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412 results on '"Hoehn, Kyle L."'

1. Superstable lipid vacuoles endow cartilage with its shape and biomechanics

Author

Ramos, Raul, Pham, Kim T, Prince, Richard C, Leiser-Miller, Leith B, Prasad, Maneeshi S, Wang, Xiaojie, Nordberg, Rachel C, Bielajew, Benjamin J, Hu, Jerry C, Yamaga, Kosuke, Oh, Ji Won, Peng, Tao, Datta, Rupsa, Astrowskaja, Aksana, Almet, Axel A, Burns, John T, Liu, Yuchen, Guerrero-Juarez, Christian Fernando, Tran, Bryant Q, Chu, Yi-Lin, Nguyen, Anh M, Hsi, Tsai-Ching, Lim, Norman T-L, Schoeniger, Sandra, Liu, Ruiqi, Pai, Yun-Ling, Vadivel, Chella K, Ingleby, Sandy, McKechnie, Andrew E, van Breukelen, Frank, Hoehn, Kyle L, Rasweiler, John J, Kohara, Michinori, Loughry, William J, Weldy, Scott H, Cosper, Raymond, Yang, Chao-Chun, Lin, Sung-Jan, Cooper, Kimberly L, Santana, Sharlene E, Bradley, Jeffrey E, Kiebish, Michael A, Digman, Michelle, James, David E, Merrill, Amy E, Nie, Qing, Schilling, Thomas F, Astrowski, Aliaksandr A, Potma, Eric O, García-Castro, Martín I, Athanasiou, Kyriacos A, Behringer, Richard R, and Plikus, Maksim V

Subjects
Biochemistry and Cell Biology, Engineering, Biological Sciences, Biomedical Engineering, Nutrition, Obesity, Animals, Humans, Mice, Adipocytes, Biomechanical Phenomena, Cartilage, Extracellular Matrix, Lipid Droplets, Lipid Metabolism, Lipogenesis, Vacuoles, General Science & Technology
Abstract

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, but not in nonmammalian tetrapods. Thus, analogous to bubble wrap, superstable lipid vacuoles confer skeletal tissue with cartilage-like properties without "packing foam-like" extracellular matrix.

Published
2025

14. Beneficial effects of MGL‐3196 and BAM15 combination in a mouse model of fatty liver disease.

Author

Zhou, Mingyan, Li, Catherine, Byrne, Frances L., Vancuylenburg, Calum S., Olzomer, Ellen M., Hargreaves, Adam, Wu, Lindsay E., Shackel, Nicholas A., Santos, Webster L., and Hoehn, Kyle L.

Subjects
FATTY liver, THYROID hormone receptors, HEPATIC fibrosis, BODY composition, FAT
Abstract

Background and Aim: Metabolic dysfunction‐associated steatohepatitis (MASH) is a metabolic disorder with limited treatment options. The thyroid hormone receptor (THR)‐β agonist resmetirom/MGL‐3196 (MGL) increases liver fat oxidation and has been approved for treating adult MASH. However, over 60% of patients receiving MGL treatment do not achieve MASH resolution. Therefore, we investigated the potential for combination therapy of MGL with the mitochondrial uncoupler BAM15 to improve fatty liver disease outcomes in the GAN mouse model of MASH. Methods: C57BL/6J male mice were fed GAN diet for 38 weeks before stratification and randomization to treatments including MGL, BAM15, MGL + BAM15, or no drug control for 8 weeks. Treatments were admixed in diet and mice were pair‐fed to control for drug intake. Treatment effectiveness was assessed by body weight, body composition, energy expenditure, glucose tolerance, tissue lipid content, and histological analyses. Results: MGL + BAM15 treatment resulted in better efficacy versus GAN control mice than either monotherapy in the context of energy expenditure, liver fat loss, glucose control, and fatty liver disease activity score. Improvements in ALT, liver mass, and plasma cholesterol were primarily driven by MGL, while improvements in body fat were primarily driven by BAM15. No treatments altered liver fibrosis. Conclusions: MGL + BAM15 treatment had overall better efficacy to improve metabolic outcomes in mice fed GAN diet than either monotherapy alone. These data warrant further investigation into combination therapies of THR‐β agonists and mitochondrial uncouplers for the potential treatment of disorders related to fatty liver, obesity, and insulin resistance. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Phenotypic screen for oxygen consumption rate identifies an anti-cancer naphthoquinone that induces mitochondrial oxidative stress

Author

Byrne, Frances L., Olzomer, Ellen M., Marriott, Gabriella R., Quek, Lake-Ee, Katen, Alice, Su, Jacky, Nelson, Marin E., Hart-Smith, Gene, Larance, Mark, Sebesfi, Veronica F., Cuff, Jeff, Martyn, Gabriella E., Childress, Elizabeth, Alexopoulos, Stephanie J., Poon, Ivan K., Faux, Maree C., Burgess, Antony W., Reid, Glen, McCarroll, Joshua A., Santos, Webster L., Quinlan, Kate GR., Turner, Nigel, Fazakerley, Daniel J., Kumar, Naresh, and Hoehn, Kyle L.

