Oxidative Stress and Neuroinflammation in a Rat Model of Co-Morbid Obesity and Psychogenic Stress

Abstract

Contributions: JMS, wrote manuscript, performed Western blot experiments and analyses; JDV, design and performed behavioral experiments, wrote manuscript; YAT, performed Western blot experiments; POA, performed and analyzed ELISA experiments, prepared illustrations, wrote manuscript; JBL, analyzed behavioral data; AYCG and EAB, performed Western blots; DZO and CAC, peformed Western blot analyses; JDF, planned experiments, analyzed data, wrote manuscript. AbstractBackground: There is growing recognition for a reciprocal, bidirectional link between anxiety disorders and obesity. Although the mechanisms linking obesity and anxiety remain speculative, this bidirectionality suggests shared pathophysiological processes. Neuroinflammation and oxidative damage are implicated in both pathological anxiety and obesity. This study investigates the relative contribution of comorbid dietinduced obesity and stress-induced anxiety to neuroinflammation and oxidative stress.Methods: Thirty-six (36) male Lewis rats were divided into four groups based on diet type and stress exposure: 1) control diet unexposed (CDU) and 2) exposed (CDE), 3)Western-like high-saturated fat diet unexposed (WDU) and 4) exposed (WDE).Neurobehavioral tests were performed to assess anxiety-like behaviors. The catalytic concentrations of glutathione peroxidase and reductase were measured from plasma samples, and neuroinflammatory/oxidative stress biomarkers were measured from brain samples using Western blot. Correlations between behavioral phenotypes and biomarkers were assessed with Pearson's correlation procedures. Results:We found that WDE rats exhibited markedly increased levels of glial fibrillary acidic protein (185%), catalase protein (215%), and glutathione reductase (GSR) enzymatic activity (418%) relative to CDU rats. Interestingly, the brain protein levels of glutathione peroxidase (GPx) and catalase were positively associated with body weight and behavioral indices of anxiety. Conclusions:Together, our results support a role for neuroinflammation and oxidative stress in heightened emotional reactivity to obesogenic environments and psychogenic stress. Uncovering adaptive responses to obesogenic environments characterized by 3 high access to high-saturated fat/high-sugar diets and toxic stress has the potential to strongly impact how we treat psychiatric disorders in at-risk populations. Highlights:• Predatory odor stress heightens footshock reactivity and anxiety-like behaviors in Lewis rats.• WD intake increases glutathione reductase activity in plasma.• WD intake and PS exposure acted synergistically to increase the brain protein levels of catalase and the glial fibrillary acidic protein.• The protein levels and activities of some redox/neuroinflammatory biomarkers are closely associated with behavioral proxies related to fear and anxiety in rats. astrocytes use glycolysis for energy production and, as a consequence, have been associated with a higher generation of mitochondrial reactive oxygen species (ROS) [26].It is known that ROS accumula...

Short-term exposure to an obesogenic diet during adolescence elicits anxiety-related behavior and neuroinflammation: modulatory effects of exogenous neuregulin-1

“…Recent work from our lab has focused on identifying early (mal)adaptive responses to obesogenic environments [ 18 , 44 , 48 , 49 , 61 ]. Having demonstrated that exposure to an obesogenic diet during adolescence alters the neural and behavioral substrates implicated with emotional regulation, we asked whether these impairments can be attenuated by administering neuregulin-1 (NRG1), a neurotrophic factor with potent neuroprotective and anti-inflammatory properties [ 38 , 41 , 45 , 62 ].…”

“…However, a fundamental goal of our investigations is to understand precisely how previous experiences alter behavior. Specifically, we are interested in understanding how adolescent dietary obesity influences stress reactivity [ 18 , 44 , 48 , 49 ]. Thus, in our battery, we have used foot shocks not only to promote fear conditioning but also as a stressor [ 44 , 48 , 49 ], as has been reported by others [ 50 – 52 ].…”

“…Specifically, we are interested in understanding how adolescent dietary obesity influences stress reactivity [ 18 , 44 , 48 , 49 ]. Thus, in our battery, we have used foot shocks not only to promote fear conditioning but also as a stressor [ 44 , 48 , 49 ], as has been reported by others [ 50 – 52 ]. In our hands, this sensitive and comprehensive test battery (and testing order) is a powerful tool to unmask the impact of an obesogenic diet on fear and anxiety-like responses.…”

Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities

“…Recent work from our lab has focused on identifying early (mal)adaptive responses to obesogenic environments (Kalyan-Masih et al, 2016; Vega-Torres et al, 2018, 2019a, 2020b; Santana et al, 2021). Having demonstrated that exposure to an obesogenic diet during adolescence alters the neural and behavioral substrates implicated with emotional regulation, we asked whether these impairments can be attenuated by administering neuregulin-1 (NRG1), a neurotrophic factor with potent neuroprotective and anti-inflammatory properties (Li et al, 2012; Depboylu et al, 2015; Guan et al, 2015; Simmons et al, 2016).…”

“…Obesity and the dietary intake of saturated fats and simple sugars have emerged as risk factors for the development of anxiety and stress-related disorders (Scott et al, 2008; Perkonigg et al, 2009; Johannessen and Berntsen, 2013; Maguen et al, 2013; Mitchell et al, 2013; Kubzansky et al, 2014; Bartoli et al, 2015; Smith et al, 2015). Consistent with studies in humans, we reported that diet-induced obesity (DIO) in rats: 1) reduces hippocampal volume (Kalyan-Masih et al, 2016), 2) impairs the maturation of the corticolimbic fear circuits (Vega-Torres et al, 2018), 3) enhances behavioral vulnerabilities to psychosocial stress (Kalyan-Masih et al, 2016; Vega-Torres et al, 2018, 2019b), 4) results in profound fear learning and extinction learning deficits (Vega-Torres et al, 2018, 2019b), even in the absence of an obesogenic phenotype (Vega-Torres et al, 2020a), and 5) leads to alterations in biomarkers implicated in inflammatory responses (Santana et al, 2021).…”