EGCG ameliorates diet-induced metabolic syndrome associating with the circadian clock

Abstract

In response to the daily light-dark (LD) cycle, organisms on Earth have evolved with the approximately 24-h endogenous oscillations to coordinate behavioral and physiological processes, including feeding, sleep, and metabolism homeostasis. Circadian desynchrony triggered by an energy-dense diet rich in fats and fructose is intimately connected with a series of metabolic disorders. Previous studies revealed that (-)-Epigallocatechin-3-gallate (EGCG) could mitigate metabolic misalignment; however, only a few reports have focused on its potential effect on directly manipulating circadian rhythms to ameliorate metabolic syndrome. Our goal was to investigate the regulating effect of EGCG treatment on metabolic misalignment triggered by a high-fat and high-fructose diet (HFFD) associating with the circadian clock. Our results indicated that HFFD treatment partially exhibited poor circadian oscillations of the core clock gene and the clock-controlled gene in the liver and fat relative to the control group. EGCG administration may ameliorate the diet-dependent decline in circadian function by controlling the Sirt1-PGC1αloop, implying the existence of an EGCG-entrainable oscillator. Subsequently, reducing fatty acid synthesis and elevating β-oxidation in the liver coupled with the increasing brown adipose tissue (BAT) energy expenditure observed in the EGCG group of mice prevented the adipocyte hypertrophy and fat accumulations common to BAT and white adipose tissue (WAT) derived from the HFFD mice. This study is the first to provide compelling evidences that EGCG may ameliorate diet-induced metabolic misalignment by regulating the rhythmic expression of the circadian clock genes in the liver and fat.

(‐)‐Epigallocatechin‐3‐gallate Ameliorates Insulin Resistance and Mitochondrial Dysfunction in HepG2 Cells: Involvement of Bmal1

“…A recent research exhibited that supplementary of EGCG altered diurnally oscillating expression pattern of key appetite‐regulating genes as well as key circadian genes like Clock and Bmal1 in hypothalamus of mice . Furthermore, our previous studies have revealed that EGCG, the most abundant catechin in green tea, may ameliorate HFFD‐induced obesity and metabolic disorders via circadian clock related mechanisms . As a continuous study to further explore the causal relationship and mechanism between the circadian clock and insulin resistance upon EGCG treatment, 50 μM EGCG was used to investigate the mechanism of EGCG against insulin resistance and results showed that EGCG co‐treatment resulted in an improvement in diurnal rhythm of the circadian clock gene under insulin‐resistance conditions (Figures and A).…”

“…The concentration of EGCG (50 μM) in the circulation after dietary intake is so difficult to attain. Fortunately, our previous study revealed that 2 g/L EGCG for 16 weeks in C57BL/6J mice exerted pleiotropic beneficial effects on obesity, circadian desynchrony, and insulin resistance . Based on allometric scaling, the used dose of 2 g/L EGCG in drinking water in mice approximate corresponds to 9 cups of green tea (containing 2 g tea leaves per cup) per day for an average person requiring 2000 kcal/day, which may represent an attainable dose .…”

“…revealed that EGCG improves insulin resistance in high‐fat diet treated mice not only by reducing body weight but also through enhancing the insulin clearance by hepatic insulin‐degrading enzyme in a dose‐dependent manner . Additionally, we have recently reported that EGCG eliminates the HFFD‐induced circadian desynchrony and metabolic misalignment in the C57BL/6 mice . Therefore, the aforementioned evidence indicated that EGCG may improve health by entraining biological rhythms.…”

“…Total RNA was extracted from cells using an RNA extraction kit (TaKaRa, MiniBEST Universal RNA Extraction Kit, Dalian, China) as previously described . For quality control, the RNA purity and integrity were evaluated using the Quawell 5000 UV‐Vis Spectrophotometer (Quawell Technology, San Jose, CA, USA).…”

“…Obesity, a major health issue worldwide, is caused by the energy imbalance between caloric intake and consumption, mostly, the high dietary intake of fats and sugars . Growing evidence has revealed that obesity is correlated with a wide spectrum of metabolic syndrome including insulin resistance, dyslipidemia, cardiovascular disease, and hypertension .…”