TABLE 2.
Summary of central neuroendocrine regions in response to TRF protocols included in this review1
| Brain area and region | Study (ref) | Animal or human model | Study design | Study duration | Fasting: feeding window (h:h) | Calorie restriction? | Weight loss? | Difference in protein/gene expression | Difference in activity of neurons/neurotransmitter | Interpretive comments/include behavior measures if any were made |
|---|---|---|---|---|---|---|---|---|---|---|
| Hypothalamus | ||||||||||
| ARC | Lauzurica et al. (65) | Animal: female rats | Restricted feeding/refeeding protocol (RFR) | 7 d | 20 h:2 h | Yes | Yes | Npy: ↑ 57.7% in TRF compared to baseline, and remained elevated 5 d after ad libitum feeding | — | Rebound hyperphagia and reduced plasma leptin were observed following restricted feeding, which was seen just before animals were killed to evaluate ARC levels of NPY and POMC |
| Pomc: ↓ (no % reported) | ||||||||||
| Verhagen et al. (69) | Animals: female outbred Wistar WU rats, n = 16 | Restricted feeding with set feeding time (RF-S, n = 9) vs. random dark phase feeding times (RF-R, n = 7) | 3 d | 23 h:1 h | No | ↑ In RF-R compared to RF-S | — | ↓ c-FOS–positive cells in RF-R compared to RF-S | Total food intake was not different between RF-S and RF-R | |
| Sorrell et al. (67) | Animal: male mice—DIO vs. WT vs. lean | High-fat-fed DIO mice subjected to dark-restricted feeding protocol (DRF) | 2 wk | 12 h:12 h | Not reported | Yes | Agrp: ↑ compared to controls | — | DRF reduced hyperphagia seen in high-fat-fed DIO mice in control group, and comparable to WT and lean groups | |
| Pomc: No change | DRF increased effectiveness of leptin and ghrelin signaling in the hypothalamus, reinforcing the strength of hunger and satiety signals | |||||||||
| Arntl/Bmal1: No change | Higher plasma ghrelin in DRF vs. controls, but no difference in food intake | |||||||||
| Ghsr: ↑ compared to controls | ||||||||||
| Fos: ↑ compared to controls | ||||||||||
| Nr1d1/Rev-erbα: ↑ compared to controls | ||||||||||
| Per2: No change | ||||||||||
| Cry1: No change | ||||||||||
| Brady et al. (66) | Animal: male and female Sprague-Dawley rats | Restricted feeding (RF) vs. ad libitum control (C) | 2 wk | 23 h:1 h | 10 g/d for RF | Yes, ∼↓ 18.5% in RF | NPY: ↑ 45.6% in RF compared to C | — | — | |
| POMC: ↓11% in RF compared to C | ||||||||||
| GAL: ↓16.5% in RF compared to C | ||||||||||
| CRH: ↓24.5% in RF compared to C | ||||||||||
| Miñana-Solis et al. (68) | Animals: male Wistar rats | Restricted light-cycle feeding (RF) vs. ad libitum controls (C) | 3 wk | 22 h:2 h for RF | No | Not reported | Bmal1: No change | — | — | |
| Per1: ↑ in RF compared to C | ||||||||||
| Per2: No change | ||||||||||
| Lewis et al. (50) | Animals: male, lean (+/+) rats JCR:LA-cp strain, n = 10 | Restricted feeding (RF) vs. ad libitum control (C) | 40 d | 23 h:1 h | Yes, 15 g/d total food provided for RF only | Yes, RF 107 g ↓ vs. control | NPY: ↑ in RF compared to C | — | — | |
| DMH | Lewis et al. (50) | Animals: male, lean (+/+) rats JCR:LA-cp strain, n = 10 | Restricted feeding (RF) vs. ad libitum control (C) | 40 d | 23 h:1 h | Yes, 15 g/d total food provided for RF only | Yes, RF 107 g ↓ vs. control | NPY: ↑ in restricted group compared to controls | — | — |
| Verhagen et al. (69) | Animals: female outbred Wistar WU rats, n = 16 | Restricted feeding with set feeding time (RF-S, n = 9) vs. random dark phase feeding times (RF-R, n = 7) | 3 d | 23 h:1 h | No | ↑ In RF-R compared to RF-S | — | ↓ c-FOS positive cells in RF-R compared to RF-S | Total food intake was not different between RF-S and RF-R | |
| Miñana-Solis et al. (68) | Animals: male Wistar rats | Restricted light-cycle feeding (RF) vs. ad libitum controls (C) | 3 wk | 22 h:2 h | No | Not reported | Bmal1: No change | — | There was a phase advancement of clock gene expression in RF compared to C | |
| Per1: ↑ in RF compared to C | ||||||||||
| Per2: ↓ in RF compared to C | ||||||||||