Published
2020
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17. Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice

Author

Chen, Sing-Young, primary, Telfser, Aiden J., additional, Olzomer, Ellen M., additional, Vancuylenberg, Calum S., additional, Zhou, Mingyan, additional, Beretta, Martina, additional, Li, Catherine, additional, Alexopoulos, Stephanie J., additional, Turner, Nigel, additional, Byrne, Frances L., additional, Santos, Webster L., additional, and Hoehn, Kyle L., additional

Published
2024
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18. Breast cancer growth and proliferation is suppressed by the mitochondrial targeted furazano[3,4-b]pyrazine BAM15

Author

Zunica, Elizabeth R. M., Axelrod, Christopher L., Cho, Eunhan, Spielmann, Guillaume, Davuluri, Gangarao, Alexopoulos, Stephanie J., Beretta, Martina, Hoehn, Kyle L., Dantas, Wagner S., Stadler, Krisztian, King, William T., Pergola, Kathryn, Irving, Brian A., Langohr, Ingeborg M., Yang, Shengping, Hoppel, Charles L., Gilmore, L. Anne, and Kirwan, John P.

Published
2021
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19. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane

Author

Kenwood, Brandon M, Weaver, Janelle L, Bajwa, Amandeep, Poon, Ivan K, Byrne, Frances L, Murrow, Beverley A, Calderone, Joseph A, Huang, Liping, Divakaruni, Ajit S, Tomsig, Jose L, Okabe, Kohki, Lo, Ryan H, Coleman, G Cameron, Columbus, Linda, Yan, Zhen, Saucerman, Jeffrey J, Smith, Jeffrey S, Holmes, Jeffrey W, Lynch, Kevin R, Ravichandran, Kodi S, Uchiyama, Seiichi, Santos, Webster L, Rogers, George W, Okusa, Mark D, Bayliss, Douglas A, and Hoehn, Kyle L

Subjects
5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 1.1 Normal biological development and functioning, Underpinning research, Mitochondria, Doenergetics, FCCP, CCCP, DNP, ischemia, ANT, adenine nucleotide translocase, Bioenergetics, ECAR, extracellular acidification rate, FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, Ischemia, OCR, oxygen consumption rate, ROS, reactive oxygen species, TCA cycle, tricarboxylic acid cycle, TMPD, N, N, N′, N′-tetramethyl-p-phenylenediamine dihydrochloride, TMRM, tetramethylrhodamine, Biochemistry and Cell Biology, Physiology
Abstract

Dysregulation of oxidative phosphorylation is associated with increased mitochondrial reactive oxygen species production and some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Chemical 'mitochondrial uncouplers' are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. Mitochondrial uncouplers also lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing production of reactive oxygen species. Thus, mitochondrial uncouplers are valuable chemical tools that enable the measurement of maximal mitochondrial respiration and they have been used therapeutically to decrease mitochondrial reactive oxygen species production. However, the most widely used protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol have off-target activity at other membranes that lead to a range of undesired effects including plasma membrane depolarization, mitochondrial inhibition, and cytotoxicity. These unwanted properties interfere with the measurement of mitochondrial function and result in a narrow therapeutic index that limits their usefulness in the clinic. To identify new mitochondrial uncouplers that lack off-target activity at the plasma membrane we screened a small molecule chemical library. Herein we report the identification and validation of a novel mitochondrial protonophore uncoupler (2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine, named BAM15, that does not depolarize the plasma membrane. Compared to FCCP, an uncoupler of equal potency, BAM15 treatment of cultured cells stimulates a higher maximum rate of mitochondrial respiration and is less cytotoxic. Furthermore, BAM15 is bioactive in vivo and dose-dependently protects mice from acute renal ischemic-reperfusion injury. From a technical standpoint, BAM15 represents an effective new tool that allows the study of mitochondrial function in the absence of off-target effects that can confound data interpretation. From a therapeutic perspective, BAM15-mediated protection from ischemia-reperfusion injury and its reduced toxicity will hopefully reignite interest in pharmacological uncoupling for the treatment of the myriad of diseases that are associated with altered mitochondrial function.

