Hypothalamic leptin sensitivity and health benefits of time‐restricted feeding are dependent on the time of day in male mice

Abstract Objectives Food intake and exercise are considered modulators of the immune system. Specifically, intermittent fasting protocols have been demonstrated to reduce inflammation and alter cytokine responses. The objective of the current study was to determine if a form of intermittent fasting known as time-restricted feeding (TRF) would alter immune parameters in response to exercise. Methods 8-week-old C57BL/6 male mice were divided into three groups based on feeding schedule; group one had access to food ad libitum (Control) and groups two and three had access to food in a time restricted manner. Access was allowed for six hours per day either immediately after running (TRF-imm) or six hours after running (TRF-del). Mice ran on a treadmill for 1 hour, 5 days per week for eight weeks. Diet consisted of 21% protein, 16% fat and 64% carbohydrate. Weight, glucose and ketone levels, and immune populations were analyzed. Systemic IL-6 and TNF-α levels were measured before and after running. In a subpopulation, cytokine response to lipopolysaccharides (LPS) was also monitored. Results All mice gained weight during the eight-week intervention, but TRF-imm gained significantly less weight than Control (P = 0.02). No differences were detected in glucose levels. The ketone body β-hydroxybutyrate (BHB) was significantly higher at week eight in TRF groups (P ≤ 0.03) but running induced BHB in all groups to approximately 1 mM. Running reduced the blood lymphocytes levels (P < 0.05), with a concomitant increase of granulocytes (P < 0.05) in all groups. There was a small increase in monocytes only in the Control group (P = 0.017). No differences were detected in splenic immune populations, including CD4 and CD8 T cells, and CD11b + cells. Both IL-6 and TNF-α levels were low in all groups before exercise; however, post exercise IL-6 was increased, but not to the same extend in all groups. The IL-6 response was blunted in the TRF groups. The reduced levels of IL-6 was not due to loss of immune function, as both IL-6 and TNF-α were readily induced by exposure of mice to LPS. Conclusions Time-restricted feeding protocols did not induce differences in immune cell composition in blood or spleen but resulted in attenuated exercise-induced IL-6 levels. Funding Sources University of Memphis, School of Health Studies.

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High‐Fat and High‐Sucrose Diets Impair Time‐of‐Day Differences in Spatial Working Memory of Male Mice

Obesity ◽

10.1002/oby.22983 ◽

2020 ◽

Vol 28 (12) ◽

pp. 2347-2356

Author(s):

Jennifer A. Davis ◽

Jodi R. Paul ◽

Laura J. McMeekin ◽

Shelly R. Nason ◽

Jessica P. Antipenko ◽

...

Keyword(s):

Working Memory ◽

Spatial Working Memory ◽

Time Of Day ◽

Male Mice ◽

High Fat ◽

High Sucrose

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17α-Estradiol Modulates IGF1 and Hepatic Gene Expression in a Sex-Specific Manner

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa215 ◽

2020 ◽

Author(s):

Silvana Sidhom ◽

Augusto Schneider ◽

Yimin Fang ◽

Samuel McFadden ◽

Justin Darcy ◽

...

Keyword(s):

Growth Hormone ◽

Insulin Sensitivity ◽

Growth Hormone Receptor ◽

Health Benefits ◽

Male Mice ◽

Wild Type ◽

Somatotropic Axis ◽

Gh Secretion ◽

17Β Estradiol ◽

Estradiol 17Β

Abstract Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of the most conserved biological pathways that regulates aging across species. 17α-Estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin sensitivity and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic insulin-like growth factor 1 (IGF1) production in male mice without inducing any changes in pulsatile growth hormone (GH) secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic IGF1 by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on IGF1 production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling IGF1 production from insulin sensitivity. In summary, 17α-E2 treatment upregulates IGF1 production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female IGF1 production are observed following 17α-E2 treatment.

