title: Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.
abstract: Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.
authors.affiliation: a Department of Integrative Biology and Physiology , University of Minnesota , Minneapolis , MN , USA .|b Department of Neuroscience , University of Parma , Parma , Italy .
authors.forename: Valentina
authors.initials: V
authors.lastname: Sanghez
authors.affiliation: c Department of Computational Genomics , Centro de Investigación Principe Felipe , Valencia , Spain .
authors.forename: Cankut
authors.initials: C
authors.lastname: Cubuk
authors.affiliation: c Department of Computational Genomics , Centro de Investigación Principe Felipe , Valencia , Spain .
authors.forename: Patricia
authors.initials: P
authors.lastname: Sebastián-Leon
authors.affiliation: d Wellcome Trust MRC Metabolic Disease Unit, Institute Metabolic Science, Addenbrooke's Hospital, University of Cambridge , Cambridge , UK , and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Carobbio
authors.affiliation: c Department of Computational Genomics , Centro de Investigación Principe Felipe , Valencia , Spain .
authors.forename: Joaquin
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: d Wellcome Trust MRC Metabolic Disease Unit, Institute Metabolic Science, Addenbrooke's Hospital, University of Cambridge , Cambridge , UK , and.|e Wellcome Trust Sanger Institute , Hinxton , UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: a Department of Integrative Biology and Physiology , University of Minnesota , Minneapolis , MN , USA .
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolomucci
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004291:Dominance-Subordination; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D007328:Insulin; D005947:Glucose
keywords: Adipose tissue; IRS1; IRS2; insulin; metabolic syndrome; obesity