Year: 2024
Type: article
Abstract: ABSTRACT Objective Spinophilin is an F-actin binding and protein phosphatase 1 (PP1) targeting protein that acts as a scaffold of PP1 to its substrates. Spinophilin knockout (Spino -/- ) mice have decreased fat mass, increased lean mass, and improved glucose tolerance, with no difference in feeding behaviors. While spinophilin is enriched in neurons, its roles in non-neuronal tissues, such as beta cells of the pancreatic islets, are unclear. Methods & Results We have corroborated and expanded upon previous studies to determine that Spino -/- mice have decreased weight gain and improved glucose tolerance in two different models of obesity. Using proteomics and immunoblotting-based approaches we identified multiple putative spinophilin interacting proteins isolated from intact pancreas and observed increased interactions of spinophilin with exocrine, ribosomal, and cytoskeletal protein classes that mediate peptide hormone production, processing, and/or release in Lepr db/db and/or high fat-fed (HFF) models of obesity. Moreover, loss of spinophilin specifically in pancreatic beta cells improved glucose tolerance without impacting body weight. Conclusion Our data further support a role for spinophilin in mediating pathophysiological changes in body weight and whole-body metabolism associated with obesity and provide the first evidence that spinophilin mediates obesity-dependent pancreatic dysfunction that leads to deficits in glucose homeostasis or diabesity.
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Indiana Clinical and Translational Sciences Institute, University of Michigan, Indiana University-Purdue University Indianapolis, National Institutes of Health, School of Medicine, Indiana University, National Institute on Drug Abuse, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, National Drug Abuse Treatment Clinical Trials Network
Awards: G3754633476, G3962577749, G4256132169, Spinophilin function in regulating pathological responses to psychostimulant drug, Transforming Growth Factor Beta-Activated Kinase 1 (Tak1) in Retinal Microglial Inflammation, Generation of cell-specific tools to determine the role of spinophilin in regulating pathological responses to psychostimulant drugs of abuse, G6276665855, Indiana Clinical and Translational Sciences Institute, Indiana Diabetes Research Center, Indiana University Melvin and Bren Simon Comprehensive Cancer Center Support Grant
OpenAlex ID: W4394873887