Jisoo Park1, Yuwen Li2, Seon-Hwan Kim3, Keum-Jin Yang4, Gyeyeong Kong5, Robin Shrestha5, Quangdon Tran5, Kyeong Ah Park5, Juhee Jeon5, Gang Min Hur5, Chul-Ho Lee4, Dong-Hoon Kim6, Jongsun Park7. 1. Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45437, USA; Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea. 2. Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Shaanxi, 710032, China. 3. Department of Neurosurgery, College of Medicine, Chungnam National University, Daejeon 301-747, South Korea. 4. Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, South Korea. 5. Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea. 6. Department of Pharmacology, Korea University College of Medicine, Seoul 136-701, South Korea. Electronic address: LDHKIM@korea.ac.kr. 7. Metabolic Disease Institute, University of Cincinnati, Cincinnati, OH 45437, USA; Department of Pharmacology, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-131, South Korea. Electronic address: insulin@cnu.ac.kr.
Abstract
OBJECTIVE: Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity. MATERIALS/ METHODS: To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabetic mice and genetically modified obese mice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection. RESULTS: We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obese mice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1. CONCLUSION: These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obese mice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.
OBJECTIVE:Obesity contributes to insulin resistance and is a risk factor for diabetes. C-terminal modulator protein (CTMP) and leucine zipper/EF-hand-containing transmembrane protein 1 (LETM1) have been reported to influence the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB) signaling pathway via the modulation of PKB activity, a key player for insulin signaling. However, it remains unclear whether CTMP and LETM1 are associated with PI3K/PKB signaling in mouse models of obesity. MATERIALS/ METHODS: To address this question, we used two different mouse models of obesity, including high-fat diet (HFD)-induced diabeticmice and genetically modified obesemice (ob/ob mice). The levels of insulin-signaling molecules in these mice were determined by immunohistochemical and Western blot analyses. The involvement of CTMP and LETM1 in PI3K/PKB signaling was investigated in HEK293 cells by transient transfection and adenovirus-mediated infection. RESULTS: We found that the levels of insulin receptor, phosphorylated PKB, and LETM1 were lower and the level of CTMP was higher in the adipose tissue of obesemice on an HFD compared to lean mice on a chow diet. Similar results were obtained in ob/ob mice. In HEK293 cells, the activation of PKB increased the LETM1 level, and inhibition of PKB increased the CTMP level. The overexpression of CTMP suppressed the insulin-induced increase in PKB phosphorylation, which was abrogated by co-overexpression with LETM1. CONCLUSION: These results suggest that CTMP and LETM1 may participate in impaired insulin signaling in the adipose tissue of obesemice, raising the possibility that these parameters may serve as new candidate biomarkers or targets in the development of new therapeutic approaches for diabetes.
Authors: Rauan Kaiyrzhanov; Sami E M Mohammed; Reza Maroofian; Ralf A Husain; Alessia Catania; Alessandra Torraco; Ahmad Alahmad; Marina Dutra-Clarke; Sabine Grønborg; Annapurna Sudarsanam; Julie Vogt; Filippo Arrigoni; Julia Baptista; Shahzad Haider; René G Feichtinger; Paolo Bernardi; Alessandra Zulian; Mirjana Gusic; Stephanie Efthymiou; Renkui Bai; Farah Bibi; Alejandro Horga; Julian A Martinez-Agosto; Amanda Lam; Andreea Manole; Diego-Perez Rodriguez; Romina Durigon; Angela Pyle; Buthaina Albash; Carlo Dionisi-Vici; David Murphy; Diego Martinelli; Enrico Bugiardini; Katrina Allis; Costanza Lamperti; Siegfried Reipert; Lotte Risom; Lucia Laugwitz; Michela Di Nottia; Robert McFarland; Laura Vilarinho; Michael Hanna; Holger Prokisch; Johannes A Mayr; Enrico Silvio Bertini; Daniele Ghezzi; Elsebet Østergaard; Saskia B Wortmann; Rosalba Carrozzo; Tobias B Haack; Robert W Taylor; Antonella Spinazzola; Karin Nowikovsky; Henry Houlden Journal: Am J Hum Genet Date: 2022-09-01 Impact factor: 11.043