Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons

Qun Wei, Yi Feng Gu, Qing Jun Zhang, Helena Yu, Yan Peng, Kevin W. Williams, Ruitao Wang, Kajiang Yu, Tiemin Liu, Zhi Ping Liu

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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 Lztfl1 f/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.

Original languageEnglish (US)
Pages (from-to)402-410
Number of pages9
JournalJournal of molecular cell biology
Volume10
Issue number5
DOIs
StatePublished - Oct 1 2018

Keywords

  • Actin/cytoskeleton
  • BBS
  • Cilia
  • Leptin-resistance
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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