2. Academic Validation
  3. Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression

Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression

  • J Nutr Biochem. 2023 Oct 29:109512. doi: 10.1016/j.jnutbio.2023.109512.
Shujing Liu 1,  Shiyu Song 1,  Shuan Wang 1,  Tong-Hui Cai 2,  Lian Qin 1,  Xinzhuang Wang 1,  Guangming Zhu 1,  Haibo Wang 1,  Wenqi Yang 1,  Chunlu Fang 1,  Yuan Wei 1,  Fu Zhou 1,  Yang Yu 3,  Shaozhang Lin 4,  Shuang Peng 5,  Liangming Li 6
Affiliations

Affiliations

  • 1 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China.
  • 2 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, P.R. China.
  • 3 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China.
  • 4 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, P.R. China. Electronic address: [email protected].
  • 5 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China. Electronic address: [email protected].
  • 6 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou 510500, P.R. China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou 510500, China. Electronic address: [email protected].
PMID: 37907171 DOI: 10.1016/j.jnutbio.2023.109512
Abstract

Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic Leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of Leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and Leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in Leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in Leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in Leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating Leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic Leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic Leptin resistance and obesity.

Keywords

CX3CL1; FTO; HFD; Hypothalamus; leptin resistance.

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