Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model
Stephania Guzman, … , Andy V. Babwah, Moshmi Bhattacharya
Stephania Guzman, … , Andy V. Babwah, Moshmi Bhattacharya
Published March 29, 2022
Citation Information: J Clin Invest. 2022;132(10):e145889. https://doi.org/10.1172/JCI145889.
View: Text | PDF
Research Article Hepatology Metabolism Article has an altmetric score of 133

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

  • Text
  • PDF
Abstract

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

Authors

Stephania Guzman, Magdalena Dragan, Hyokjoon Kwon, Vanessa de Oliveira, Shivani Rao, Vrushank Bhatt, Katarzyna M. Kalemba, Ankit Shah, Vinod K. Rustgi, He Wang, Paul R. Bech, Ali Abbara, Chioma Izzi-Engbeaya, Pinelopi Manousou, Jessie Y. Guo, Grace L. Guo, Sally Radovick, Waljit S. Dhillo, Fredric E. Wondisford, Andy V. Babwah, Moshmi Bhattacharya

×

Figure 10

Kisspeptin inhibits triglyceride accumulation in isolated primary mouse hepatocytes.

Options: View larger image (or click on image) Download as PowerPoint
Kisspeptin inhibits triglyceride accumulation in isolated primary mouse ...
(A) Representative confocal image of endogenous KISS1 immunostaining in control (CTRL) hepatocytes. Scale bars: 50 μm. (B and C) Effect of KP10 (100 nM) or KPA (3 nM) on triglyceride (TG) accumulation (expressed as fold change over vehicle) in (B) CTRL and (C) hepatic Kiss1r-knockout (LKO) hepatocytes treated with oleic and palmitic acid (150 μM each). (D) Expression of indicated genes by RT-qPCR. (E) Representative Western blots of indicated proteins in hepatocytes following KP10 (100 nM) or KPA (3 nM) treatment. Quantification of blots is shown in Supplemental Figure 13, A and B. (F and G) Representative Western blots of indicated proteins in hepatocytes in the presence or absence of (F) compound C (CC; 10 μM) treatment, with quantification of blots, as well as in the presence or absence of (G) YM-25489 (YM; 3 μM), with quantification of blots. *P < 0.05 versus controls; 1-way ANOVA followed by Dunnett’s post hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 17 news outlets
Posted by 29 X users
Referenced in 1 patents
On 1 Facebook pages
40 readers on Mendeley
See more details