TABLE 1.
Summary of central neuroendocrine regions in response to CR protocols included in this review1
| Brain area and region | Study (ref) | Animal or human model | Study duration | Calorie restriction | Weight change or difference? | Difference in protein/gene expression | Difference in activity of neurons | Interpretive comments/include behavior measures if any were made |
|---|---|---|---|---|---|---|---|---|
| Hypothalamus | ||||||||
| ARC | Derous et al. (55) | Animal; C57BL/6 mice (male, n = 8) | 3 mo | 10%, 20%, 30%, and 40% energy restriction | Not reported | Npy: ↑ in all CR groups | — | RNA-seq (transcriptome sequencing) used to determine differential gene expression |
| Agrp: ↑ in 30% and 40% CR | Expression of Agrp and Npy was negatively correlated with leptin, insulin, and IGF-I. Pomc was positively correlated with IGF-1 only | |||||||
| Pomc: ↓ in 40% CR only | ||||||||
| Rogers et al. (56) | Animal; C57BL/6 mice (male, n = 7) | 1 y | 40% kcal deficit | Weight and length: ↓ vs. controls | Npy: ↑ | — | Measured mRNA levels for gene expression (qPCR for transcription factors) | |
| Agrp: ↑ | Ghrelin and GHSR1a controls and ablation (+/+ and −/−). No difference in gene expression from CR between ghrelin/GHSR1a groups | |||||||
| Pomc: ↓ | ||||||||
| Hambly et al. (57) | Animal; MF1 mice (n = 10) | 50 d total: 25 d preintervention + 25 d intervention | 50% energy restriction vs. ad libitum control | ↓ Average 2.6 g lower vs. control | Npy: ↑ after CR, not significantly different after 4 d of ad libitum refeeding | — | Used in situ hybridization to measure mRNA levels for gene expression | |
| Agrp: ↑ after CR, not significantly different after 4 d of ad libitum refeeding | ||||||||
| Pomc: ↓ after CR, not significantly different after 4 d of ad libitum refeeding | ||||||||
| Bi et al. (58) | Animal; Sprague-Dawley rats (male, n = 6) | 14 d | 30% kcal deficit vs. ad libitum control | ↓ Rate of weight gain (27.3% lower) | Npy: ↑ 156% compared to control | — | Used in situ hybridization to measure mRNA levels for gene expression | |
| Agrp: slight increase but not significantly different than control | Significant reduction in plasma leptin concentrations, but normal glucose and insulin. No significant change in ObRb gene expression in the ARC | |||||||
| Pomc: ↓ 26.4% compared to control | ||||||||
| Kinzig et al. (59) | Animal; Long-Evans rats (male, n = 7) | 4 wk | 30% kcal deficit vs. ad libitum control | ↓ 19% lower than control | Npy: not significantly different than controls | — | Plasma insulin and leptin concentrations were significantly lower. Plasma ghrelin concentrations were significantly higher | |
| Agrp: not significantly different than controls | Used in situ hybridization to measure mRNA levels for gene expression | |||||||
| Pomc: ↓ 32.2% compared to control | ||||||||
| Jarvie et al. (64) | Animal; Background C57BL/6 mice (n = 7) | 2 wk | ∼30% kcal deficit vs. ad libitum control | Maintained at 80% of starting weight | Gad1 in POMC neurons: ↓ 39–44% compared to control | — | Gad1 correlates with GABA release from neurons | |
| Gad1 in ARC: not significantly different than control | Used in situ hybridization to measure mRNA levels for gene expression | |||||||
| Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | SIRT1: no difference | c-FOS: no difference between CR and ad libitum | Immunostaining used to measure SIRT1 and c-FOS | |
| Peripheral ghrelin injection increased c-FOS-positive cells over 2 h | ||||||||
