Leptin signaling and the intervertebral disc: Sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model

• Type of Material: Article
• Authors: Devorah M. Natelson, Icahn School of Medicine at Mount Sinai; Alon Lai, Icahn School of Medicine at Mount Sinai; Divya Krishnamoorthy, Icahn School of Medicine at Mount Sinai; Robert C. Hoy, Icahn School of Medicine at Mount Sinai; James C. Iatridis, Icahn School of Medicine at Mount Sinai; Svenja Illien-Junger, Emory University
• Language: English
• Date: 2020-05-06
• Publisher: Public Library Science
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Natelson et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0227527
• Title of Journal or Parent Work: PLoS ONE
• Volume: 15
• Issue: 5
• Start Page: e0227527
• End Page: e0227527
• Grant/Funding Information: This study was Funded by NIH/NIAMS R01 AR069315 (JCI).
• Keywords: Obesity; Fat; Degeneration; Fracture risk; Cells; Multidisciplinary Sciences; Bone mineral density; Low-back pain; Health; Science & Technology; Science & Technology - Other Topics; Overweight; Lumbar spine
• Research Categories: Health Sciences, Public Health; Biology, Cell; Health Sciences, Nutrition

Abstract

Type 2 diabetes and obesity are associated with back pain in juveniles and adults and are implicated in intervertebral disc (IVD) degeneration. Hypercaloric Western diets are associated with both obesity and type 2 diabetes. The objective of this study was to determine if obesity and type 2 diabetes result in spinal pathology in a sex-specific manner using in vivo diabetic and dietary mouse models. Leptin is an appetite-regulating hormone, and its deficiency leads to polyphagia, resulting in obesity and diabetes. Leptin is also associated with IVD degeneration, and increased expression of its receptor was identified in degenerated IVDs. We used young, leptin receptor deficient (Db/Db) mice to mimic the effect of diet and diabetes on adolescents. Db/Db and Control mice were fed either Western or Control diets, and were sacrificed at 3 months of age. Db/Db mice were obese, while only female mice developed diabetes. Female Db/Db mice displayed altered IVD morphology, with increased intradiscal notochordal band area, suggesting delayed IVD cell proliferation and differentiation, rather than IVD degeneration. Motion segments from Db/Db mice exhibited increased failure risk with decreased torsional failure strength. Db/Db mice also had inferior bone quality, which was most prominent in females. We conclude that obesity and diabetes due to impaired leptin signaling contribute to pathological changes in vertebrae, as well as an immature IVD phenotype, particularly of females, suggesting a sex-dependent role of leptin in the spine.