Published
2014

21. High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice

Author

Burchfield, James G., Kebede, Melkam A., Meoli, Christopher C., Stöckli, Jacqueline, Whitworth, P. Tess, Wright, Amanda L., Hoffman, Nolan J., Minard, Annabel Y., Ma, Xiuquan, Krycer, James R., Nelson, Marin E., Tan, Shi-Xiong, Yau, Belinda, Thomas, Kristen C., Wee, Natalie K.Y., Khor, Ee-Cheng, Enriquez, Ronaldo F., Vissel, Bryce, Biden, Trevor J., Baldock, Paul A., Hoehn, Kyle L., Cantley, James, Cooney, Gregory J., James, David E., and Fazakerley, Daniel J.

Published
2018
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22. Liver-selective imidazolopyrazine mitochondrial uncoupler SHD865 reverses adiposity and glucose intolerance in mice

Author

Beretta, Martina, primary, Dai, Yumin, additional, Olzomer, Ellen M., additional, Vancuylenburg, Calum S., additional, Santiago-Rivera, José A., additional, Philp, Ashleigh M., additional, Hargett, Stefan R., additional, Li, Keyong, additional, Shah, Divya P., additional, Chen, Sing-Young, additional, Alexopoulos, Stephanie J., additional, Li, Catherine, additional, Harris, Thurl E., additional, Lee, Brendan, additional, Wathier, Michel, additional, Cermak, Jennifer M., additional, Tucker, Simon P., additional, Turner, Nigel, additional, Bayliss, Douglas A., additional, Philp, Andrew, additional, Byrne, Frances L., additional, Santos, Webster L., additional, and Hoehn, Kyle L., additional

Published
2023
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23. Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism

Author

Krycer, James R., Yugi, Katsuyuki, Hirayama, Akiyoshi, Fazakerley, Daniel J., Quek, Lake-Ee, Scalzo, Richard, Ohno, Satoshi, Hodson, Mark P., Ikeda, Satsuki, Shoji, Futaba, Suzuki, Kumi, Domanova, Westa, Parker, Benjamin L., Nelson, Marin E., Humphrey, Sean J., Turner, Nigel, Hoehn, Kyle L., Cooney, Gregory J., Soga, Tomoyoshi, Kuroda, Shinya, and James, David E.

Published
2017
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25. BAM15‐mediated mitochondrial uncoupling protects against obesity and improves glycemic control

Author

Axelrod, Christopher L, King, William T, Davuluri, Gangarao, Noland, Robert C, Hall, Jacob, Hull, Michaela, Dantas, Wagner S, Zunica, Elizabeth RM, Alexopoulos, Stephanie J, Hoehn, Kyle L, Langohr, Ingeborg, Stadler, Krisztian, Doyle, Haylee, Schmidt, Eva, Nieuwoudt, Stephan, Fitzgerald, Kelly, Pergola, Kathryn, Fujioka, Hisashi, Mey, Jacob T, Fealy, Ciaran, Mulya, Anny, Beyl, Robbie, Hoppel, Charles L, and Kirwan, John P

Published
2020
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28. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice

Author

Alexopoulos, Stephanie J., Chen, Sing-Young, Brandon, Amanda E., Salamoun, Joseph M., Byrne, Frances L., Garcia, Christopher J., Beretta, Martina, Olzomer, Ellen M., Shah, Divya P., Philp, Ashleigh M., Hargett, Stefan R., Lawrence, Robert T., Lee, Brendan, Sligar, James, Carrive, Pascal, Tucker, Simon P., Philp, Andrew, Lackner, Carolin, Turner, Nigel, Cooney, Gregory J., Santos, Webster L., and Hoehn, Kyle L.

Published
2020
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34. Targeting negative energy balance with calorie restriction and mitochondrial uncoupling in db/db mice

Author

Chen, Sing -Young, Beretta, Martina, Olzomer, Ellen M., Shah, Divya P., Wong, Derek Y. H., Alexopoulos, Stephanie J., Aleksovska, Isabella, Salamoun, Joseph M., Garcia, Christopher J., Cochran, Blake J., Rye, Kerry-Anne, Smith, Greg C., Byrne, Frances L., Morris, Margaret J., Santos, Webster L., Cantley, James, Hoehn, Kyle L., Chen, Sing -Young, Beretta, Martina, Olzomer, Ellen M., Shah, Divya P., Wong, Derek Y. H., Alexopoulos, Stephanie J., Aleksovska, Isabella, Salamoun, Joseph M., Garcia, Christopher J., Cochran, Blake J., Rye, Kerry-Anne, Smith, Greg C., Byrne, Frances L., Morris, Margaret J., Santos, Webster L., Cantley, James, and Hoehn, Kyle L.