| Radler et al. (60) | Animals; C57BL/6J mice (male, n = 15–16) | 4 wk | 50% kcal deficit vs. ad libitum controls | Not reported | NPY: ↑ vs. control | — | Immunostaining used to measure NPY present in tissue samples | |
| DMH | Bi et al. (58) | Animal; Sprague-Dawley rats (male, n = 6) | 14 d | 30% kcal deficit vs. ad libitum control | ↓ Rate of weight gain (27.3% lower) | Npy: ↑ ∼50% compared to control | — | Used in situ hybridization to measure mRNA levels for gene expression |
| Signification reduction in plasma leptin concentrations, but normal glucose and insulin. No significant change in ObRb gene expression in the DMH | ||||||||
| Kinzig et al. (59) | Animal; Long-Evans rats (male, n = 7) | 4 wk | 30% kcal deficit vs. ad libitum control | ↓ 19% lower than control | Npy: ↑ 451.6% compared to control | — | Used in situ hybridization to measure mRNA levels for gene expression | |
| Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | Ox2r: ↑ number of Ox2r-positive cells and total signal [14 d] | c-FOS: ↑ expression at 14 d and 104 d; ↑ 32% expression (14 d CR) in BRASTO mice | Immunostaining used to measure SIRT1 and c-FOS. Used in situ hybridization to measure mRNA levels for gene expression | |
| SIRT1: ↑ at 14 d and 104 d | Peripheral ghrelin injection increased c-FOS-positive cells over 2 h | |||||||
| VMH | Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | Ox2r: no difference | c-FOS: no difference | Immunostaining used to measure SIRT1 and c-FOS. Used in situ hybridization to measure mRNA levels for gene expression |
| SIRT1: no difference | ||||||||
| PVN | Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | SIRT1: no difference | c-FOS: no difference | Immunostaining used to measure SIRT1 and c-FOS |
| Saeed et al. (99) | Animals; B6D2F1 mice (female, n = not reported) | 22 mo total: 14 wk adjustment + 74 wk CR | 40% kcal deficit vs. ad libitum controls | Not reported | IGF-IR%: ↑ vs. controls | — | Immunostaining used to measure IGF-IR and all cells in the PVN | |
| Total PVN cell count: ↓ 13% vs. control | Compared to younger mice (7 wk old), both CR and control mice had lower PVN cells counts, but percentage of IGF-IR immunoreactive cells was not significantly different from the young mice and CR mice. Control mice has significantly less than both | |||||||
| Radler et al. (60) | Animals; C57BL/6J mice (male, n = 15–16) | 4 wk | 50% kcal deficit vs. ad libitum controls | Not reported | NPY: no difference | — | Immunostaining used to measure NPY present in tissue samples | |
| Kenny et al. (100) | Animals; Wistar rats (male, n = 36) | 3 wk | 25% kcal deficit vs. ad libitum control | ↓ vs. control | — | Fos-positive cells: increased with with stress, but not significantly different than controls | Neuronal activation measured by positive Fos immunoreactivity | |
| Significantly higher basal corticosterone levels but exhibited less grooming during open field tests | ||||||||
| LHA | Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | Ox2r: ↑ number of Ox2r-positive cells and total signal | c-FOS: ↑ expression at 14 d and 104 d; ↑ 43% expression (14 d CR) in BRASTO mice | Immunostaining used to measure SIRT1 and c-FOS. Used in situ hybridization to measure mRNA levels for gene expression |
| SIRT1: ↑ at 14 d and 104 d | Peripheral ghrelin injection increased c-FOS-positive cells over 2 h | |||||||
| Valenzano et al. (114) | Human – 10 W, 10 M; BMI 32.19 ± 4.78 kg/m2; age: 48 ± 10 y | 8 wk | 700–900 kcal/d (ketogenic VLCD) | ↓ 12.6 kg weight loss | Plasma orexin-A: ↓ 6.33 pg/mL from baseline | — | Plasma orexin-A concentrations measured by ELISA. Blood samples were taken before and after intervention after a 12-h fast | |
