Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
PERK in POMC neurons connects celastrol with metabolism
Zhenyan He, … , Ling Hu, Kevin W. Williams
Zhenyan He, … , Ling Hu, Kevin W. Williams
Published September 22, 2021
Citation Information: JCI Insight. 2021;6(18):e145306. https://doi.org/10.1172/jci.insight.145306.
View: Text | PDF
Research Article Endocrinology Neuroscience

PERK in POMC neurons connects celastrol with metabolism

  • Text
  • PDF
Abstract

ER stress and activation of the unfolded protein response in the periphery as well as the central nervous system have been linked to various metabolic abnormalities. Chemically lowering protein kinase R–like ER kinase (PERK) activity within the hypothalamus leads to decreased food intake and body weight. However, the cell populations required in this response remain undefined. In the current study, we investigated the effects of proopiomelanocortin-specific (POMC-specific) PERK deficiency on energy balance and glucose metabolism. Male mice deficient for PERK in POMC neurons exhibited improvements in energy balance on a high-fat diet, showing decreased food intake and body weight, independent of changes in glucose and insulin tolerances. The plant-based inhibitor of PERK, celastrol, increases leptin sensitivity, resulting in decreased food intake and body weight in a murine model of diet-induced obesity (DIO). Our data extend these observations by demonstrating that celastrol-induced improvements in leptin sensitivity and energy balance were attenuated in mice with PERK deficiency in POMC neurons. Altogether, these data suggest that POMC-specific PERK deficiency in male mice confers protection against DIO, possibly providing a new therapeutic target for the treatment of diabetes and metabolic syndrome.

Authors

Zhenyan He, Linh Lieu, Yanbin Dong, Sadia Afrin, Dominic Chau, Anita Kabahizi, Briana Wallace, Jianhong Cao, Eun-Sang Hwang, Ting Yao, Yiru Huang, Jennifer Okolo, Bo Cheng, Yong Gao, Ling Hu, Kevin W. Williams

×

Figure 1

Body weight and metabolic assessment of male POMC-cre:PERKloxp/loxp mice.

Options: View larger image (or click on image) Download as PowerPoint
Body weight and metabolic assessment of male POMC-cre:PERKloxp/loxp mice...
(A and B) Body weight curve of male POMC-cre:PERKloxp/loxp and littermate control mice on a chow diet (A) or a 58% HFD (B). Statistical analyses were performed using 2-way repeated-measures ANOVA, with Bonferroni post hoc analyses applied. (C and D) Fat mass (C) and lean mass (D) of male POMC-cre:PERKloxp/loxp and littermate control mice on a 58% HFD at 20 weeks (A, n = 8–17 per group; B–D, n = 14–17 per group). (E) Male mice with PERK deficiency of POMC neurons displayed decreased food intake in both the 24-hour period and the dark cycle, while the food intake in the light cycle was unaffected. (F–J) Male POMC-cre:PERKloxp/loxp mice displayed decreased ambulatory activity in both light and dark cycles (F), while VO2 (G), VCO2 (H), respiratory exchange ratio (RER) (I), and heat production (J) remained unchanged in both the dark and light cycles. Black bars indicate littermate control mice. Red bars indicate POMC-cre:PERKloxp/loxp mice. (E–J) Data are from male mice (n = 5–7 per group) and are expressed as mean ± SEM. Unpaired t test, *P < 0.05, **P < 0.01.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts