Time-restricted eating with or without low-carbohydrate diet reduces visceral fat and improves metabolic syndrome: A randomized trial

Overconsumption of carbohydrate-rich food combined with adverse eating patterns contributes to the increasing incidence of metabolic syndrome (MetS) in China. Therefore, we conducted a randomized trial to determine the effects of a low-carbohydrate diet (LCD), an 8-h time-restricted eating (TRE) schedule, and their combination on body weight and abdominal fat area (i.e., primary outcomes) and cardiometabolic outcomes in participants with MetS. Compared with baseline, all 3-month treatments significantly reduce body weight and subcutaneous fat area, but only TRE and combination treatment reduce visceral fat area (VFA), fasting blood glucose, uric acid (UA), and dyslipidemia. Furthermore, compared with changes of LCD, TRE and combination treatment further decrease body weight and VFA, while only combination treatment yields more benefits on glycemic control, UA, and dyslipidemia. In conclusion, without change of physical activity, an 8-h TRE with or without LCD can serve as an effective treatment for MetS (ClinicalTrials.gov: NCT04475822 ).

Despite being an underdeveloped and less prosperous part of the country, the prevalence of abdominal obesity in the Shaanxi province in Northwestern China is close to the national average of 31.5%,and it can thus be regarded as a representative sample of China. In this region, regular eating habits include carbohydrate-rich staple foods, and an eating pattern of consuming three meals a day with late dinner and multiple snacks including a midnight snack is prevalent. In this study, we conducted a 3-month randomized clinical trial (RCT) to determine the effects of an LCD, TRE, and their combination on body weight, fat mass, and cardiometabolic outcomes in adults with MetS in Shaanxi, China. Furthermore, we allowed participants to choose freely between eTRE and lTRE, to keep their social eating pattern. We hypothesized that TRE effectively improves metabolic disease risk parameters without restricting carbohydrate consumption and that combination of TRE with LCD leads to additional metabolic benefits.

Geographic variation in prevalence of adult obesity in China: results from the 2013-2014 national chronic disease and risk factor surveillance.

Among dietary interventions, low-carbohydrate diet (LCD) seems more ideal to induce weight loss in overweight individuals compared with low-fat diet,as LCD generally exerts more rapid weight reduction with a greater loss in body fat and maintenance of lean mass.LCD restricts carbohydrate consumption to <26% of energy intake (or <130 g carbohydrate/day) and does not contain specific carbohydrates, such as starch and sugar, while containing healthy fats and a moderate protein content.The lower carbohydrate content of LCD is known to reduce insulin secretion, which promotes fat oxidation and lipolysis during negative energy balance.In addition to LCD, time-restricted eating (TRE) has become increasingly popular in recent years for inducing clinically significant weight reduction and ameliorating metabolic disorders.TRE is defined by intentionally restricting the times during the day when energy is consumed, confining the temporal window of food access to a specified number of hours each day, and fasting (water and tea without sugar or any artificial sweeteners are permitted) for the remainder of the day. Importantly, it is not necessary to monitor caloric intake in any way during the eating window. Chronic circadian disruption can aggravate the risk for components of MetS,and TRE maintains a robust daily cycle of eating and fasting to support circadian rhythm.One of the most popular regimens of TRE is 8-h TRE (also known as “the 16:8 diet”). There are specific regimens of TRE according to the timing of the eating window,including early TRE (eTRE) that involves eating earlier in the day and late TRE (lTRE) that skips breakfast. Although both LCD and TRE have been demonstrated to be metabolically beneficial,whether these 8-h TREs could exert a rapid weight reduction effect comparable to that of LCD in adults with MetS has not been assessed yet.

Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes.

The relationship between working schedule patterns and the markers of the metabolic syndrome: comparison of shift workers with day workers.

Health consequences of electric lighting practices in the modern world: a report on the National Toxicology Program's workshop on shift work at night, artificial light at night, and circadian disruption.

Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes.

Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity.

A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes.

Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base.

Dietary carbohydrates: a review of international recommendations and the methods used to derive them.

A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes.

Effects of diet macronutrient composition on body composition and fat distribution during weight maintenance and weight loss.

A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes.

Metabolic syndrome (MetS) is characterized by abdominal obesity, elevated blood pressure, and fasting blood glucose (FBG) as well as atherogenic dyslipidemia with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-c) levels,and it remarkably increases the risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD).MetS has long been highly prevalent in Western countries and has steeply increased in the Chinese population over the past decades as well. Abdominal obesity is of central importance in the induction of metabolic dysfunctions including hypertension, hyperglycemia, atherogenic dyslipidemia, and release of proinflammatory cytokines by adipose tissue. Since 2004, the prevalence of general obesity in China has increased 3-fold, and abdominal obesity has increased by more than 50%; concomitantly, a rapid increase in the incidences of T2DM and CVD was also observed.Since even mild body weight reduction can ameliorate metabolic dysfunction,the first line of therapy for MetS comprises lifestyle interventions including aggressive dietary adjustment to reduce body weight.Nevertheless, long-term adherence to lifestyle intervention is always a challenge.

The CardioMetabolic health alliance: working toward a new care model for the metabolic syndrome.

Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association: national cross sectional study.

Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity.

The CardioMetabolic health alliance: working toward a new care model for the metabolic syndrome.

We also analyzed acceptability and feasibility of the interventions. As shown in Table 2 , participants’ self-reported compliance with their meal-eating window during the 8-h TRE intervention was on average 65.9 ± 3.0 days out of the 3-month intervention period, which was significantly more to adherence to LCD (55.5 ± 3.5 days; p = 0.024). In addition, adherence to eTRE was substantially less (61.4 ± 4.0 days) compared with lTRE (74.9 ± 2.7 days; p = 0.031, Table S6 ). Nonetheless, at the end of our study, 46 out of 47 participants (98%) in the LCD group and 43 out of 44 participants (98%) in the TRE group who completed the intervention period reported to be willing to continue. In contrast, only 36 out of 44 participants (82%) in the combination group reported to be willing to continue with the intervention, which was significantly lower compared with LCD (p = 0.010) and TRE (p = 0.014).

No serious adverse events were observed. Approximately five adverse events were regarded as probably associated with the diet interventions, including constipation, dizziness, insomnia, dry mouth, and alopecia. The occurrence rate of adverse events was not significantly different among the three groups ( Table 3 ). Independent of the diet intervention, two participants reported the exacerbation of lumbar disc herniation and lithangiuria requiring surgery during the 3-month intervention, which caused withdrawal from the trial.

LCD, low-carbohydrate diet; TRE, time-restricted eating; Both, combination treatment. Differences between treatment arms (LCD, TRE, and Both) were tested by Chi-square test.

Although none of the treatments had benefits on systolic blood pressure (SBP) ( Figure 3 I), diastolic blood pressure (DBP) was significantly reduced by combination treatment, but not by LCD and TRE alone ( Figure 3 J) after 3 months of intervention. Compared with changes of each group, no significant difference in DBP was observed among three treatments ( Table 2 ). When combined with LCD, eTRE significantly reduced DBP, whereas lTRE did not ( Table S3 ), albeit that eTRE did not induce a significantly different effect on DBP compared with lTRE. Both SBP and DBP strongly correlated to VFA but not SFA ( Figure S2 D).

TRE with and without LCD, but not LCD alone, reduces diastolic blood pressure

LCD did not cause any significant differences in plasma levels of TG, HDL-c, or the ratio between TG and HDL-c (TG/HDL-c ratio) after 3 months of intervention ( Figures 3 F, 3G, and 3H and Table 2 ). In marked contrast, TRE with and without LCD significantly reduced TG level and TG/HDL-c ratio, and the change in TG and TG/HDL-c ratio was significantly different between LCD and combination treatment (TG: −0.15 [1.20] mmol/L versus −0.51 [2.01] mmol/L, p = 0.011; TG/HDL-c: −0.02 [1.20] versus −0.59 [2.13], p = 0.003). While TRE did not affect low-density lipoprotein cholesterol (LDL-c) levels, LCD with and without TRE even significantly increased LDL-c levels ( Table 2 ). Moreover, we did not find any significant difference between eTRE and lTRE in the improvements of dyslipidemia ( Table S6 ). In line with the prominent contribution of VFA to glycemic control, TG/HDL-c ratio was only significantly correlated with VFA, not SFA ( Figure S2 C). Taken together, while LCD adversely affects LDL-c, TRE improves the lipoprotein profile.

TRE with and without LCD, but not LCD alone, improves dyslipidemia

We next compared the effects of LCD, TRE, and their combination on glycemic control. In line with findings on abdominal VFA, TRE with or without LCD, but not LCD alone, significantly improved FBG and UA ( Figures 3 A and 3B and Table 2 ). Only combination treatment significantly decreased hemoglobin A1c (HbA1c) ( Figure 3 C and Table 2 ). In contrast, compared with baseline, all three treatments clearly improved fasting insulin levels ( Figure 3 D), C-peptide, homeostasis model assessment of insulin resistance (HOMA-IR), homeostatic model assessment of insulin sensitivity (HOMA-IS) ( Figure 3 E), and quantitative insulin-sensitivity check index (QUICKI) ( Table 2 ). Notably, combination treatment caused more prominent changes on UA (combination: −51 ± 13 μmol/L, versus LCD: −17 ± 11 μmol/L, p = 0.039), HOMA-IR (combination: −2.16 [4.82], versus LCD: −1.15 [2.99], p = 0.049), HOMA-IS (combination: 0.10 [0.20], versus LCD: 0.03 [0.12], p = 0.042) and QUICKI (combination: 0.02 [0.03], versus LCD: 0.01 [0.02], p = 0.004) compared with LCD ( Figures 3 B and 3E and Table 2 ), indicating that the combination of LCD and TRE is most effective to combat cardiometabolic risk factors among the three interventions. Furthermore, we did not observe any significant differences in parameters related to glucose and insulin metabolism between eTRE and lTRE, whereas combined with LCD, eTRE displayed a further improvement of HOMA-IS ( Table S6 ). As shown in Figures S2 A and S2B, HOMA-IS and UA were significantly correlated with VFA but not with SFA.

(A–J) Change in (A) fasting blood glucose (FBG), (B) uric acid, (C) hemoglobin A1c (HbA1c), (D) fasting insulin, (E) homeostasis model assessment-IS (HOMA-IS), (F) triglycerides (TG), (G) high-density lipoprotein cholesterol (HDL-c), (H) triglycerides/high-density lipoprotein cholesterol (TG/HDL-c), (I) systolic blood pressure (SBP), and (J) diastolic blood pressure (DBP) among the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), and combination treatment (Both) groups after 3 months of the intervention. Analyses were conducted using all participants (intention-to-treat), using a multiple imputation approach for other missing data. Each black data point represents an individual participant (LCD, n = 55; TRE, n = 55; Both, n = 52). Change from baseline is presented as mean ± standard error of the mean (SEM) for normally distributed variables or the median (interquartile range) for abnormal distribution. # p < 0.05, ## p < 0.01, ### p < 0.001: pairwise comparisons of change scores between the groups (e.g., TRE versus LCD, TRE versus Both, LCD versus Both) were evaluated by t test or Mann-Whitney U test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001: significant differences shown at x axis compared with baseline (paired t test or paired Wilcoxon test).

Both abdominal visceral fat area (VFA) and abdominal subcutaneous fat area (SFA) play important but distinct roles in metabolic function. Thus, we further dissected the changes in these two fat depots using bioelectrical impedance analysis. Although after 3 months of intervention all three treatments induced similar reduction of SFA ( Figure 2 H), VFA was only decreased by TRE (−13 ± 5 cm) and combination treatment (−10 ± 3 cm Figure 2 I and Table 2 ). Compared with LCD (6 ± 5 cm), VFA was significantly reduced by both TRE (p = 0.009) and combination treatment (p = 0.016). Furthermore, as shown in Table S6 , eTRE significantly reduced VFA and SFA, whereas lTRE did not, albeit that the change of VFA or SFA induced by eTRE and lTRE alone or combined with LCD did not differ.

Abdominal fat is a pivotal risk factor and one of the drivers of the metabolic risk related to overweight and obesity. Waist-to-hip ratio (WHR), an indicator of abdominal obesity, is more closely correlated to MetS than body mass index (BMI).As compared with baseline, all three treatments induced a significant reduction of waist circumference, hip circumference, and body fat mass ( Figures 2 D, 2E, and 2F) after 3 months of intervention. Nevertheless, only TRE induced a more prominent reduction of WHR (−0.04 ± 0.01, Figure 2 G and Table 2 ) compared with LCD (−0.01 ± 0.01, p = 0.023) and combination (−0.01 ± 0.01, p = 0.033), suggesting that TRE more effectively alleviates abdominal obesity than LCD.

The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study.

Obesity and the risk of myocardial infarction in 27, 000 participants from 52 countries: a case-control study.

TRE, LCD, and their combination reduce subcutaneous fat, while only TRE with and without LCD reduces abdominal visceral fat

As compared with baseline, after 3 months of intervention a significant reduction of body weight was observed in all three groups ( Figures 2 A and 2B ), and only combination treatment induced a further reduction of body weight at month 3 compared with month 2 ( Figure 2 C and Table 2 ). Moreover, as shown in Table 2 , combination treatment induced a higher reduction in body weight (−5.0 ± 0.4 kg) compared with either LCD (−2.2 ± 0.3 kg, p < 0.001) or TRE alone (−3.4 ± 0.4 kg, p = 0.004), and a significant difference in body weight reduction was also observed between LCD and TRE treatment (p = 0.013). Furthermore, both eTRE and lTRE alone or combined with LCD led to a sustained reduction of body weight as early as after 1 month, which persisted over 3 months ( Table S6 ).

LCD, low-carbohydrate diet; TRE, time-restricted eating; Both, combination treatment; BMI, body mass index; HOMA-IR, homeostasis model assessment insulin resistance; HOMA-IS, homeostatic model assessment of insulin sensitivity; QUICKI, quantitative insulin-sensitivity check index; LDL-c, low-density lipoprotein cholesterol; HDL-c, high-density lipoprotein cholesterol. All data were presented as mean ± standard error of the mean (SEM) for normally distributed variables or the median (interquartile range) for abnormal distribution. Change scores from baseline were represented by “Δ” in the table. Analyses were conducted using all participants (intention-to-treat), using a linear mixed model with randomized dietary intervention as factor to correct for the correlations of repeated measurements on changes in body weight, and using a multiple imputation approach for other missing data. After 3 months of intervention, pairwise comparisons of change scores between the groups (e.g., TRE vs. LCD, TRE vs. Both, LCD vs. Both) were evaluated by t test or Mann-Whitney U test. For weight a : significant differences compared with 1 month before (paired t test); for other parameters: significant differences compared with baseline (paired t test or paired Wilcoxon test).

