02634nas a2200289   4500008004100000022001400041245015800055210006900213260001500282300000900297520167800306653001901984653001202003653000902015653000902024653002302033653001202056653002102068100002302089700001802112700003002130700002302160700002002183700002402203700002902227856008802256       2016                        eng d  a1607-888800aChronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.0 aChronic subordination stress selectively downregulates the insul  c2016 Mar 7  a1-113 aChronic 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.10aAdipose tissue10ainsulin10aIRS110aIRS210ametabolic syndrome10aobesity10apathway analysis1 aSanghez, Valentina1 aCubuk, Cankut1 aSebastián-Leon, Patricia1 aCarobbio, Stefania1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aBartolomucci, Alessandro  uhttp://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists20