Restricted feeding modulates peripheral clocks and nutrient sensing pathways in rats

The suprachiasmatic nucleus is the master circadian clock and resets the peripheral clocks via various pathways. Glucocorticoids and daily feeding are major time cues for entraining most peripheral clocks. However, recent studies have suggested that the dominant timing factor differs among organs and tissues. In our current study, we reveal differences in the entrainment properties of the peripheral clocks in the liver, kidney, and lung through restricted feeding (RF) and antiphasic corticosterone (CORT) injections in adrenalectomized rats. The peripheral clocks in the kidney and lung were found to be entrained by a daily stimulus from CORT administration, irrespective of the meal time. In contrast, the liver clock was observed to be entrained by an RF regimen, even if daily CORT injections were given at antiphase. These results indicate that glucocorticoids are a strong zeitgeber that overcomes other entrainment factors regulating the peripheral oscillators in the kidney and lung and that RF is a dominant mediator of the entrainment ability of the circadian clock in the liver.

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The Role of Inositol Phosphate Multikinase (IPMK) in Time Restricted Feeding in Animal Model

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.666 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A326-A327

Author(s):

Ik-Rak Jung ◽

Becky Tu-Sekine ◽

Frederick Anokye-Danso ◽

Rexford S Ahima ◽

Sangwon Kim

Keyword(s):

Circadian Rhythm ◽

Inositol Phosphate ◽

Hepatic Glucose Production ◽

Public Health Problem ◽

Glucose Production ◽

Hepatic Metabolism ◽

Nutrient Sensing ◽

Major Public Health Problem ◽

Restricted Feeding ◽

Beneficial Effects

Abstract Obesity is a major public health problem of the U.S. and is associated with diabetes, cardiovascular diseases and other diseases. Most research studies focus on excessive food consumption as the main cause of obesity. However, emerging data indicate that the timing of feeding can have significant effects on body weight and metabolism. Numerous studies in animals and small clinical studies in humans have shown that eating erratically over the 24 hour period or out of phase with the circadian rhythm predisposes toward weight gain, steatosis, dyslipidemia, insulin resistance and diabetes. Furthermore, studies indicate that restricting food intake to the active period synchronizes the circadian rhythm and metabolism, enhances weight loss and improves metabolic outcomes. Time restricted feeding (TRF) increases the amplitudes of clock gene expression and pathways mediating nutrient sensing and hepatic metabolism. However, the mechanisms mediating the effects of TRF are not fully understood. Here we characterized mice (10 week-old) fed a high-fat diet ad libitum (ALF) or from 7 pm to 7 am (TRF) for 2 weeks. The basal glucose production rate was similar between the two groups. Under hyperinsulinemic-euglycemic clamp, the glucose infusion rate (GIR) was significantly greater in TRF group compared to ALF group indicating an increase in insulin sensitivity. Using radioisotopic tracers, we demonstrated that the hepatic glucose production (HGP) was significantly reduced and the glucose disappearance rate was increased in TRF group compared to ALF group. Moreover, a biochemical analyses of liver tissues revealed that Inositol phosphate multikinase (IPMK) act as a key enzyme for inositol polyphosphate biosynthesis and play a role in insulin-, nutrient-, and energy-mediated metabolic signaling, was increased during TRF. Moreover, deletion of IPMK in hepatocytes decreased insulin stimulated AKT phosphorylation while increased lipid accumulation and gluconeogenesis. Importantly, hepatic deletion of IPMK attenuated the beneficial effects of TRF suggesting that IPMK in the liver may contributes to beneficial effects of TRF. Our findings provide the potential mechanism by which TRF confers the beneficial effects and may provide a novel therapeutic strategy for treating diabetes.

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Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant

eLife ◽

10.7554/elife.04617 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 71

Author(s):

Mariko Izumo ◽

Martina Pejchal ◽

Andrew C Schook ◽

Ryan P Lange ◽

Jacqueline A Walisser ◽

...

Keyword(s):

Knockout Mice ◽

Temporal Order ◽

Constant Darkness ◽

Restricted Feeding ◽

Peripheral Tissues ◽

Liver And Kidney ◽

Circadian Organization ◽

Peripheral Clocks ◽

Central Clock ◽

Circadian Behavior

In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks, and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain.

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Functional CLOCK is not involved in the entrainment of peripheral clocks to the restricted feeding: entrainable expression of mPer2 and BMAL1 mRNAs in the heart of Clock mutant mice on Jcl:ICR background

Biochemical and Biophysical Research Communications ◽

10.1016/s0006-291x(02)02427-0 ◽

2002 ◽

Vol 298 (2) ◽

pp. 198-202 ◽

Cited By ~ 75

Author(s):

Katsutaka Oishi ◽

Koyomi Miyazaki ◽

Norio Ishida

Keyword(s):

Mutant Mice ◽

Restricted Feeding ◽

Clock Mutant ◽

Peripheral Clocks

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Time-restricted feeding prolongs lifespan in Drosophila in a peripheral clock-dependent manner

10.1101/2020.09.14.296368 ◽

2020 ◽

Author(s):

Daniel Cabrera ◽

Michael W. Young ◽

Sofia Axelrod

Keyword(s):

Food Intake ◽

Dietary Intervention ◽

Time Window ◽

Model Organism ◽

Model Organisms ◽

Dependent Manner ◽

Restricted Feeding ◽

Positive Effects ◽

Peripheral Clocks ◽

Positive Effect

AbstractTime-restricted feeding/eating (TRF/TRE) – limiting not the amount of food but the daily time window of food intake – is a dietary intervention that has been shown to improve health markers in model organisms and humans, but whether these benefits translate into positive effects on aging and longevity is not clear. We demonstrate here that TRF robustly prolongs lifespan in the short-lived genetically tractable model organism Drosophila melanogaster. Median TRF lifespan extensions range between ∼10% and ∼50% dependent on sex, reproductive status, TRF duration, and genotype. TRF’s positive effect on longevity is independent of food intake and at least in part relies on a functioning circadian clock: TRF benefits on longevity are abolished in arrhythmic per0 and tim01 mutants as well as in constant light, suggesting that timed feeding acts as a zeitgeber partitioning eating and associated metabolic processes into certain phases of day and night. TRF-mediated longevity extension is unaffected in flies whose neural circadian clocks have been abolished genetically, pointing towards peripheral clocks as the target of TRF mediating lifespan extension.

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