Ive stress improves lipid storage function in SMS1-KO adipocytes. Analysis of SMS1-KO mice under fasting conditions further confirmed these findings. Blood CM levels in SMS1-KO mice were significantly decreased, suggesting that triglycerides derived from CM in peripheral tissues are completely consumed as an energy source. Again, anti-oxidant treatment partially normalized CM levels and also increased epiWAT volume in 
SMS1-KO mice. Overall, these results indicate that increased oxidative stress underlies lipid storage failure in adipocytes of SMS1-KO mice. In conclusion, we demonstrate that manipulation of sphingolipid flux in vivo and consequent ceramide accumulation in WATcells leads to oxidative stress and defects in lipid storage function. Our approach identifies an essential role for SMS1 in adipocyte function and provides molecular insight into the role of the de novo sphingolipid biosynthetic pathway in regulating oxidative stress, observations Autophagy highly relevant to metabolic disease. To date, it has also been reported that SMS1-KO mice exhibit hearing impairment [54] and T-cell dysfunction [55]. These observations would be also attributable to loss of fundamental function of the cells by disturbance of sphingolipid. Further study is necessary to clarify the common nature of these observations.Supporting InformationTable S1 Primer sequences used in quantitative RT-PCR. (PDF)AcknowledgmentsWe thank our colleagues for valuable suggestions and discussion. We also thank Mss. Rieko Shindo and Yasuko Indo for technical assistance.Author ContributionsConceived and designed the experiments: MY TY KW. Performed the experiments: MY TY NN KW KI YG. Analyzed the data: MY TY NN TG KW KI RT KN TO YO. Contributed reagents/materials/analysis tools: MY TG YO. Wrote the paper: MY.
Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem. NPS selectively binds with high affinity to Gs and Gq protein-coupled receptors, identified as GPR 154 previously and now referred to as NPSR, to produce mobilization of intracellular Ca2+ and to increase in cAMP levels [1]. NPS precursor mRNA in the rat is expressed in a group of neurons located between the locus ceruleus (LC) and Barrington’s nucleus, the principle sensory trigeminal nucleus, and the lateral parabrachial nucleus [1]. In the mouse, NPS precursor mRNA is only expressed in the Kolliker-Fuse nucleus and pericoerulear area of ?the brainstem [2]. In contrast, NPSR mRNA is found widely distributed 15755315 in the rat and mouse brain, mainly in the olfactory cortex, cerebral cortex, thalamus, hypothalamus, amygdala, and subculum [1?]. This profile of NPSR mRNA expression suggests involvement of NPS-NPSR system in the regulation of multiple central functions. Actually, activation of NPSR by central administration of NPSenhances locomotor and exploratory activities, and evokes anxiolytic-like effects in mice [1,5,6], and promotes wakefulness in rats [1,7]. NPS is also involved in antinociception [8,9], fear expression and extinction [10] and memory Epigenetic Reader Domain processes in mice [11,12], and facilitates relapse to cocaine seeking in rats [13]. NPS-NPSR system is proposed as a newly identified olfactory regulating system involved in regulation of olfactory perception and/or integration of olfactory or pheromonal information [3], because the high levels of NPSR mRNA expression have been found in many regions of olfactory cortex including the anterior olfactory nucleus (AON), piriform cortex (Pir), tenia tec.Ive stress improves lipid storage function in SMS1-KO adipocytes. Analysis of SMS1-KO mice under fasting conditions further confirmed these findings. Blood CM levels in SMS1-KO mice were significantly decreased, suggesting that triglycerides derived from CM in peripheral tissues are completely consumed as an energy source. Again, anti-oxidant treatment partially normalized CM levels and also increased epiWAT volume in SMS1-KO mice. Overall, these results indicate that increased oxidative stress underlies lipid storage failure in adipocytes of SMS1-KO mice. In conclusion, we demonstrate that manipulation of sphingolipid flux in vivo and consequent ceramide accumulation in WATcells leads to oxidative stress and defects in lipid storage function. Our approach identifies an essential role for SMS1 in adipocyte function and provides molecular insight into the role of the de novo sphingolipid biosynthetic pathway in regulating oxidative stress, observations highly relevant to metabolic disease. To date, it has also been reported that SMS1-KO mice exhibit hearing impairment [54] and T-cell dysfunction [55]. These observations would be also attributable to loss of fundamental function of the cells by disturbance of sphingolipid. Further study is necessary to clarify the common nature of these observations.Supporting InformationTable S1 Primer sequences used in quantitative RT-PCR. (PDF)AcknowledgmentsWe thank our colleagues for valuable suggestions and discussion. We also thank Mss. Rieko Shindo and Yasuko Indo for technical assistance.Author ContributionsConceived and designed the experiments: MY TY KW. Performed the experiments: MY TY NN KW KI YG. Analyzed the data: MY TY NN TG KW KI RT KN TO YO. Contributed reagents/materials/analysis tools: MY TG YO. Wrote the paper: MY.
Neuropeptide S (NPS) is a newly identified neuromodulator located in the brainstem. NPS selectively binds with high affinity to Gs and Gq protein-coupled receptors, identified as GPR 154 previously and now referred to as NPSR, to produce mobilization of intracellular Ca2+ and to increase in cAMP levels [1]. NPS precursor mRNA in the rat is expressed in a group of neurons located between the locus ceruleus (LC) and Barrington’s nucleus, the principle sensory trigeminal nucleus, and the lateral parabrachial nucleus [1]. In the mouse, NPS precursor mRNA is only expressed in the Kolliker-Fuse nucleus and pericoerulear area of ?the brainstem [2]. In contrast, NPSR mRNA is found widely distributed 15755315 in the rat and mouse brain, mainly in the olfactory cortex, cerebral cortex, thalamus, hypothalamus, amygdala, and subculum [1?]. This profile of NPSR mRNA expression suggests involvement of NPS-NPSR system in the regulation of multiple central functions. Actually, activation of NPSR by central administration of NPSenhances locomotor and exploratory activities, and evokes anxiolytic-like effects in mice [1,5,6], and promotes wakefulness in rats [1,7]. NPS is also involved in antinociception [8,9], fear expression and extinction [10] and memory processes in mice [11,12], and facilitates relapse to cocaine seeking in rats [13]. NPS-NPSR system is proposed as a newly identified olfactory regulating system involved in regulation of olfactory perception and/or integration of olfactory 
or pheromonal information [3], because the high levels of NPSR mRNA expression have been found in many regions of olfactory cortex including the anterior olfactory nucleus (AON), piriform cortex (Pir), tenia tec.