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Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons Free
Qun Wei 1,2,† , Yi-Feng Gu 2,† , Qing-Jun Zhang 2 , Helena Yu 2 , Yan Peng 3 , Kevin W. Williams 2 , Ruitao Wang 4 , Kajiang Yu 4 , Tiemin Liu 5,* , and Zhi-Ping Liu 2,6,*
1 Department of Surgical Oncology and Institute of Clinical Medicine, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou 310016,
China
2 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75235, USA
3 Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA
4 Department of Intensive Care Unit, The Third Affiliated Hospital, Harbin Medical University, Harbin 150081, China
5 Sate Key Laboratory of Genetic Engineering, School of Life Sciences, Department of Endocrinology and Metabolism, Zhongshan Hospital, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200438, China
6 Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75235, USA
These authors contributed equally to this work.
*Correspondence to:Tiemin Liu, E-mail: Tiemin_Liu@fudan.edu.cn; Zhi-Ping Liu, E-mail: Zhi-Ping.Liu@UTSouthwestern.edu
J Mol Cell Biol, Volume 10, Issue 5, October 2018, Pages 402-410  https://doi.org/10.1093/jmcb/mjy022
Keyword: obesity, BBS, leptin-resistance, cilia, actin/cytoskeleton

Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet–Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1−/− mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1−/− mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1−/− mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1−/− mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.