4-ROS in driving senescent bone marrow mesenchymal stem cell phenotype in mice. Bone Marrow Microenvironment and Niches. J Bone Miner Res, Volume 37, Pages 1-371, Supplement 1. Available at https://www.asbmr.org/meetings/annualmeeting/AbstractDetail?aid=c8289b63-cd6b-4bac-977e-3d799e486b51. Accessed April 18th, 2025.

  • Oral presentation: Jacob Bond, Andrea Benova, Michaela Ferencakova, Binu Prakash, Adele Addington, Kalyn Specht, Siobhan Craige, Michaela Tencerova. The role of Nox4-ROS in driving obesogenic bone marrow mesenchymal stem cell phenotype in mice. September 8th, 2021. International Bone Marrow Adiposity Society Summer School. September 6th-8th.

  • Oral presentation and abstract at online conference: Jacob Bond, Andrea Benova, Michaela Ferencakova, Binu Prakash, Adele Addington, Kalyn Specht, Siobhan Craige, Michaela Tencerova. The role of Nox4-ROS in driving obesogenic bone marrow mesenchymal stem cell phenotype in mice. September 30th, 2021. Abstract #627. Session: SO 53 - New insights from animal models of complications. 57th Annual Meeting for the European Association for the Study of Diabetes.

  • Poster: Jacob Bond, Martina Dzubanova, Andrea Benova, Michaela Ferencakova, Greet Kerckhofs, Binu Prakash, Adele Addington, Kalyn Specht, Rebecca Mammel, Siobhan Craige, Michaela Tencerova. Deletion of NADPH oxidase 4 produces sexually dimorphic phenotypes resembling osteosarcopenic obesity syndrome in mice. April 30th, 2024. 7th Annual Virginia Tech Muscle Symposium.

  • Poster: Jacob Bond, Martina Dzubanova, Andrea Benova, Michaela Ferencakova, Greet Kerckhofs, Adele Addington, Rebecca Mammel, Michaela Tencerova, Siobhan Craige. Loss of NOX4 results in a sexually dimorphic response to high fat diet feeding in liver, bone and muscle, Free Radical Biology and Medicine, Volume 224, Supplement 1, 2024, Pages S19-S20, ISSN 891-5849, https://doi.org/10.1016/j.freeradbiomed.2024.10.036.
  • 2024 Roanoke County Schools Science Fair - Volunteer Judge

About this Dissertation

Reactive oxygen species (ROS) are critical mediators of metabolic signaling, playing essential roles in the regulation of glucose and lipid homeostasis. Among enzymatic sources of ROS, NADPH oxidase 4 (NOX4) uniquely generates hydrogen peroxide in response to metabolic stimuli, influencing physiological processes such as glucose and lipid uptake and adipogenesis through redox-sensitive mechanisms. However, NOX4-derived hydrogen peroxide may also drive counterproductive cellular responses in pathological conditions, potentiating metabolic dysfunction. Importantly, the influence of NOX4 on whole-body metabolic regulation, particularly in the context of biological sex, remains incompletely understood. This work investigates the role of NOX4 in shaping metabolic responses to chronic dietary excess by characterizing glucose and lipid handling in male and female mice lacking NOX4 following 20 weeks of high-fat diet (HFD) feeding. In males, NOX4 deficiency led to reduced adiposity, protection against hepatic lipid accumulation, and improved glucose and insulin tolerance. Conversely, in females, NOX4 deficiency resulted in increased fat mass and peripheral adipose tissue expansion, accompanied by impaired glucose tolerance. Comparing changes in mRNA levels in the liver and skeletal muscle revealed sexually dimorphic shifts in the expression of genes governing lipid metabolism, suggesting that NOX4 regulates metabolism via redox-sensitive pathways that are differentially modulated by sex. Collectively, these findings position NOX4 as a central redox mediator of metabolic homeostasis and demonstrate that its effects on lipid and glucose handling are highly sex-specific. By using HFD to unmask regulatory roles of NOX4-hydrogen peroxide, this work enhances our understanding of how NOX4 contributes to systemic glucose and lipid handling and highlights the importance of considering sex in redox biology and metabolic research.