| Pankevich et al. (115) | Animals; C57BL/6J mice (male, n = 37–47) | 3 wk | 25% kcal deficit vs. ad libitum control, then fed HFD for 1 wk | ↓ 4.6 g vs. control | Mch: ↑ in CR mice after HFD refeeding | — | Measured mRNA levels for gene expression (qPCR for transcription factors) | |
| Hcrt (orexin): ↑ in CR mice after HFD refeeding | Leptin was significantly lower and basal corticosterone was higher than control | |||||||
| SCN | Satoh et al. (62) | Animals; C57BL/6 mice and BRASTO (male, n = 2–6) | 14 d (short-term CR); 104 d (long-term CR) | 40% kcal deficit vs. ad libitum control | Not reported | SIRT1: ↑ at 14 d and 104 d | c-FOS: no difference | Immunostaining used to measure SIRT1 and c-FOS |
| Mesocorticolimbicsystem | ||||||||
| NAc | Diao et al. (143) | Animal; Fischer-344 rats (female, n = 5–7) | 4 mo | 40% kcal deficit vs. ad libitum control | Not reported | — | DA overflow: ↑ amount and duration in response/DA clearance | In vivo electrochemistry used to determine potassium-evoked dopamine overflow from the dorsal striatum across the ventral striatum/nucleus accumbens |
| Kolta et al. (144) | Animal; Fischer-344 rats (male and female, n = 5–10) | 18.75 mo | 40% kcal deficit vs. ad libitum controls | ↓ 46–48% vs. control | [DA] and [DOPAC]: not significantly different than control | — | Neurotransmitter assays using HPLC were used to determine concentration of monoamines and metabolites | |
| [5-HT] and [5-HIAA]: ↓ 37% and 55% than control in female rats only | ||||||||
| Maswood et al. (145) | Animal; rhesus monkeys (male, n = 6–7) | 6 mo | 30% kcal deficit vs. ad libitum control | ↓ 12% vs. control | [DA], [DOPAC], [HVA]: ↑ than control after injection of a Parkinson's-inducing neurotoxin | — | HPLC was used to determine concentrations of DA and metabolites in the striatal regions of the brain | |
| Similar doses of the neurotoxin given to both groups, causes selective degeneration of DA neurons | ||||||||
| Vialou et al. (146) | Animal; C57BL6/J background mice (n = 7) | 10 d | 40% kcal deficit (then 2 d ad libitum to return to baseline body weight) vs. ad libitum controls | ↓ 15–20% from baseline, then not different from control after 2 d ad libitum feeding | ΔFosB + cells in NAc shell: ↑ vs. control | — | Immunostaining methods used to count cells containing ΔFosB in the NAc | |
| ΔFosB + cells in NAc core: no difference | CR group had significantly high rewards earned than control using operant response tests using a high-fat pellet reward | |||||||
| VTA | Roseberry (151) | Animals: adult male C57BL/6J mice | 1 d | Acute 24-h fast vs. ad libitum fed | Not reported | None | ↑ Dopamine receptor (D2R) activity following fasting compared to fed | DA neuron in the VTA were recorded by electrophysiology |
| ↓ Release of low-calcium aCSF following fasting compared to fed | Forskolin was given to compare second messenger systems involved in dopamine release | |||||||
| ↓ Response to forskolin following fasting compared to fed | ||||||||
| No difference in response to l-DOPA between groups | ||||||||
| Maswood et al. (145) | Animal; rhesus monkeys (male, n = 6–7) | 6 mo | 30% kcal deficit vs. ad libitum control | ↓ 12% vs. control | TH-positive cells: ↑ 15% in VTA/SN vs. control after injection of a Parkinson's-inducing neurotoxin | — | PET scans and immunostaining used to measure DA neurons in VTA/SN | |
