title: LMO4 is required to maintain hypothalamic insulin signaling.
abstract: Insulin action at the hypothalamus controls glucose homeostasis by suppressing hepatic glucose production and promoting glucose uptake by muscle. However, the mechanisms that control central insulin signaling have not been fully elucidated. Previously, we showed that LMO4 is highly expressed in hypothalamic nuclei that regulate glucose homeostasis. Here, we determined how loss of LMO4 in the hypothalamus would affect central insulin signaling and glucose homeostasis. In transgenic mice that have LMO4 in ablated in glutamatergic neurons, we found that insulin signaling is impaired in the hypothalamus as well as in peripheral tissues (liver and skeletal muscle). Impaired glucose homeostasis was associated with a markedly elevation in hypothalamic protein tyrosine phosphatase 1B (PTP1B) activity. PTP1B is a key phosphatase that terminates insulin signaling by dephosphorylating its receptor and downstream signaling molecules. Importantly, we found that administration of a selective PTP1B inhibitor Trodusquemine to the hypothalamus restored central insulin signaling and improved the response of peripheral tissues to insulin in these LMO4-deficient mice. Thus, our study reveals an essential requirement for LMO4 to modulate central insulin signaling.
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Pandey
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Tariq
authors.initials: T
authors.lastname: Zaman
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Shelly A
authors.initials: SA
authors.lastname: Cruz
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Ottawa Hospital Research Institute, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Lu
authors.affiliation: University of Ottawa, Canada.
authors.forename: Kianoosh
authors.initials: K
authors.lastname: Keyhanian
authors.affiliation: Aix-Marseille Université, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.affiliation: University of Ottawa, Canada; University of Ottawa Heart Institute, Canada. Electronic address: AStewart@ottawaheart.ca.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Ottawa Hospital Research Institute, Canada; University of Ottawa, Canada. Electronic address: hchen@uottawa.ca.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D060588:LIM Domain Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007328:Insulin; D060588:LIM Domain Proteins; C491976:Lmo4 protein, mouse; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose
keywords: Hypothalamus; Insulin resistance; LMO4; Protein tyrosine phosphatase 1B; Trodusquemine