"Science": Not eating late-night snacks is the essence of weight loss! Scientists have cracked the mystery of eating according to circadian rhythms and are not easy to get fat

*For medical professionals only

Not long ago, singularity cake introduced to you, the study of limiting eating time to 7-15 o'clock to limit eating and weight loss effect has received a lot of messages, and everyone has introduced their own experience and experience, so, are there any friends curious, why? The same calories, eating earlier can you have less meat? Where is the scientific basis?

Today, Science magazine gives us the answer
.
The research team at Northwestern University's Feinberg School of Medicine found that according to the circadian rhythm, time-restricted eating during the "active period" of the day can inhibit weight gain by enhancing thermogenesis, and the enhancement of thermogenesis is achieved through the circadian rhythm of fat cells and the ineffective creatine cycle [1].

Previous studies have found that mice that eat a high-fat diet during the inactive period (daytime) (mice are nocturnal animals, as opposed to humans during the active period) gain significantly more weight than those who eat a high-fat diet during the active period (night) over a one-week period [2].

In order to understand the effect of eating time on weight gain, the researchers arranged the mice into a constant temperature room of 30 ° C, which is the temperature at which the mice consume the least energy when maintaining body temperature, which can be maintained independently of body temperature and better reflect the "contribution"
of the thermogenic effect of diet to energy balance.

The mice were divided into 3 groups, one group ate at random for unlimited time, one group ate during the day (inactive period, ZT0-12 time period), and one group ate at night (active period, ZT12-24 time period), and the high-fat diet
was uniformly provided when eating.
About 30% of the food of the mice that eat randomly is eaten during the day (even mice can't help but eat "late" snacks?).
After a week, although all three groups of mice had weight gain, the night feeding group had much
less.

Weight gain in mice that eat ad libitum (black), eat during the day (red), and eat at night (blue).

Although the activity rhythms were similar, mice that ate during the day had lower oxygen consumption at night than mice that ate at night, and energy expenditure analysis with body weight as a covariate showed that mice that ate at night consumed more
energy than mice that ate during the day.
This is consistent with other studies that have found that mice that eat at night have increased thermogenesis compared to those that eat during the day [3].

Together, these results suggest that the weight gain from eating during periods of inactivity is partly due to reduced
energy expenditure.

This conclusion also prompted the researchers to compare the metabolism of adipose tissue in the two groups of mice, and they found that in the white adipose tissue (iWAT) and brown adipose tissue (BAT) of the groin eating mice at night, the conversion of pyruvate and lactic acid from glucose increased, indicating enhanced
glycolysis.

They also analyzed the RNA expression peaks and troughs of circadian genes in iWAT and BAT, and found that only mice that ate at night had the highest amplitude of core rhythm gene expression, and mice that ate casually and during the day decreased, and the expression of uncoupling protein 1 (UCP1) in iWAT and BAT in day-eating mice decreased, which indicated that the disturbance of circadian rhythm and thermogenic rhythm of adipocytes may be the basic cause
of metabolic problems in mice that eat during the day.

The antipyregenic transcription factor ZFP423 inhibits thermogenic transcription processes, including the UCP1 adrenergic activation pathway
.
The researchers constructed mice with specific deletion of ZFP423 (Zfp423-KO) in adipocytes, and let them eat time-limited, beige adipocytes in the mouse WAT accumulated widely and activated thermogenesis, compared with the control group (non-Zfp423-KO), the same daytime eating, Zfp423-KO mice had reduced weight gain and improved
glucose tolerance.

Changes in body weight (B) and glucose tolerance (C) in the control group and Zfp423-KO mice

The main thermogenic mechanisms of adipocytes include proton leakage via UCP1, creatine-substrate cycling, calcium-dependent ATP hydrolysis, and lipid cycling
.
In order to understand what are the metabolic mechanisms of enhanced thermogenesis in Zfp423-KO mice, the researchers performed bioenergetic and metabolomic analysis on adipocytes and found that glycolysis was enhanced and β3-adrenergic receptors were activated
in Zfp423-KO adipocytes.

