Sincronização pela alimentação em tempo restrito: papel do TRPV1

Abstract

Feeding is a strong entrainment cue for the biological clock. The liver is the first organ to respond to time restricted feeding to the resting phase of the circadian rhythm of activity with alteration in expression of clock genes. This can compromise the glucose metabolism, which may lead to metabolic diseases. Transient receptor potential vanilloid1 (TRPV1) channel regulates glucose metabolism and its activation prevents hyperglycemia. Therefore, the aim of this study was to investigate the role of TRPV1 channel in the entrainment and in the metabolic changes induced by time restricted feeding (TR). For this purpose, adult Wistar rats were fed with normal chow in the resting phase or ad libitum (AD) for 21 days. From AD and TR animals, telemetric records were obtained to evaluate spontaneous locomotor activity (ALE) and core body temperature (Tinterna). Intraperitoneal glucose tolerance test (IPTTG) was performed at ZT 12 and ZT 22. And determination of oxygen consumption (VO2) was done between ZT 4 and 5 for the calculation of the energy expenditure (EE) and respiratory quotient (QR). Another group of AD and TR animals was euthanized at ZT 1 and at ZT 13 to obtain the trunk blood for insulin and leptin measurements by ELISA and the liver to analyse clock gene (Per1, Cry1, Cry2, RevErbα e Bmal1) and the metabolic genes expression (TRB-3 e glicose-6-fosfatase, PEPCK e PPARα) by qPCR. All these parameters were also evaluated in a group of TR animals previously subjected to resiniferatoxin (RTX) i.p. injection or its vehicle to desensitize TRVP1 channel in the abdominal cavity. TR feeding reduced the EE and increased the QR which resulted in smaller body weight gain. In addition, TR feeding entrained Tinterna and ALE rhythms, phase shifted Per1 and Bmal1 expression, and abolished the temporal variation of Cry1 e Reverbα. These changes were accompanied by abolishment of the temporal variation in the Pparα and glucose-6-phosphatase expression in the liver. Also, TR feeding increased insulin secretion at ZT 1 and phase-shifted the temporal variation of leptin serum levels, together with an improvement in the glucose tolerance. Although TRPV1 desensitization has anticipated the onset and acrophase of ALE and Tinterna rhythms, it did not alter the pattern of ALE and Tinterna induced by TR feeding. This treatment impaired the response in the IPTTG induced by TR feeding without affecting insulin secretion. Furthermore, it abolished the temporal variation in Per1, RevErbα, glucose-6-phosphatase, PEPCK, TRB-3 liver expression, and leptin secretion. Therefore, the ability of the biological clock to entrain to the new schedule of feeding improves glucose metabolism. This feature of the circadian time system seems to depend on TRPV1 channel because the lack of this channel interferes in the signaling of the temporal cue (TR feeding) to the biological clock.