Research reportEarly life stress and the programming of eating behavior and anxiety: Sex-specific relationships with serotonergic activity and hypothalamic neuropeptides
Introduction
Obesity is a disorder characterized by an excess of body fat and it may lead to health complications such as cardiovascular disorders, hypertension, and type-2 diabetes [1]. It is a multifactorial problem, which has been prevalent for many years in developed countries, but it is also becoming increasingly present in developing countries [2]. Given that obesity has become a worldwide public health problem, it is important to try and understand the processes and mechanisms involved in eating behavior and in body weight gain.
Causes of the obesity epidemic include environmental factors such as lifestyle, physical activity, diet, and pollution [3,1]. Among environmental factors, acute or chronic exposure to stress evokes physiological and behavioral responses that alter the metabolic and behavioral state of animals [4,5]. The effects of stress exposure on food intake are complex and can be bidirectional. Studies have shown that effects are dependent on the level of stress: acute stress is associated with reduced food intake while chronic social stress is associated with increased food intake [6]. These early life stressors hold great importance as they may lead to effects that persist during the entirety of an animal’s life [[7], [8], [9], [10], [11], [12], [13]]. Studies with animal models that have evaluated the effects of neonatal stress on feeding behavior and weight of the animals observed different results for different models of neonatal stress. Maternal separation for 180 min per day for fourteen days may promote hyperphagia (evaluated considering standard chow) and weight gain during the development until adulthood [14]. On the other hand, studies with maternal deprivation for 24 h have shown slow growing rate and reduced intake of standard chow as well as reduction of neuropeptide Y (NPY) in the arcuate nucleus of hypothalamus [15]. However, the mechanisms involved in the difference between these results still need a better understanding.
The hypothalamus is an important region for regulating food intake [16]. This region has two groups of neuropeptides involved in the regulation of food intake: the first group is composed of anorexigenic neuropeptides pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), and the second group is composed of orexigenic neuropeptides neuropeptide Y (NPY) and the agouti-related peptide (AgRP) [17]. The release of these neuropeptides is influenced by leptin, a hormone produced by adipocytes whose action leads to a reduction in food intake and an increase in energy expenditure. Leptin functions are mediated by receptors, ObRb, located in the arcuate nucleus of the hypothalamus. When bound to these receptors, leptin induces an increase in the expression of POMC / CART in neurons which produces the neuropeptides mentioned above, and antagonizes the activity of NPY / AgRP neurons [18,19].
In addition to the physiological and homeostatic regulation of food control, feeding behavior is modulated by systems involved in mood control. One important neurotransmitter involved with this response is the serotonin [20]. Psychological factors also play an important role in food control. Studies indicate that levels of anxiety and depression have a direct action on appetite and type of food preferences [[21], [22], [23]]. In addition, the serotoninergic system is highly related to satiety [20].
Therefore, we propose to evaluate how different protocols of neonatal stress affect anxiety and feeding behavior in adulthood, as well as the mechanisms involved in the body weight control of these animals. We analyzed whether maternal deprivation and maternal separation alter appetite and body weight, quantified the expression of leptin receptors and of the neuropeptides POMC, CART, NPY in the hypothalamus, and evaluated whether the serotonergic system in the amygdala and in the hypothalamus could be affected. Throughout the experiments, we evaluated sex-specific effects for all analyzed parameters.
Section snippets
Experimental subjects
Animal proceedings were performed in accordance to the recommendations of the Brazilian Society for Neurosciences (SBNeC) and Brazilian Law on the use of animals (Federal Law 11.794/2008), and were approved by the Institutional Ethical Committee. Wistar rats from our own colony were used. The animals were kept at room temperature (23 ± 1 °C), water and food were available ad libitum, and 12-h light/12-h dark cycle was maintained throughout the experiments (lights on from 6:00 AM to 6:00 PM). At
Early life stress changes body weight
Fig. 2 shows the effects of maternal separation and maternal deprivation on body weight. Three-way ANOVA indicated main effect of the sex (F (5,69) = 10489.64, p < 0.0001), and interaction between sex and time (F (5,69) = 92.70, p < 0.0001). As expected for both main effect and interaction, females weighed less than males. No interaction between group and time or group, time and sex were observed (p > 0.05). For males, there was an effect of time (repeated measures ANOVA, F (2,38) = 1239.39,
Discussion
The present study demonstrated that different protocols of neonatal stress cause distinct and sex-specific effects on feeding behavior and body weight. We observed a decrease in standard rat chow consumption in males that had been exposed to MD. At the same time, both neonatal stress protocols increased the consumption of palatable food, and led to anxiogenic behavior in male animals. In females, we did not observe effects on behaviors related to standard chow consumption or anxiety, but we did
CRediT authorship contribution statement
Randriely Merscher Sobreira de Lima: Conceptualization, Investigation, Formal analysis, Writing - original draft. Lucas Victor dos Santos Bento: Investigation. Marcelo di Marcello Valladão Lugon: Investigation. Valerio Garrone Barauna: Investigation, Resources. Athelson Stefanon Bittencourt: Investigation, Resources. Carla Dalmaz: Conceptualization, Methodology, Visualization, Writing - original draft, Supervision. Ana Paula Santana de Vasconcellos Bittencourt: Conceptualization, Methodology,
Acknowledgments
This research was supported by National Research Council of Brazil (CNPq), Coordination of Improvement of Higher Level Personnel (CAPES), Foundation for the protection of research and innovation in Espírito Santo (FAPES) and National Institutes of Science and Technology (INCT). In addition, we acknowledge the Laboratório Multiusuário de Análises Biomoleculares (LABIOM) of the Universidade Federal do Espírito Santo, and the professors Dr. Vanessa Beijamini Harres and Dr. Luiz Carlos Schenberg
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