| Angeles-Castellanos et al. (80) | Animals: adult male Wistar rats n = 6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h for RF | No | Not reported | — | No difference in c-FOS-IR between groups | ↑ c-FOS-IR in DMH at feed deprivation and mealtimes in both groups. Control animals that were evaluated after a 22-h acute feed deprivation showed similar activation/entrainment as the 3-wk feed-deprived rats, but this was not seen in rats that were not feed deprived | |
| VMH | Angeles-Castellanos et al. (80) | Animals: adult male Wistar rats n = 6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h for RF | No | Not reported | — | No difference in c-FOS-IR between groups | No effect of mealtime or fasting on c-FOS-IR VMH. Control animals that were evaluated after a 22-h acute feed deprivation showed similar activation/entrainment as the 3-wk feed-deprived rats, but this was not seen in rats that were not feed deprived |
| Lewis et al. (50) | Animals: male, lean (+/+) rats JCR:LA-cp strain, n = 10 | Restricted feeding (RF) vs. ad libitum control (C) | 40 d | 23 h:1 h | Yes, 15 g/d total food provided for RF only | Yes, RF 107 g ↓ vs. control | NPY: no difference between groups | — | — | |
| Kurumiya and Kawamura (92) | Animals: male albino Wistar rats, blinded with bilateral SCN lesions | Time-restriction (TR) followed by complete restriction | 10 d | 22 h:2 h | No | None reported | — | ↑ Multiple-unit activity 3-4 h prior to feeding time, and stayed 6-7 h after consumption, and lasted 4 d into the complete caloric restriction | Chronically implanted electrodes used to measure food entrainment in the absence of SCN and light entrainment | |
| Miñana-Solis et al. (68) | Animals: male Wistar rats | Restricted light-cycle feeding (RF) vs. ad libitum controls (C) | 3 wk | 22 h:2 h for RF | No | Not reported | Bmal1: No change | — | — | |
| Per1: No change | ||||||||||
| Per2: ↓ in RF compared to C | ||||||||||
| PVN | Brady et al. (66) | Animal: male and female Sprague-Dawley rats | Restricted feeding (RF) vs. control (C) | 2 wk | 23 h:1 h | 10 g/d for TR | Yes, ∼↓ 18.5% in TR | NPY: ↑ 45.6% in RF compared to C | — | — |
| POMC: ↓11% in RF compared to C | ||||||||||
| GAL: ↓16.5% in RF compared to C | ||||||||||
| CRH: ↓24.5% in RF compared to C | ||||||||||
| Angeles-Castellanos et al. (80) | Animals: adult male Wistar rats n = 6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h for RF | No | Not reported | — | No difference in c-FOS-IR between groups | Control animals that were evaluated after a 22-h acute feed deprivation showed similar activation/entrainment as the 3-wk feed-deprived rats, but this was not seen in rats that were not feed deprived | |
| Verhagen et al. (69) | Animals: female outbred Wistar WU rats, n = 16 | Restricted feeding with set feeding time (RF-S, n = 9) vs. random dark phase feeding times (RF-R, n = 7) | 3 d | 23 h:1 h | No | ↑ In RF-R compared to RF-S | — | No difference in c-FOS positive cells between RF-R and RF-S groups | Total food intake was not different between RF-S and RF-R | |
| Miñana-Solis et al. (68) | Animals: male Wistar rats | Restricted light-cycle feeding (RF) vs. ad libitum controls (C) | 3 wk | 22 h:2 h for RF | No | Not reported | Bmal1: No change | — | — | |
| Per1: No change | ||||||||||
| Per2: No change | ||||||||||
| Kurose et al. (103) | Animals: male Wistar rats, n = 3–6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h | No | ↓ In RF compared to C, but not significant | Oxr2: 16.6% ↓ in RF compared to AL-fed animals | — | — | |
| Lewis et al. (50) | Animals: male, lean (+/+) rats JCR:LA-cp strain, n = 10 | Restricted feeding (RF) vs. ad libitum control (C) | 40 d | 23 h:1 h | Yes, 15 g/d total food provided for RF only | Yes, RF 107 g ↓ vs. control | NPY: no difference between groups | — | — | |
| LHA | Verhagen et al. (69) | Animals: female outbred Wistar WU rats, n = 16 | Restricted feeding with set feeding time (RF-S, n = 9) vs. random dark phase feeding times (RF-R, n = 7) | 3 d | 23 h:1 h | No | ↑ In RF-R compared to RF-S | — | ↓ c-FOS–positive cells in RF-R compared to RF-S | Total food intake was not different between RF-S and RF-R |
