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.
Highlights
The aging process is characterized by the loss of several physiological functions that can lead to diseases [1]
We described the role of hypothalamic sphingosine-1phosphate receptor 1 (S1PR1) in the control of energy homeostasis through the Jak/STAT signaling and melanocortin systems in rodents [21]
We investigated the role of the S1P/S1PR1 axis in the control of energy homeostasis of middle-aged rodents
Summary
The aging process is characterized by the loss of several physiological functions that can lead to diseases [1]. While middle-aged rats displayed higher body weight (Fig. 3a) and epididymal fat (Fig. 3b) compared to younger group, these rats presented alteration in color of the BAT (Fig. 3c) with low protein levels of UCP1 in this tissue (Fig. 3d) These data were accompanied by low levels of S1PR1 expression and STAT3 phosphorylation in the hypothalamus (Fig. 3e). We observed that both agonists, S1P and SEW2871, promoted a strong reduction in food consumption (Fig. 5a and b) which was accompanied by high levels of STAT3 phosphorylation in the hypothalamus of middleaged rats (Fig. 5c and d) It was not found difference in body weight (data not shown). Thereafter, we used the CSF from exercised rats with very high levels of S1P, and we observed that the ICV injection of CSF from exercised animals into middle-aged rats promoted a strong anorexigenic effect (Fig. 5f), suggesting that physiological concentrations of S1P mediates a potent anorexigenic signal
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