ABSTRACT
Several psychiatric disorders increase the risk of cardiovascular disease, including posttraumatic stress disorder and major depression. While the precise mechanism for this association has not yet been established, it has been shown that certain disorders promote an unfavorable lipid profile. To study the interaction of stress and lipid dysregulation, we utilized chronic social defeat stress (CSDS), a mouse model of chronic stress with features of posttraumatic stress disorder and major depression. Following exposure to CSDS, mice were given access to either regular chow or a Western-style diet high in fat and cholesterol (HFD). The combination of social stress and HFD resulted in significant perturbations in lipid regulation, including two key features of the metabolic syndrome: increased plasma levels of non-HDL cholesterol and intrahepatic accumulation of triglycerides. These effects were accompanied by a number of changes in the expression of hepatic genes involved in lipid regulation. Transcriptional activity of LXR, SREBP1c, and ChREBP were significantly affected by exposure to HFD and CSDS. We present CSDS as a model of social stress induced lipid dysregulation and propose that social stress alters lipid metabolism by increasing transcriptional activity of genes involved in lipid synthesis.
Subject(s)
Lipids/biosynthesis , Stress, Physiological , Animals , Cholesterol/biosynthesis , Cholesterol/blood , Cholesterol/metabolism , Chronic Disease , Depression/metabolism , Depression/physiopathology , Dietary Fats , Disease Models, Animal , Fatty Acids, Nonesterified/metabolism , Insulin Resistance , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Stress Disorders, Post-Traumatic/metabolism , Stress Disorders, Post-Traumatic/physiopathology , Time Factors , Triglycerides/metabolismABSTRACT
BACKGROUND: Calorie restriction (CR) induces long-term changes in motivation to eat highly palatable food and, in body weight regulation, through an unknown mechanism. METHODS: After a period of CR and refeeding, mice were assessed by behavioral and metabolic studies and for levels of the transcription factor ΔFosB. The ΔFosB levels were then increased specifically in nucleus accumbens (NAc) with viral-mediated gene transfer, and behavioral and metabolic studies were conducted. RESULTS: We show that accumulation of ΔFosB in the NAc shell after CR in mice corresponds to a period of increased motivation for high fat reward and reduced energy expenditure. Furthermore, ΔFosB overexpression in this region increases instrumental responding for a high fat reward via an orexin-dependent mechanism while also decreasing energy expenditure and promoting adiposity. CONCLUSIONS: These results suggest that ΔFosB signaling in NAc mediates adaptive responses to CR.
Subject(s)
Caloric Restriction , Gene Expression Regulation/physiology , Nucleus Accumbens/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Analysis of Variance , Animals , Body Weight/physiology , Carbon Dioxide/metabolism , Conditioning, Operant/physiology , Eating/genetics , Luminescent Proteins/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motivation/genetics , Motor Activity/genetics , Neurons/physiology , Nucleus Accumbens/cytology , Oxygen Consumption/geneticsABSTRACT
BACKGROUND: Obesity has been associated with an increased risk of developing several psychiatric illnesses, including major depression and posttraumatic stress disorder. Likewise, these stress-related disturbances are associated with a higher rate of obesity; yet, the neurobiological mechanisms linking obesity and stress remain incompletely understood. METHODS: Following exposure to chronic social defeat stress (CSDS), mice were given free access to either regular chow or a Western-style diet high in triglycerides and cholesterol. Comprehensive metabolic and behavioral testing was then conducted. RESULTS: Mice subjected to CSDS and then fed a high-fat diet for 30 days display severe behavioral deficits accompanied by redistribution of body fat. Stressed mice have decreased adipose tissue as well as decreased serum leptin levels compared with control mice. Pharmacological inhibition of beta(3)-adrenergic signaling during CSDS normalizes these metabolic abnormalities but worsens behavioral symptoms. Furthermore, mice subjected to CSDS display central leptin resistance including reduced expression of pro-opiomelanocortin in hypothalamus. Administration of a central melanocortin agonist worsens stress-induced behavioral deficits, while mice lacking the melanocortin-4 receptor display attenuated symptoms. CONCLUSIONS: These results indicate that chronic signaling through beta(3)-adrenergic receptors during social stress is an adaptive response that improves behavioral function. However, these responses come at the expense of central leptin resistance and melanocortin signaling alterations that contribute to significant and long-lasting metabolic abnormalities.