In Zfp423-KO adipocytes, 29 metabolites were differentiated and enriched, including an increase in creatine, pyruvate, and lactic acid, and a decrease
in phosphocreatine and ATP.
Increased creatine synthesis, input, and circulation provide "fuel" for an ineffective cycle of mitochondrial ATP conversion in thermogenic cells (also known as the substrate cycle, where hydrolysis ATP converts chemical energy into thermal energy) [4], and significantly increased levels of creatine kinase B (CKB), the main kinase isoenzyme
of the ineffective creatine cycle in fat thermogenesis.

In addition, the phosphocreatine/creatine ratio was significantly reduced, reflecting the adrenergic response
to norepinephrine-stimulated (NE).

Phosphocreatine/creatine ratio between control group and Zfp423-KO mice

Taken together, the deletion of Zfp423 promotes adipocyte thermogenesis
by increasing uncoupled respiration, norepinephrine-stimulated respiration, glucose flux into glycolysis, and creatine cycle.

The increase in CKB and ineffective creatine circulation in Zfp423-KO adipocytes led the researchers to speculate that thermogenesis achieved through creatine conversion may be a health-improving metabolic mechanism
during the active period.
To test this hypothesis, the researchers constructed mice with adipocyte-specific deletion of glycinamimididase (GATM) that had reduced creatine synthesis genes in
adipocytes.

Consistent with the researchers' expectations, the mice had similar weight gain whether they ate during the day or at night, and did not differ
from the non-missing mice that ate during the day.

Changes in body weight (B), body composition (C), and food intake (D) in the control group and Gatm-KO mice

Adipocyte rhythms may affect the activation of bioenergetic transcription factors or CLOCK-BMAL1-dependent activation of creatine metabolism, and in adipocytes lacking the core rhythm activator BMAL1, the expression of creatine metabolism genes and creatine levels are significantly reduced, and the phosphocreatine/creatine ratio is increased
.

The adenosine methionine transferase 2A gene (Mat2a) plays an important role in creatine metabolism, and the researchers found the binding site of BMAL1 on its promoter, and the expression of the Mat2a gene is reduced in fat cells that lack Bmal1, so it may mediate the regulation
of creatine synthesis by BMAL1.

Overall, this study suggests that time-restricted feeding during active periods of the day can inhibit weight gain by enhancing thermogenesis, which is achieved through circadian rhythms of fat cells and the ineffective creatine cycle
.

Researchers say that time-restricted eating is a promising way to lose weight and improve metabolic health with few side effects, and a deeper understanding of the mechanisms behind time-restricted eating may help us expand the benefits of time-restricted eating [5]
.

References:

[1] style="white-space: normal;margin: 0px;padding: 0px;box-sizing: border-box;">[2] Arble D M, Bass J, Laposky A D, et al.
Circadian timing of food intake contributes to weight gain[J].
Obesity, 2009, 17(11): 2100-2102.

[3] Mina A I, LeClair R A, LeClair K B, et al.
CalR: a web-based analysis tool for indirect calorimetry experiments[J].
Cell metabolism, 2018, 28(4): 656-666.
e1.

[4] Chouchani E T, Kazak L, Spiegelman B M.
New advances in adaptive thermogenesis: UCP1 and beyond[J].
Cell metabolism, 2019, 29(1): 27-37.

[5] style="margin-bottom: 0em;outline: 0px;max-width: 100%;box-sizing: border-box;color: rgb(34, 34, 34);white-space: normal;font-family: -apple-system, BlinkMacSystemFont, "Helvetica Neue", "PingFang SC", "Hiragino Sans GB", "Microsoft YaHei UI", "Microsoft YaHei", Arial, sans-serif;font-size: 16px;background-color: rgb(255, 255, 255);text-align: center;overflow-wrap: break-word !important;">

The author of this article Ying Yuyan