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Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.

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Sanghez, Valentina 
Cubuk, Cankut 
Sebastián-Leon, Patricia 
Carobbio, Stefania 
Dopazo, Joaquin 


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.



Adipose tissue, IRS1, IRS2, insulin, metabolic syndrome, obesity, Adipose Tissue, White, Animals, Diet, High-Fat, Dominance-Subordination, Down-Regulation, Glucose, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Obesity, Real-Time Polymerase Chain Reaction, Signal Transduction, Stress, Psychological

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Informa UK Limited
Medical Research Council (MC_G0802535)
Medical Research Council (G0802051)
Medical Research Council (MC_UU_12012/2)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/5)
Medical Research Council (MC_PC_12012)
Supported by UofMN Medical School start-up funds to AB, Medical Research Council MRC Disease Model Core and British Heart Foundation program grants to AVP, and BIO2011-27069 from the Spanish Ministry of Economy and Competitiveness and PROMETEOII/2014/025 from the GVA-FEDER to JD. VS was supported by a graduate student fellowship of the University of Parma. CC was supported by EU FP7-People Project(ref 316861) "MLPM2012: Machine Learning For Personalized Medicine".