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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5675
JournalInternational journal of molecular sciences
Volume23
Issue number10
DOIs
StatePublished - May 1 2022

Keywords

  • NAFLD
  • SGLT2 inhibitors
  • TallyHo mouse
  • brown adipose
  • steatosis
  • white adipose

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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