Physical exercise ameliorates mood disorder-like behavior on high fat diet-induced obesity in mice

Highlights

• Obesity increased mood disorder-like behavior such as depression and anxiety.

• Obesity decreased expression of 5-HT, TPH, 5-HT_1A and 5-HTT in dorsal raphe.

• Physical exercise ameliorated obesity-induced mood disorder symptoms.

• Physical exercise enhanced expression of 5-HT, TPH, 5-HT_1A and 5-HTT in dorsal raphe.

Abstract

Obesity is associated with mood disorders such as depression and anxiety. The aim of this study was to investigate whether treadmill exercise had any benefits on mood disorder by high fat diet (HFD) induced obesity. Mice were randomly divided into four groups: control, control and exercise, high fat diet (HFD), and HFD and exercise. Obesity was induced by a 20-week HFD (60%). In the exercise groups, exercise was performed 6 times a week for 12 weeks, with the exercise duration and intensity gradually increasing at 4-week intervals. Mice were tested in tail suspension and elevated plus maze tasks in order to verify the mood disorder like behavior such as depression and anxiety on obesity. In the present study, the number of 5-HT- and TPH-positive cells, and expression of 5-HT_1A and 5-HTT protein decreased in dorsal raphe, and depression and anxiety like behavior increased in HFD group compared with the CON group. In contrast, treadmill exercise ameliorated mood disorder like behavior by HFD induced obesity and enhanced expression of the serotonergic system in the dorsal raphe. We concluded that exercise increases the capacity of the serotonergic system in the dorsal raphe, which improves the mood disorders associated with HFD-induced obesity.

Introduction

Obesity can negatively affect an individual's quality of life and health. The prevalence of obesity in most countries is increasing steadily and is a large health burden (Wang et al., 2011). Obesity increases the risk of various chronic diseases, such as cardiovascular disease, high blood pressure, and diabetes (Nguyen et al., 2008). Obesity is also associated mood disorders with altered brain functions as well as changes in the peripheral organs. Wroolie et al. (2015) reported that cognitive performance in adult patients with mood disorders is affected by insulin resistance, steady-state plasma glucose levels, and body mass index.

Mood disorders associated with depression and anxiety symptoms are divided into many categories, including major depressive disorder (MDD) and bipolar disorder (BD). Many studies have demonstrated the association of obesity and mood disorders (Stunkard et al., 2003, Hung et al., 2015; Mansur et al., 2015). For example, several polymorphisms in fat mass- and obesity-associated genes are linked to an increase in body mass index (BMI) in people with MDD (Rivera et al., 2012), and people with MDD may show a predisposition to be overweight or obese (Farmer et al., 2008; Łojko et al., 2015; Nigatu et al., 2015). In addition, diseases such as mental disorders and obesity occur frequently in patients with BD (Regier et al., 1990; Harris and Barraclough 1997; Hsu et al., 2015). Furthermore, in chronic MDD and BD, there is a high risk of developing the metabolic changes of obesity (Díaz-Anzaldúa et al., 2015).

Mood is regulated by the central nervous system, with the neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, linked to the pathogenesis of depression (Cowen, 2008). Serotonin levels are regulated by tryptophan hydroxylase (TPH), which is the rate-limiting enzyme for serotonin biosynthesis and controls the release of synaptic 5-HT by the 5HT_1A receptor. The 5HT_1A receptor acts as an autoreceptor for 5-HT, and is one of several serotonin receptors localized to the dorsal raphe nucleus and the medial raphe nucleus of the brain. The raphe nucleus regulates serotonin release in various regions of the brain, as a key modulator of central serotonin secretion (Graeff, 1997). The sodium-dependent serotonin transporter (5-HTT) has been shown to play an important role in the pathogenesis of both mood disorders and eating disorders (Borkowska et al., 2015). The central serotonergic system originates in the dorsal raphe nucleus (DRN) in the midbrain, has widespread projections to emotion-related brain regions including the amygdala, hippocampus, basal ganglia, and cortex, and has been associated with antidepressant/anxiolytic properties (Vertes, 1991; Jacobs and Azmitia, 1992). In particular, the activity of serotonergic neurons in the dorsal raphe is known to be affected by various forms of metabolic, psychological, and physical stresses (Jocobs and Azmitia, 1992). The raphe nuclei contain the majority of the cell bodies of 5-HT neurons and are responsible for the production of 5-HT in the brain (Goda et al., 2015). Furthermore, depression decreases the activity of 5-HT and TPH and reduces the secretion of neurotransmitters and TPH levels in the raphe nucleus of the brainstem (Quan et al., 2010).

Many studies have suggested that physical exercise has a positive effect on brain function. Exercise ameliorates the neural response to stress in the brain and is protective against the progression of several neurological diseases, including Alzheimer's disease (Adlard et al., 2005), Parkinson's disease (Sung et al., 2012), and ischemic stroke (Willey et al., 2009). Studies have also provided strong evidence to suggest that exercise also improves anxiety and depression (Wipfli et al., 2011). However, little information is available regarding the effects of exercise on mood disorders such as depression and anxiety related to the behavioral effects associated with obesity. Further, the links between exercise, mood, and the central serotonin system are poorly understood. In the present study, we investigated the effects of treadmill exercise on mood disorders in relation to the serotonergic system in the dorsal raphe in an animal model of HFD-induced obesity.