SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity

Gung Lee; Ye Young Kim; Hagoon Jang; Ji Seul Han; Hahn Nahmgoong; Yoon Jeong Park; Sang Mun Han; Changyun Cho; Sangsoo Lim; Jung-Ran Noh; Won Keun Oh; Chul-Ho Lee; Sun Kim; Jae Bum Kim

doi:10.1016/j.cmet.2022.03.010

SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity

Cell Metab. 2022 May 3;34(5):702-718.e5. doi: 10.1016/j.cmet.2022.03.010. Epub 2022 Apr 12.

Authors

Gung Lee¹, Ye Young Kim¹, Hagoon Jang¹, Ji Seul Han¹, Hahn Nahmgoong¹, Yoon Jeong Park¹, Sang Mun Han¹, Changyun Cho², Sangsoo Lim³, Jung-Ran Noh⁴, Won Keun Oh⁵, Chul-Ho Lee⁴, Sun Kim⁶, Jae Bum Kim⁷

Affiliations

¹ Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
² Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea.
³ Bioinformatics Institute, Seoul National University, Seoul 08826, South Korea.
⁴ Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Yuseong-gu, Daejeon 34141, South Korea.
⁵ Korea Bioactive Natural Material Bank, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
⁶ Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 08826, South Korea; Bioinformatics Institute, Seoul National University, Seoul 08826, South Korea; Department of Computer Science and Engineering, Institute of Engineering Research, Seoul National University, Seoul 08826, South Korea.
⁷ Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea. Electronic address: jaebkim@snu.ac.kr.

PMID: 35417665
DOI: 10.1016/j.cmet.2022.03.010

Abstract

Emerging evidence indicates that the accretion of senescent cells is linked to metabolic disorders. However, the underlying mechanisms and metabolic consequences of cellular senescence in obesity remain obscure. In this study, we found that obese adipocytes are senescence-susceptible cells accompanied with genome instability. Additionally, we discovered that SREBP1c may play a key role in genome stability and senescence in adipocytes by modulating DNA-damage responses. Unexpectedly, SREBP1c interacted with PARP1 and potentiated PARP1 activity during DNA repair, independent of its canonical lipogenic function. The genetic depletion of SREBP1c accelerated adipocyte senescence, leading to immune cell recruitment into obese adipose tissue. These deleterious effects provoked unhealthy adipose tissue remodeling and insulin resistance in obesity. In contrast, the elimination of senescent adipocytes alleviated adipose tissue inflammation and improved insulin resistance. These findings revealed distinctive roles of SREBP1c-PARP1 axis in the regulation of adipocyte senescence and will help decipher the metabolic significance of senescence in obesity.

Keywords: DNA repair process; PARP1; SASP; SREBP1c; adipocyte; adipose tissue inflammation; cellular senescence; energy homeostasis; insulin resistance; obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism
Adipose Tissue / metabolism
Humans
Insulin Resistance* / physiology
Obesity / metabolism
Poly (ADP-Ribose) Polymerase-1 / genetics
Poly (ADP-Ribose) Polymerase-1 / metabolism
Sterol Regulatory Element Binding Protein 1 / genetics
Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

Sterol Regulatory Element Binding Protein 1
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1