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CIRCADIAN VARIATION IN CONCENTRATIONS OF TESTOSTERONE IN THE PLASMA OF MALE MICE: A DIFFERENCE BETWEEN BALB/cBy AND C57BL/6By INBRED STRAINS

Journal of Endocrinology ◽

10.1677/joe.0.0870037 ◽

1980 ◽

Vol 87 (1) ◽

pp. 37-46 ◽

Cited By ~ 19

Author(s):

LINDA A. LUCAS ◽

B. E. ELEFTHERIOU

Keyword(s):

Strain Difference ◽

Circadian Variation ◽

Inbred Strains ◽

Time Of Day ◽

High Mode ◽

Blood Levels ◽

Male Mice ◽

Inbred Strains Of Mice ◽

Tissue Responses ◽

Chi Squared

Diurnal variations in testosterone in plasma were studied in two inbred strains of mice, BALB/cBy and C57BL/6By. Blood was taken every 4 h over 24 h from male mice at 70 days of age using a lighting regimen of 12 h light to 12 h darkness (lights on 07.00–19.00 h). Values of testosterone in plasma were transformed to log(testosterone in ng/ml) to reduce inequality of variance between groups. In both strains, the distribution of pooled values over all times of day was bimodal, and bimodality was present at most times of day. Circadian variation was evaluated by dividing the transformed values into high and low modes at each time of day and testing for significant variation in the number of animals in each mode over time using the chi-squared test. Significant circadian variation was found in the BALB/cBy strain of mice but not in the C57BL/6By strain. The highest number of high mode cases for BALB/cBy mice was at 22.00 h and the lowest number of high mode cases was at 10.00 h. The log transformation and bimodality of these values are presented as biological expressions of blood levels of testosterone and of tissue responses to these levels in the male mouse. The strain difference in circadian variation may be related to reported circadian changes in behaviour and to possible genetic effects on sensitivity to environmental change or capacity to express circadian rhythms.

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Critical role of food amount for prefeeding corticosterone peak in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1983.245.3.r339 ◽

1983 ◽

Vol 245 (3) ◽

pp. R339-R344 ◽

Cited By ~ 12

Author(s):

K. I. Honma ◽

S. Honma ◽

T. Hiroshige

Keyword(s):

Food Intake ◽

Food Deprivation ◽

Hormone Level ◽

Critical Role ◽

Fixed Time ◽

Plasma Corticosterone ◽

Time Of Day ◽

Restricted Feeding ◽

Ad Libitum ◽

Ad Libitum Feeding

The effects of food on plasma corticosterone levels were examined in rats under restricted daily feeding or prolonged food deprivation. High hormone levels before feeding were observed when the daily meal was restricted to 2 h at a fixed time of day, but it was not detected when food availability was extended to 6 h. The amount of food intake under the latter condition was comparable to that in 24 h of ad libitum feeding. After the termination of restricted feeding, the prefeeding hormone peak was maintained in rats fasted subsequently but disappeared when rats were returned to ad libitum feeding. Food deprivation for 10 days increased plasma corticosterone levels in the light period, resulting in abolition of the circadian rhythm. A subsequent meal decreased the hormone level such that the 24-h mean hormone level after food ingestion was inversely related to the amount of food intake. When rats were allowed to feed for 6 h after prolonged food deprivation, the prefeeding hormone peak observed at the second meal disappeared at the fourth meal. The amount of food consumption in these rats increased and reached a level comparable to that with ad libitum feeding at the third meal. It is concluded that the amount of food intake is critical for the development and maintenance of the prefeeding hormone peak under restricted feeding; prolonged fasting.

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Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00341.2014 ◽

2014 ◽

Vol 307 (12) ◽

pp. H1777-H1785 ◽

Cited By ~ 4

Author(s):

Elizabeth A. Schroder ◽

Don E. Burgess ◽

Cody L. Manning ◽

Yihua Zhao ◽

Arthur J. Moss ◽

...

Keyword(s):

Heart Rate ◽

Long Qt Syndrome ◽

Time Of Day ◽

Restricted Feeding ◽

Light Phase ◽

Long Qt ◽

Qt Intervals ◽

Qt Syndrome ◽

Time Of Feeding ◽

Type 3

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice ( Scn5a+/ΔKPQ). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a+/ΔKPQ mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a+/ΔKPQ mice, light phase-restricted feeding shifted the RR and QT rhythms ∼12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ∼10%. In contrast to WT mice, the QTc interval in Scn5a+/ΔKPQ mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a+/ΔKPQ mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.