| Similar doses of the neurotoxin given to both groups, causes selective degeneration of DA neurons | ||||||||
| PfC | Siep et al. (157) | Human; 12 W; BMI 21.5 ± 1.9 kg/m2; age: 19.3 ± 0.9 y | 1 d | 18-h food deprivation vs. satiated | Not reported | — | Medial PfC: ↓ inhibition activity after presentation of high caloric foods | fMRI used to measure BOLD signal change in various regions of interest in the brain |
| Willette et al. (158) | Animal; rhesus monkeys (n = 18–26) | 13–16 y | 30% kcal deficit vs. ad libitum control | Not reported | — | Association between stress reactivity and PfC volume/tissue density was ↓ in CR group than control | MRI used to measure changes in volume and tissue density. Urinary cortisol was also measured | |
| Amg | Siep et al. (157) | Human; 12 W; BMI 21.5 ± 1.9 kg/m2; age: 19.3 ± 0.9 y | 1 d | 18-h food deprivation vs. satiated | Not reported | — | Left Amg: no difference between conditions with shown high- and low-calorie foods | fMRI used to measure BOLD signal change in various regions of interest in the brain |
| Willette et al. (158) | Animal; rhesus monkeys (n = 18–26) | 13–16 y | 30% kcal deficit vs. ad libitum control | Not reported | — | Association between stress reactivity and Amg volume/tissue density was ↓ in CR group compared with control | MRI used to measure changes in volume and tissue density. Urinary cortisol was also measured | |
| Zséli et al. (161) | Animal; Wistar rats (male, n = 24) | 2 d | 40-h food deprivation followed by ad libitum refeeding | Not reported | — | ↑ c-Fos from other regions to Amg: PVT and PBN | Immunocytochemistry used to map the location of refeeding-activated neurons projecting to the central Amg. C-Fos immunoreactivity for neuron activity | |
| Dorsal vagal complex | ||||||||
| NTS | Zséli G et al. (161) | Animal; Wistar rats (male, n = 24) | 2 d | 40-h food deprivation followed by ad libitum refeeding | Not reported | — | ↑ c-Fos from Amg to other regions: BNST, LHA, PVT, and NTS | Immunocytochemistry used to map the location of refeeding-activated neurons projecting to the central Amg. C-Fos immunoreactivity for neuron activity |
1
aCSF, artifical cerebrospinal fluid; Agrp, agouti-related peptide; Amg, amygdala; ARC, arcuate nucleus of the hypothalamus; BNST, bed nuclei of stria terminalis; BOLD, blood oxygenation level dependent; BRASTO, transgenic mice that overexpress SIRT1; CR, calorie restriction; DA, dopamine; DMH, dorsomedial hypothalamic nucleus; DOPAC, 3,4-dihydroxyphenylacetic acid (metabolite of dopamine); GABA, γ-aminobutyric acid; Gad1, glutamate decarboxylase 1; GHSR1a, growth hormone secretagogue receptor 1a; Hcrt, hypocretin/orexin; HFD, high-fat diet; HVA, homovanillic acid (metabolite of dopamine); IGF-I, insulin-like growth factor I; IGF-IR, insulin-like growth factor 1 receptor; l-DOPA, l-3,4-dihydroxyphenylalanine; LHA, lateral hypothalamic area; M, men; Mch, melanin-concentrating hormone; NAc, nucleus accumbens; Npy, neuropeptide Y; NTS, nucleus tractus solitarius; ObRb, leptin receptor (long isoform); OxR2, orexin receptor 2; PET, positron emission tomography; PfC, prefrontal cortex; Pomc, proopiomelanocortin; PVN, paraventricular nucleus of the hypothalamus; PVT, paraventricular thalamus; ref, reference; SIRT1, sirtuin-1; TH, tyrosine hydroxylase; VLCD, very low-calorie diet; VMH, ventromedial hypothalamic nucleus; VTA/SN, ventral tegmental area/substantia nigra; W, women; 5-HIAA, 5-hydroxyindoleacetic acid (metabolite of serotonin); 5-HT, serotonin; ↓, significant decrease; ↑, significant increase.