Swimming reduces fatty acids-associated hypothalamic damage in mice

Highlights

• A high fat diet causes inflammation, reduction of synapses and astrogliosis in hypothalamus.

• Swimming was able to protect the synapses in the hypothalamus and to reduce astrogliosis.

• Swimming prevents the elevation of caspase 3 in the hypothalamus of the high-fat diet animals.

• Moderate to intense exercise could be a tool to reduce the damage in the hypothalamus caused by diet-induced obesity.

Abstract

The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.

Introduction

A sedentary lifestyle contributes to the development of obesity and obesity-associated disorders such as cardiovascular disease, type 2 diabetes, atherosclerosis, and stroke. Physical activity is considered a cornerstone for the treatment of obesity. Exercise increases energy expenditure, reduces adiposity, and improves glycemic control (Hayes and Kriska, 2008). Some of these beneficial actions of exercise might be mediated by enhanced responsiveness of hypothalamic cells to endocrine signals that modulate feeding and energy expenditure (Thaler et al., 2012).

An imbalance between caloric intake and energy expenditure promotes weight gain and, consequently obesity, triggering a proinflammatory response in the hypothalamus. In hypothalamic diet-induced inflammation, TLR4 plays a central role in the development of resistance to leptin and insulin, contributing to the obese phenotype (Moraes et al., 2009). Also, cytokines such as TNF (tumor necrosis factor) and IL-1β (interleukin 1 beta), which are highly expressed in the hypothalamus of rodents fed a high-fat diet, can induce apoptosis of different cell types, including neurons. A reduction of specific groups of neurons in the arcuate, paraventricular, or lateral nuclei leads to an imbalance in orexigenic and anorexigenic signals which may have an impact on the control of body adiposity (Milanski et al., 2009; Arruda et al., 2011). The maintenance of these neurons ensures the proper functioning of the brain circuit that promotes satiety, in this sense our goal was testing, through the exercise of swimming, a tool to provide neuroprotection to this neural network and other neural cells in this microenvironment.

Besides inflammation and apoptosis, the hypothalamus of animals fed a diet rich in saturated fatty acids presents significant astrogliosis which alters the functionality of the astrocyte in energy homeostasis (Chowen et al., 2016). The astrogliosis varies according to the nature and severity of the insult and is characterized by cellular hypertrophy, proliferation, and the production of inflammatory and trophic substances (Wanner et al., 2013; Anderson et al., 2014). Astrocytes are fundamental cells for the maintenance of the Central Nervous System (CNS) and participate effectively in the synapses (Pekny and Pekna, 2014), in the process of apoptosis (Fan et al., 2016), and in inflammation mediated by TLR4 (Ghaemi et al., 2017). Additionally, astrocytes present tools for sensitivity to fatty acids (Heneka and Landreth, 2007) and satiety hormones, especially leptin receptors (Kim et al., 2014). They are also the main source of oxidation of fatty acids (Taib et al., 2013). These evidences place astrocytes as effective participants in the changes that occur in the hypothalamus induced by a high-fat diet.

Wu et al. (2018) showed the possibility of exercise influencing the level of astrocyte reactivity. The authors presented the swimming effects in Alzheimer's rat model. Swimmer animals displayed decreased reactive astrogliosis, release of proinflammatory cytokines, and oxidative damage in the hippocampus. With the same idea of Wu and colleagues, in our work we used swimming in an attempt to reverse alterations caused by excess fat in the hypothalamus. Our results showed reduction of caspases expression and preservation of synapses coupled with a reduction of astrogliosis in the hypothalamus.