title: Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/β-catenin signaling in the hypothalamus.
abstract: BACKGROUND
  Insulin plays diverse roles in the brain. Although insulin produced by pancreatic β-cells that crosses the blood-brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known.
  
  
  RESULTS
  Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/β-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/β-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro.
  
  
  CONCLUSIONS
  Taken together, these results suggest that BDI production is regulated by the Wnt/β-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus.
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. jmlee@dgist.ac.kr.
authors.forename: Jaemeun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. kgc817@dgist.ac.kr.
authors.forename: Kyungchan
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. yusw@dgist.ac.kr.
authors.forename: Seong-Woon
authors.initials: SW
authors.lastname: Yu
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. ekkim@dgist.ac.kr.|Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. ekkim@dgist.ac.kr.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Kim
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000494:pharmacology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D060509:Wnt3A Protein; C561967:Ins2 protein, mouse; C093564:Neurogenic differentiation factor 1