| Angeles-Castellanos et al. (80) | Animals: adult male Wistar rats n = 6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h for RF | No | Not reported | — | ↑ c-FOS-IR at fasting and mealtimes in RF compared to C group | Control animals that were evaluated after a 22-h acute feed deprivation showed similar activation/entrainment as the 3-wk feed-deprived rats, but this was not seen in rats that were not feed deprived | |
| Lewis et al. (50) | Animals: male, lean (+/+) rats JCR:LA-cp strain, n = 10 | Restricted feeding (RF) vs. ad libitum control (C) | 40 d | 23 h:1 h | Yes, 15 g/d total food provided for RF only | Yes, RF 107 g ↓ vs. control | NPY: ↑ in RF compared to C | — | — | |
| Kurumiya and Kawamura (92) | Animals: male albino Wistar rats, blinded with bilateral SCN lesions | Time-restriction (TR) followed by food deprivation | 10 d | 22 h:2 h | No | None reported | — | Multiple-unit activity was higher 3-4 h prior to feeding time, and stayed 6–7 h after consumption, and lasted 4 d into the food deprivation | Chronically implanted electrodes used to measure food entrainment in the absence of SCN and light entrainment | |
| Kurose et al. (103) | Animals: male Wistar rats, n = 3–6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h | No | ↓ In RF compared to C, but not significant | — | c-FOS-LI: ↑ in RF (22.2%) compared to C (5.6%) | — | |
| SCN | Mendoza et al. (127) | Animals: C3H mice | Calorie and time Restricted (C-TR) vs. ad libitum (AL) controls | 3 wk | Food given once at 0600 h for C-TR group | Yes 4.6 g/d for AL vs. ∼3 g/d for C-TR | Yes, ↓ 20% in C-TR compared to AL | PER-1: phase advanced in C-TR compared to AL | — | — |
| PER-2: ↑ amplitude in C-TR compared to AL | ||||||||||
| CLOCK: ↓ amplitude in C-TR compared to AL | ||||||||||
| AVP: phase advanced in C-TR compared to AL | ||||||||||
| Sorrell et al. (67) | Animal: male mice—DIO vs. WT vs. lean | High-fat-fed DIO mice subjected to dark-restricted feeding protocol (DRF) | 2 wk | 12 h:12 h | Not reported | Yes | Agrp: No change | — | DRF reduced hyperphagia seen in high-fat-fed DIO mice in control group, and comparable to WT and lean groups | |
| Pomc: No change | DRF increased effectiveness of leptin and ghrelin signaling in the hypothalamus, reinforcing the strength of hunger and satiety signals | |||||||||
| Arntl/Bmal1: No change | Higher plasma ghrelin in DRF vs. controls, but no difference in food intake | |||||||||
| Ghsr: No change | ||||||||||
| Fos: No change | ||||||||||
| Nr1d1/Rev-erbα: No change | ||||||||||
| Per2: No change | ||||||||||
| Cry1: No change | ||||||||||
| Angeles-Castellanos et al. (80) | Animals: adult male Wistar rats, n = 6 | Restricted feeding (RF) vs. ad libitum control (C) | 3 wk | 22 h:2 h for RF | No | Not reported | — | No difference in c-FOS-IR between groups | Control animals that were evaluated after a 22-h acute feed deprivation showed similar activation/entrainment as the 3-wk feed deprived rats, but this was not seen in rats that were not feed deprived | |
| Verhagen et al. (69) | Animals: female outbred Wistar WU rats, n = 16 | Restricted feeding with set feeding time (RF-S, n = 9) vs. random dark phase feeding times (RF-R, n = 7) | 3 d | 23 h:1 h | No | ↑ In RF-R compared to RF-S | — | No difference in c-FOS–positive cells between RF-R and RF-S | Total food intake was not different between RF-S and RF-R | |
| Mesocorticolimbic system | ||||||||||
| NAc | Wallace et al. (147) | Animals: male and female C57BL/6 mice | High-fat diet vs. control-fed mice used in a 12-h fasting vs. ad libitum–fed protocol | 3 wk | 12 h:12 h | Not reported | No difference between groups | — | ↑ DA release and re-uptake in NAc after 12-h fast | |
| Olivo et al. (148) | New Zealand white rabbits, mother and pups | Mother rabbits entrained to 12-h:12-h LD cycle; pups, 24-h dark cycle | 7 d | Pups fed once a day for 2–4 min to feed | Not reported | Not reported | — | Cytochrome oxidase–based brain metabolic activity ↑ in NAc 2–3 h before feeding time, suggesting entrainment | Elevated FAA alongside increased brain metabolic activity | |