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Brown adipose tissue of mice with GTG-induced obesity: altered circadian control

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1989.256.6.e773 ◽

1989 ◽

Vol 256 (6) ◽

pp. E773-E779 ◽

Cited By ~ 2

Author(s):

J. Eley ◽

J. Himms-Hagen

Keyword(s):

Adipose Tissue ◽

Circadian Rhythm ◽

Brown Adipose Tissue ◽

Time Of Day ◽

Cafeteria Diet ◽

Obese Mouse ◽

Restricted Feeding ◽

Obese Mice ◽

Brown Adipose ◽

Stimulation Of

The effect of feeding a "cafeteria" diet and of feeding a restricted amount of chow on brown adipose tissue (BAT) of lean and gold thioglucose (GTG)-obese mice was studied at various times of the day and night. Objectives were to find out 1) whether our previous finding of diet-induced growth of BAT of the GTG-obese mouse without thermogenic activation could be explained by a transient stimulation at a time of day not studied and 2) whether lack of stimulation of BAT thyroxine 5'-deiodinase (TD) by diet seen previously in lean mice and rats could be explained by a transient increase at times of day not studied. A transient activation of BAT thermogenesis, indicated by an increase in mitochondrial GDP binding, occurs immediately after cafeteria food is presented to the GTG-obese mouse, but the effect of diet is absent at other times. This transient stimulation of BAT in the GTG-obese mouse may be sufficient to produce the tissue growth observed. A circadian rhythm in GDP binding occurred in both lean and obese mice, whether they were eating chow or the cafeteria diet. Restricted feeding suppressed BAT mitochondrial GDP binding in lean mice but did not suppress any further the low level in GTG-obese mice. A circadian rhythm in TD activity in BAT also occurred in lean and obese mice, but no effect of cafeteria diet or of restricted feeding on this enzyme was detected at any time of day, except for a brief increase in obese mice at 0500.(ABSTRACT TRUNCATED AT 250 WORDS)

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Daytime Restricted Feeding Affects Day–Night Variations in Mouse Cerebellar Proteome

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.613161 ◽

2021 ◽

Vol 14 ◽

Author(s):

Fabrice Bertile ◽

Marine Plumel ◽

Pauline Maes ◽

Aurélie Hirschler ◽

Etienne Challet

Keyword(s):

Food Access ◽

Large Scale ◽

Time Of Day ◽

Feeding Time ◽

Restricted Feeding ◽

Experimental Conditions ◽

Guanine Nucleotide Binding Protein ◽

Zebrin Ii ◽

Guanine Nucleotide Binding ◽

Sensor Proteins

The cerebellum harbors a circadian clock that can be shifted by scheduled mealtime and participates in behavioral anticipation of food access. Large-scale two-dimensional difference gel electrophoresis (2D-DIGE) combined with mass spectrometry was used to identify day–night variations in the cerebellar proteome of mice fed either during daytime or nighttime. Experimental conditions led to modified expression of 89 cerebellar proteins contained in 63 protein spots. Five and 33 spots were changed respectively by time-of-day or feeding conditions. Strikingly, several proteins of the heat-shock protein family (i.e., Hsp90aa1, 90ab1, 90b1, and Hspa2, 4, 5, 8, 9) were down-regulated in the cerebellum of daytime food-restricted mice. This was also the case for brain fatty acid protein (Fabp7) and enzymes involved in oxidative phosphorylation (Ndufs1) or folate metabolism (Aldh1l1). In contrast, aldolase C (Aldoc or zebrin II) and pyruvate carboxylase (Pc), two enzymes involved in carbohydrate metabolism, and vesicle-fusing ATPase (Nsf) were up-regulated during daytime restricted feeding, possibly reflecting increased neuronal activity. Significant feeding × time-of-day interactions were found for changes in the intensity of 20 spots. Guanine nucleotide-binding protein G(o) subunit alpha (Gnao1) was more expressed in the cerebellum before food access. Neuronal calcium-sensor proteins [i.e., parvalbumin (Pvalb) and visinin-like protein 1 (Vsnl1)] were inversely regulated in daytime food-restricted mice, compared to control mice fed at night. Furthermore, expression of three enzymes modulating the circadian clockwork, namely heterogeneous nuclear ribonucleoprotein K (Hnrnpk), serine/threonine-protein phosphatases 1 (Ppp1cc and Ppp1cb subunits) and 5 (Ppp5), was differentially altered by daytime restricted feeding. Besides cerebellar proteins affected only by feeding conditions or daily cues, specific changes in in protein abundance before food access may be related to behavioral anticipation of food access and/or feeding-induced shift of the cerebellar clockwork.

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