Clusterin/ApoJ enhances central leptin signaling through Lrp2-mediated endocytosis.
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.
Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
Kyunghee
K
Byun
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
So Young
SY
Gil
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Churl
C
Namkoong
Department of Anatomy, Wonkwang University School of Medicine, Iksan, Korea.
Byung-Soo
BS
Youn
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Hu
H
Huang
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Mi-Seon
MS
Shin
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Gil Myoung
GM
Kang
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
Hyun-Kyong
HK
Kim
Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
Bonghee
B
Lee
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Young-Bum
YB
Kim
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea mskim@amc.seoul.kr.
Min-Seon
MS
Kim
D000818:Animals; D051152:Clusterin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction
D051152:Clusterin; D020738:Leptin; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D054411:Receptors, Leptin
Lrp2; Stat3; clusterin; endocytosis; leptin