For (A) and (D)–(I), analyses were conducted using all participants (intention-to-treat) using a linear mixed model with randomized dietary intervention as factor to correct for the correlations of repeated measurements on changes in body weight and using a multiple imputation approach for other missing data. Each black data point represents an individual participant (LCD, n = 55; TRE, n = 55; Both, n = 52). Change from baseline is presented as mean ± standard error of the mean (SEM). # p < 0.05, ## p < 0.01, ### p < 0.001: pairwise comparisons of change scores between the groups (e.g., TRE versus LCD, TRE versus Both, LCD versus Both) were evaluated by t test or Mann-Whitney U test. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001: significant differences shown at x axis compared with baseline (paired t test or paired Wilcoxon test). For (B), each column represents relative body weight change for each participant. For (C), change from baseline is presented as mean ± SEM, a p < 0.05, b p < 0.001: significant differences compared with 1 month before (paired t test).

(C–I) Mean decrease in (C) body weight after 1, 2, and 3 months among three groups. Change in (D) waist circumstance, (E) hip circumstance, (F) body fat mass, (G) waist-to-hip ratio (WHR), (H) subcutaneous fat area (SFA), (I) visceral fat area (VFA) among three groups after 3 months of the intervention.

(A and B) Body weight change (A), relative body weight change (B) for the low-carbohydrate diet (LCD), 8-h time-restricted eating (TRE), and combination treatment (Both) groups during the 3-month intervention period.

As illustrated in Figure 1 , 290 participants were screened for this study, and 121 were excluded because they did not meet the inclusion criteria, had scheduling conflicts, or declined to participate. A total of 169 participants were randomized to receive intervention with LCD (group A; n = 56), TRE (group B; n = 57), or their combination (group C; n = 56), and after dropout of seven individuals, 162 individuals finally participated in the study. All participants met three or more MetS criteria at enrollment, and a minority (n = 62) of participants were on medication. This trial started with a 2-week weight stabilization and was followed by a 3-month intervention. At the end of the 3-month trial, 47 participants completed LCD, 44 completed TRE, and 44 completed their combination intervention. The main reason for dropout was scheduling conflicts. Table 1 and Table S1 show the baseline characteristics of the participants (n = 162). In this trial, we allowed participants to choose freely between two meal-eating windows for participants: 8 a.m. to 4 p.m. (eTRE) and 12 p.m. to 8 p.m. (lTRE), and we compared effects of two meal-eating windows using an exploratory analysis. In the TRE group, 38 participants (m/f 23/15) chose eTRE, and 17 participants (m/f 12/5) chose lTRE. In the combination group, 32 participants (m/f 22/10) chose eTRE, and 20 participants (m/f 15/5) chose lTRE. Table S2 shows the baseline characteristics of the eTRE and lTRE subgroups within the TRE and combination groups. At baseline, there were no significant differences in primary outcomes (i.e., body weight and abdominal fat area) or any secondary outcomes (i.e., body composition, glycemic control, plasma lipids, uric acid [UA], and blood pressure) between groups and subgroups. Table S3 clearly shows that participants receiving LCD or combination intervention had decreased intake of food containing high carbohydrates, such as rice, wheat flour, and pastry. Table S4 and Figure S1 show physical activity and daily step counts of participants, respectively, and demonstrate that participants maintained their usual physical activity throughout the study. Furthermore, participants with or without more than 50% dietary log records during the first 2 weeks of the intervention period showed similar responses to every treatment on primary outcomes after 3 months of intervention ( Table S5 ).

A total of 290 individuals were screened, and 77 were excluded because they did not meet one or more inclusion criteria. A total of 169 participants were randomized into the low-carbohydrate diet (LCD) group (n = 56), the 8-h time-restricted eating (TRE) group (n = 57), or the combination group (n = 56), and 162 participants received a diet intervention. During the 3 months of intervention, eight participants (LCD group, n = 1; TRE group, n = 6; combination group, n = 1) discontinued diet intervention due to lack of motivation or inability to stick to the diet. At the end of the 3-month trial, 47 participants (m/f 27/20) completed the LCD treatment, 44 participants (m/f 31/13) completed the TRE treatment (30 [m/f 20/10] completed early TRE, and 14 [11/3] completed late TRE), and 44 participants (m/f 31/13) completed the combination treatment (27 [m/f 18/9] completed early TRE, and 17 [13/4] completed late TRE).