| PfC | Guerrero-Vargas et al. (159) | Animals: adult male Wistar rats, n = 48 | Control (C) vs. weekday shift work with ad libitum food intake (W-AL) vs. weekday shift work with time-restricted food intake (W-TR); weekend schedules were matched | 6 wk | 12 h:12 h (light cycle) | C: 16% during light and 84% in dark; W-AL: 30% during light and 70% during dark; W-TR: 100% in dark | ↑14% in W-AL vs. C | ↓ Microglia fibrillary acidic protein and IBA-1 positive cells in W-TR compared to W-AL in PfC | — | ↓ Anhedonia, hypoactivity in W-TR compared to W-AL; ↑ anxiety-like symptoms in open field tests in W-AL compared to W-TR |
| W-AL > W-TR; W-AL > C | ↓ 12% in W-TR vs. C | C and W-TR were not significantly different. These effects on the PfC suggests reduced neuroinflammation in W-TR compared to W-AL | ||||||||
| Amg | Olivo et al. (148) | New Zealand white rabbits, mother and pups | Mother rabbits entrained to 12-h:12-h LD cycle; pups, 24-h dark cycle | 7 d | Pups fed once a day for 2–4 min to feed | Not reported | Not reported | — | Cytochrome oxidase-based brain metabolic activity ↑ in Amg 2–3 h before feeding time | Elevated FAA alongside increased brain metabolic activity. Increased activity before feeding suggests entrainment |
| Guerrero-Vargas et al. (159) | Animals: adult male Wistar rats, n = 48 | Control (C) vs. weekday shift work with ad libitum food intake (W-AL) vs. weekday shift work with time-restricted food intake (W-TR); weekend schedules were matched | 6 wk | 12 h:12 h (light cycle) | C: 16% during light and 84% in dark; W-AL: 30% during light and 70% during dark; W-TRF: 100% in dark | ↑14% in W-AL vs. C | ↓ Microglia fibrillary acidic protein and IBA-1 positive cells in W-TR compared to W-AL in Amg | — | ↓ Anhedonia, hypoactivity in W-TR compared to W-AL; ↑ anxiety-like symptoms in open field tests in W-AL compared to W-TR | |
| W-AL > W-TRF; W-AL > C | ↓ 12% in W-TR vs. C | C and W-TR were not significantly different. These effects on the Amg suggest reduced neuroinflammation in W-TR compared to W-AL | ||||||||
| Dorsal vagal complex | ||||||||||
| NTS | Begriche et al. (164) | Animals: C57BL/6J mice WT and Mc3r−/− | Calorie and time restriction and ad libitum control | 3 d–2 wk | 12 h:12 h, single meal in time-restricted group at 1300 h | 30–40% Calorie restriction | Not reported | Bmal1: ↓ in Mc3r−/− compared to WT in restricted and control-fed mice | — | ↑Wakefulness and activity 2 h prior to “entrained” mealtime in WT, but absent in Mc3r−/− mice |
| Rev-erbα: ↓ in Mc3r−/− compared to WT in restricted and control-fed mice | ||||||||||
| Olivo et al. (148) | New Zealand white rabbits, mother and pups | Mother rabbits entrained to 12-h:12-h LD cycle; pups, 24-h dark cycle | 7 d | Pups fed once a day for 2–4 min to feed | Not reported | Not reported | — | Cytochrome oxidase-based brain metabolic activity ↑ in NTS 2–3 h before feeding time | Elevated FAA alongside increased brain metabolic activity. Increased activity before feeding suggests entrainment |
1
Agrp, agouti-related peptide; Amg, amygdala; ARC, arcuate nucleus of the hypothalamus; Arntl, Aryl Hydrocarbon Receptor Nuclear Translocator Like; Bmal1, brain and muscle ARNT-like 1; Clock, clock circadian regulator; Cry1/2, Cryptochrome 1/2; AVP, arginine vasopressin; CRH, corticotrophin-releasing hormone; DA, dopamine; DIO, diet-induced obesity; DMH, dorsomedial hypothalamic nucleus; FAA, food anticipatory activity; GAL, galanin; GHSR, growth hormone secretagogue receptor; IBA-1, ionized calcium binding adaptor molecule 1; LD, light:dark; LHA, lateral hypothalamic area; Mc3r, melanocortin 3 receptor; NAc, nucleus accumbens; Npy, neuropeptide Y; NTS, nucleus tractus solitarius; OxR2, orexin receptor 2; Per 1/2, Period Circadian Regulator 1/2; PfC, prefrontal cortex; Pomc, proopiomelanocortin; PVN, paraventricular nucleus of the hypothalamus; ref, reference;Rev-erba/Nr1d1, Nuclear Receptor Subfamily 1 Group D Member 1; VMH, ventromedial hypothalamic nucleus; VTA/SN, ventral tegmental area/substantia nigra; WT, wild-type; WU, Unilever Outbred; ↓, significant decrease; ↑, significant increase.