Sleep disorders are prevalent in chronic kidney disease patients, although the underlying mechanisms are not understood. The current study demonstrates that adenine-induced tubulointerstitial nephropathy disrupted the circadian system both centrally and in peripheral organs. Clock mutant mice were also more vulnerable to the effects of adenine. These findings aid the understanding of sleep disturbances in adenine phosphoribosyltransferase deficiency, a rare inherited metabolic disorder that leads to the accumulation of 2,8dihydroxyadenine. More broadly, the results suggest that circadian disruption caused by environmental factors such as nighttime shift work may be a risk factor for chronic kidney disease development.

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Highlights d Distribution of dietary protein across meals influences muscle hypertrophy d BCAAs are involved in hypertrophic effects of protein feeding distribution d Hypertrophic effects of protein feeding distribution require the muscle clock d Breakfast protein intake is correlated with skeletal muscle functions in older women

BackgroundAtrogin1, which is one of the key genes for the promotion of muscle atrophy, exhibits day-night variation. However, its mechanism and the role of its day-night variation are largely unknown in a muscle atrophic context.MethodsThe mice were induced a muscle atrophy by hindlimb-unloading (HU). To examine a role of circadian clock, Wild-type (WT) and Clock mutant mice were used. To test the effects of a neuronal effects, an unilateral ablation of sciatic nerve was performed in HU mice. To test a timing-dependent effects of weight-bearing, mice were released from HU for 4 h in a day at early or late active phase (W-EAP and W-LAP groups, respectively).FindingsWe found that the day-night oscillation of Atrogin1 expression was not observed in Clock mutant mice or in the sciatic denervated muscle. In addition, the therapeutic effects of weight-bearing were dependent on its timing with a better effect in the early active phase.InterpretationThese findings suggest that the circadian clock controls the day-night oscillation of Atrogin1 expression and the therapeutic effects of weight-bearing are dependent on its timing.FundCouncil for Science, Technology, and Innovation, SIP, “Technologies for creating next-generation agriculture, forestry, and fisheries”.

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Cholecystokinin (CCK) is a peptide hormone secreted from enteroendocrine cells and regulates the exocrine pancreas, gastric motility, and appetite. Dietary triacylglycerols are hydrolyzed to fatty acids (FA) and 2‐monoacylglycerols (2‐MAG) in the small intestine. Although it is well known that FA stimulate CCK secretion, whether 2‐MAG have the CCK‐releasing activity remains unclear. We examined the CCK‐releasing activity of four commercially available 2‐MAG in a murine CCK‐producing cell line, STC‐1, and the molecular mechanism underlying 2‐MAG‐induced CCK secretion. CCK released from the cells was measured using ELISA. Among four 2‐MAG (2‐palmitoyl, 2‐oleoyl, 2‐linoleoyl, and 2‐arachidonoyl monoacylglycerols) examined, 2‐arachidonoyl glycerol (2‐AG) potently stimulated CCK secretion in a dose‐dependent manner. Structurally related compounds, such as 2‐arachidonoyl glycerol ether and 1‐arachidonoyl glycerol, did not stimulate CCK secretion. Both arachidonic acid and 2‐AG stimulated CCK secretion at 100 μM, but only 2‐AG did at 50 μM. 2‐AG‐induced CCK secretion but not arachidonic acid‐induced CCK secretion was attenuated by treatment with a cannabinoid receptor 1 (CB1) antagonist. These results indicate that a specific 2‐MAG, 2‐AG, directly stimulates CCK secretion via CB1.

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2‐Monoacylglycerol (2‐MAG) is one of the digestion products of dietary lipids. We recently demonstrated that a 2‐MAG, 2‐arachidonoyl glycerol (2‐AG) potently stimulated cholecystokinin (CCK) secretion via cannabinoid receptor 1 (CB1) in a murine CCK‐producing cell line, STC‐1. CCK plays a crucial role in suppressing postprandial gastric emptying. To examine the effect of 2‐AG on gastric emptying, we performed acetaminophen and phenol red recovery tests under oral or intraperitoneal administration of 2‐AG in mice. Orally administered 2‐AG (25 mg/kg) suppressed the gastric emptying rate in mice, as determined by the acetaminophen absorption test and phenol red recovery test. Intraperitoneal administration of a cholecystokinin A receptor antagonist (0.5 mg/kg) attenuated the gastric inhibitory emptying effect. In addition, both oral (10 mg/kg) and intraperitoneal (0.5 mg/kg) administration of a CB1 antagonist counteracted the 2‐AG‐induced gastric inhibitory effect. Furthermore, intraperitoneal 2‐AG (25 mg/kg) suppressed gastric emptying. These results indicate that 2‐AG exhibits an inhibitory effect on gastric emptying in mice, possibly mediated by stimulating both CCK secretion via CB1 expressed in CCK‐producing cells and acting on CB1 expressed in the peripheral nerves. Our findings provide novel insights into the 2‐MAG‐sensing mechanism in enteroendocrine cells and the physiological role of 2‐MAG.