Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise

Abstract

Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.

The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration

“…S1PR2 undergoes low-level, gender-specific brain expression [ 55 ]. Neurons, astrocytes, and microglia express S1PR1–3 and S1PR5, while oligodendrocytes and their precursors possess S1P1, S1P3, and S1P5 [ 53 , 56 ]. Cell surface receptor-mediated S1P signaling includes feedback effects such as reduction of SphK1 expression in response to S1PR2 activation or ligand-induced receptor internalization (this phenomenon is exploited in the therapy of relapsing remitting multiple sclerosis that employs fingolimod, a S1P receptor modulator [ 53 ]), [ 57 , 58 ].…”

Exercise activates the hypothalamic S1PR1–STAT3 axis through the central action of interleukin 6 in mice

“…In addition, aberrant signaling of S1PR1–STAT3 was found in the hypothalamus of mice and rats during cancer‐induced anorexia (Silva et al, ). Conversely, low expression of S1PR1 and defective signaling of hypothalamic S1PR1–STAT3 were observed in several animal models of obesity (Silva et al, ) and aging (Silva et al, ). However, in the current study, we reported that an acute exercise session elicited the S1PR1–STAT3 axis in the hypothalamus of both lean and obese mice.…”

“…All data are expressed as mean ± SEM. ICV, intracerebroventricular; IL-6, interleukin 6; KO, knockout; S1PR1, sphingosine-1-phosphate receptor 1; WT, wild type [Color figure can be viewed at wileyonlinelibrary.com] S1P in middle-age animals (Silva et al, 2016). Other studies have shown that exercise rapidly stimulates the circulating levels of S1P in animal models (Banitalebi et al, 2013) and humans (Baranowski, Charmas, Długołęcka, & Górski, 2011;Baranowski et al, 2015).…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…Exercise also increases S1P and S1PR1 levels in rodents and S1P content in humans [132,133] and improves insulin sensitivity in the rat skeletal muscle tissue [134].…”