Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

Kurtz, Ryan; Libby, Andrew; Jones, Bryce A.; Myakala, Komuraiah; Wang, Xiaoxin; Lee, Yichien; Knoer, Grace; Lo Cascio, Julia N.; McCormack, Michaela; Nguyen, Grace; Choos, Elijah N. D.; Rodriguez, Olga; Rosenberg, Avi Z.; Ranjit, Suman; Albanese, Christopher; Levi, Moshe; Ecelbarger, Carolyn M.; Shepard, Blythe D.

doi:10.3390/ijms23105675

Open AccessArticle

Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

by

Ryan Kurtz

¹,

Andrew Libby

²

,

Bryce A. Jones

³,

Komuraiah Myakala

⁴

,

Xiaoxin Wang

⁴,

Yichien Lee

^5,6,

Grace Knoer

⁵,

Julia N. Lo Cascio

¹,

Michaela McCormack

⁵,

Grace Nguyen

¹,

Elijah N. D. Choos

¹,

Olga Rodriguez

^5,6

,

Avi Z. Rosenberg

⁷,

Suman Ranjit

^4,8

,

Christopher Albanese

^5,6,9,

Moshe Levi

⁴

,

Carolyn M. Ecelbarger

¹⁰ and

Blythe D. Shepard

^1,*

¹

Department of Human Science, Georgetown University Medical Center, Washington, DC 20057, USA

²

Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80012, USA

³

Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20057, USA

⁴

Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA

⁵

Department Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

⁶

Center for Translational Imaging, Georgetown University Medical Center, Washington, DC 20057, USA

⁷

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA

⁸

Microscopy & Imaging Shared Resources, Georgetown University Medical Center, Washington, DC 20057, USA

⁹

Department of Radiology, Georgetown University Medical Center, Washington, DC 20057, USA

¹⁰

Department of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(10), 5675; https://doi.org/10.3390/ijms23105675

Submission received: 1 April 2022 / Revised: 13 May 2022 / Accepted: 16 May 2022 / Published: 18 May 2022

(This article belongs to the Special Issue SGLT2 Inhibitors: Emerging "Magic Bullets" beyond Glycemic Control (Volume 2))

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Abstract

Sodium-glucose co-transporters (SGLTs) serve to reabsorb glucose in the kidney. Recently, these transporters, mainly SGLT2, have emerged as new therapeutic targets for patients with diabetes and kidney disease; by inhibiting glucose reabsorption, they promote glycosuria, weight loss, and improve glucose tolerance. They have also been linked to cardiac protection and mitigation of liver injury. However, to date, the mechanism(s) by which SGLT2 inhibition promotes systemic improvements is not fully appreciated. Using an obese TallyHo mouse model which recapitulates the human condition of diabetes and nonalcoholic fatty liver disease (NAFLD), we sought to determine how modulation of renal glucose handling impacts liver structure and function. Apart from an attenuation of hyperglycemia, Empagliflozin was found to decrease circulating triglycerides and lipid accumulation in the liver in male TallyHo mice. This correlated with lowered hepatic cholesterol esters. Using in vivo MRI analysis, we further determined that the reduction in hepatic steatosis in male TallyHo mice was associated with an increase in nuchal white fat indicative of “healthy adipose expansion”. Notably, this whitening of the adipose came at the expense of brown adipose tissue. Collectively, these data indicate that the modulation of renal glucose handling has systemic effects and may be useful as a treatment option for NAFLD and steatohepatitis.

Keywords: SGLT2 inhibitors; steatosis; white adipose; brown adipose; TallyHo mouse; NAFLD

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MDPI and ACS Style

Kurtz, R.; Libby, A.; Jones, B.A.; Myakala, K.; Wang, X.; Lee, Y.; Knoer, G.; Lo Cascio, J.N.; McCormack, M.; Nguyen, G.; et al. Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice. Int. J. Mol. Sci. 2022, 23, 5675. https://doi.org/10.3390/ijms23105675

AMA Style

Kurtz R, Libby A, Jones BA, Myakala K, Wang X, Lee Y, Knoer G, Lo Cascio JN, McCormack M, Nguyen G, et al. Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice. International Journal of Molecular Sciences. 2022; 23(10):5675. https://doi.org/10.3390/ijms23105675

Chicago/Turabian Style

Kurtz, Ryan, Andrew Libby, Bryce A. Jones, Komuraiah Myakala, Xiaoxin Wang, Yichien Lee, Grace Knoer, Julia N. Lo Cascio, Michaela McCormack, Grace Nguyen, and et al. 2022. "Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice" International Journal of Molecular Sciences 23, no. 10: 5675. https://doi.org/10.3390/ijms23105675

APA Style

Kurtz, R., Libby, A., Jones, B. A., Myakala, K., Wang, X., Lee, Y., Knoer, G., Lo Cascio, J. N., McCormack, M., Nguyen, G., Choos, E. N. D., Rodriguez, O., Rosenberg, A. Z., Ranjit, S., Albanese, C., Levi, M., Ecelbarger, C. M., & Shepard, B. D. (2022). Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice. International Journal of Molecular Sciences, 23(10), 5675. https://doi.org/10.3390/ijms23105675

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Empagliflozin Treatment Attenuates Hepatic Steatosis by Promoting White Adipose Expansion in Obese TallyHo Mice

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