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Clusterin/ApoJ enhances central leptin signaling through Lrp2‐mediated endocytosis

Kyunghee Byun, So Young Gil, Churl Namkoong, Byung‐Soo Youn, Hu Huang, Mi‐Seon Shin, Gil Myoung Kang, Hyun‐Kyong Kim, Bonghee Lee, Young‐Bum Kim, Min‐Seon Kim

Author Affiliations

  1. Kyunghee Byun1,,
  2. So Young Gil2,,
  3. Churl Namkoong2,,
  4. Byung‐Soo Youn3,
  5. Hu Huang4,
  6. Mi‐Seon Shin5,
  7. Gil Myoung Kang2,
  8. Hyun‐Kyong Kim2,
  9. Bonghee Lee1,
  10. Young‐Bum Kim4 and
  11. Min‐Seon Kim*,2,5
  1. 1Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea
  2. 2Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
  3. 3Department of Anatomy, Wonkwang University School of Medicine, Iksan, Korea
  4. 4Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
  5. 5Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  1. *Corresponding author. Tel: +82 2 3010 3245; Fax: +82 2 3010 6962; E‐mail: mskim{at}amc.seoul.kr
  1. These authors contributed equally to this work.

Abstract

Hypothalamic leptin signaling plays a central role in maintaining body weight homeostasis. Here, we show that clusterin/ApoJ, recently identified as an anorexigenic neuropeptide, is an important regulator in the hypothalamic leptin signaling pathway. Coadministration of clusterin potentiates the anorexigenic effect of leptin and boosts leptin‐induced hypothalamic Stat3 activation. In cultured neurons, clusterin enhances receptor binding and subsequent endocytosis of leptin. These effects are mainly mediated through the LDL receptor‐related protein‐2 (Lrp2). Notably, inhibition of hypothalamic clusterin, Lrp2 or endocytosis abrogates anorexia and hypothalamic Stat3 activation caused by leptin. These findings propose a novel regulatory mechanism in central leptin signaling pathways.

Synopsis

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The current study demonstrates that clusterin/ApoJ regulates hypothalamic leptin signaling by inducing Lrp2‐dependent leptin internalization, thereby potentiating leptin‐induced Stat3 activation. These findings propose a novel, clusterin‐ and Lrp2‐dependent regulatory mechanism of leptin‐mediated feeding regulation.

  • Clusterin promotes leptin receptor binding and endocytosis via Lrp2‐dependent mechanisms, which are critical for leptin‐induced hypothalamic Stat3 activation.

  • Hypothalamic clusterin/ApoJ potentiates central leptin signaling and metabolic actions.

  • Received December 8, 2013.
  • Revision received April 14, 2014.
  • Accepted April 15, 2014.

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