Hypothalamic S1P/S1PR1 axis controls energy homeostasis

Abstract

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

“…Neuronal deletion of Stat3 resulted in marked reduction of POMC expression, thermal dysregulation, and obesity in mice (52). In addition, studies in cultured cells and in the hypothalamus showed that STAT3 activation depends on the phosphorylation by the protein-tyrosine kinase JAK2 (53)(54)(55). We have observed decreased JAK2/STAT3 signals in Gpr45 mutants.…”

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice

“…Previous work suggested that in the hypothalamus, S1P regulates energy homeostasis in rats. Microinjection of S1P into the third ventricle of rats increased Tb and energy expenditure, and microinjection of S1PR1 agonist SEW2871 decreased food intake and activated leptin signalling (Silva et al ., 2014). We also observed correlations between these metabolites and aspects of physiology of the CR mice, including Tb and FAA, but the correlation with respect to Tb was opposite that previously observed in the brain.…”

“…The lack of effect seen may indicate that S1P is not causally linked to the responses observed under CR, such as decreased physical activity, increased FAA and lowered Tb. However, this could be due to the peripheral injection of S1P not reaching a certain threshold in the liver to be effective, compared to the previous study where S1P was injected directly into the brain of rats (Silva et al ., 2014). The physical changes we see with CR, along with the increase in S1P, may be downstream of other CR related responses such as lowered leptin levels.…”

Molecular and neuroendocrine mechanisms of cancer cachexia

“…This system is mainly composed of POMC neurons that secrete aMSH and exert their anorexigenic effects on neurons that contain the melanocortin 4 receptor (MC4R; Balthasar et al 2005, Cone 2005, Silva et al 2014. It is noteworthy that mouse neuronal cells express both POMC and CART in the same neurons, while CART is not found in perikarya and axons of human POMC neurons (Menyhért et al 2007).…”

“…Interestingly, MC4R-, but not MC3R-knockout mice, are resistant to cachexia (Marks et al 2001(Marks et al , 2003. Accordingly, the administration of MC4R antagonists directly to the hypothalamus ameliorates cancer-associated and chronic-kidney-disease-associated cachexia and attenuates the anorexigenic actions of the sphingosine 1 phosphate (Wisse et al 2001, Cheung et al 2007, DeBoer et al 2008, Silva et al 2014.…”