Abstract

Objective: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. Methods: Male db/db mice were treated with w50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. Results: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. Conclusions: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice

Published
2023

35. Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

Author

Sing-Young Chen, Telfser, Aiden J., Olzomer, Ellen M., Vancuylenberg, Calum S., Mingyan Zhou, Beretta, Martina, Li, Catherine, Alexopoulos, Stephanie J., Turner, Nigel, Byrne, Frances L., Santos, Webster L., and Hoehn, Kyle L.

Subjects
ANTIOBESITY agents, WEIGHT loss, WESTERN diet, LEAN body mass, GASTRIC emptying
Abstract

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Supplemental Figures S1-8 from Metabolic Vulnerabilities in Endometrial Cancer

Author

Byrne, Frances L., primary, Poon, Ivan K.H., primary, Modesitt, Susan C., primary, Tomsig, Jose L., primary, Chow, Jenny D.Y., primary, Healy, Marin E., primary, Baker, William D., primary, Atkins, Kristen A., primary, Lancaster, Johnathan M., primary, Marchion, Douglas C., primary, Moley, Kelle H., primary, Ravichandran, Kodi S., primary, Slack-Davis, Jill K., primary, and Hoehn, Kyle L., primary

Published
2023
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40. Data from Metabolic Vulnerabilities in Endometrial Cancer

Author

Byrne, Frances L., primary, Poon, Ivan K.H., primary, Modesitt, Susan C., primary, Tomsig, Jose L., primary, Chow, Jenny D.Y., primary, Healy, Marin E., primary, Baker, William D., primary, Atkins, Kristen A., primary, Lancaster, Johnathan M., primary, Marchion, Douglas C., primary, Moley, Kelle H., primary, Ravichandran, Kodi S., primary, Slack-Davis, Jill K., primary, and Hoehn, Kyle L., primary

Published
2023
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41. Supplemental Methods from Metabolic Vulnerabilities in Endometrial Cancer

Author

Byrne, Frances L., primary, Poon, Ivan K.H., primary, Modesitt, Susan C., primary, Tomsig, Jose L., primary, Chow, Jenny D.Y., primary, Healy, Marin E., primary, Baker, William D., primary, Atkins, Kristen A., primary, Lancaster, Johnathan M., primary, Marchion, Douglas C., primary, Moley, Kelle H., primary, Ravichandran, Kodi S., primary, Slack-Davis, Jill K., primary, and Hoehn, Kyle L., primary

Published
2023
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42. Oxadiazolopyridine Derivatives as Efficacious Mitochondrial Uncouplers in the Prevention of Diet-Induced Obesity

Author

Murray, Jacob H., primary, Burgio, Ariel L., additional, Beretta, Martina, additional, Hargett, Stefan R., additional, Harris, Thurl E., additional, Olzomer, Ellen, additional, Grams, R. Justin, additional, Garcia, Christopher J., additional, Li, Catherine, additional, Salamoun, Joseph M., additional, Hoehn, Kyle L., additional, and Santos, Webster L., additional

Published
2023
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44. Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Author

Chow, Jenny D.Y., Lawrence, Robert T., Healy, Marin E., Dominy, John E., Liao, Jason A., Breen, David S., Byrne, Frances L., Kenwood, Brandon M., Lackner, Carolin, Okutsu, Saeko, Mas, Valeria R., Caldwell, Stephen H., Tomsig, Jose L., Cooney, Gregory J., Puigserver, Pere B., Turner, Nigel, James, David E., Villén, Judit, and Hoehn, Kyle L.

Published
2014
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46. A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Author

Turner, Nigel, Lim, Xin Ying, Toop, Hamish D., Osborne, Brenna, Brandon, Amanda E., Taylor, Elysha N., Fiveash, Corrine E., Govindaraju, Hemna, Teo, Jonathan D., McEwen, Holly P., Couttas, Timothy A., Butler, Stephen M., Das, Abhirup, Kowalski, Greg M., Bruce, Clinton R., Hoehn, Kyle L., Fath, Thomas, Schmitz-Peiffer, Carsten, Cooney, Gregory J., Montgomery, Magdalene K., Morris, Jonathan C., and Don, Anthony S.

Published
2018
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