Discussion

To our knowledge, this is the first clinical trial that directly compared the efficacy of weight loss and improvement of metabolic parameters of an LCD, 8-h TRE, and their combination in adults with MetS. We showed that although all three treatments significantly reduce body weight accompanied by a reduction in SFA, TRE yielded more benefits on abdominal visceral obesity and cardiometabolic outcomes and caused higher adherence to intervention compared with LCD. Moreover, both meal-eating windows of TRE (i.e., eTRE and lTRE) showed comparable beneficial effects on body weight, abdominal visceral fat, glucose metabolism, lipoprotein profile and blood pressure, as well as adherence. In addition, we observed that VFA, but not SFA, significantly correlated with several cardiometabolic parameters, including HOMA-IS, UA, the TG/HDL-c ratio, SBP, and DBP.

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Ryan D.H. Is 5% weight loss a satisfactory criterion to define clinically significant weight loss?. In this study, we have followed the ADA recommendation on the LCD, restricting subjects’ carbohydrate intake to <130 g/day and demonstrated a slight but significant reduction in body weight (−2.2 kg; −2.7%) in adults with MetS over the course of 3 months without apparent adverse effects. Similarly, a previous clinical trial showed that LCD treatment of T2DM patients, i.e., 130 g/day carbohydrates without other specific restrictions, caused 1.6 kg body weight loss over 6 monthsA 12-week randomized study also showed that LCD (<100 g carbohydrates/day) reduced body weight in type 1 diabetes subjects by 2.0 kg.In addition, the beneficial effects of very-low-carbohydrate ketogenic diets (VLCKD; < 50 g carbohydrates/day)on body weight reduction have been assessed.Samaha et al.showed that severely obese subjects with MetS significantly lost body weight (−5.8 kg) after 6 months on a VLCKD (<30 g carbohydrates/day). Another 1-year clinical trial showed that a VLCKD (<40 g carbohydrates/day) intervention resulted in significant weight loss (−3.5 kg) in obese individuals without T2DM or CVD.However, the efficacy and safety of VLCKD and adherence during long-term intervention are still under debate.Besides, we found participants from Northwestern China showed a 10.6-h baseline meal-eating window, which was calculated by participants’ self-report of average three meal times on 2-week recall. This baseline meal-eating window is comparable with the finding from a recent 1-year RCT study in Southern China,which was 10.4-h baseline eating window that was calculated by daily dietary log, food photograph, and eating time. We further demonstrated that an 8-h TRE significantly reduces body weight in adults with MetS (−4.0%), independent of timing of TRE. Several previous clinical trials have evaluated the weight-reduction efficiency of TRE in individuals with MetS.Wilkinson et al.found that a 10-h TRE led to an approximately 3% weight reduction and improvements in cardiovascular risk parameters in individuals with MetS. A recent trial showed that 8-h TRE decreased body weight of obese individuals by 2.6% after 3 monthsNonetheless, in our study only the combination of LCD and TRE produced clinically significant weight loss,i.e., a reduction of 5.8% from baseline over 3 months.

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Peterson C.M. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. Our results showed that LCD decreased SFA without affecting VFA, while TRE and the combination treatment decreased SFA as well as VFA. Accumulating evidence indicates that visceral fat is crucially associated with many aspects of MetS, including hypertension, dyslipidemia, glucose intolerance, and insulin resistance, and it is more closely linked to inflammatory and oxidative stress biomarkers than subcutaneous fat.Our results suggest that compared with LCD, TRE might yield more benefits on cardiometabolic outcomes in adults with MetS. Indeed, in our study, LCD intervention did not significantly decrease FBG levels but prominently reduced insulin levels and ameliorated insulin sensitivity, which are consistent with previous trials,suggesting that LCD is more effective in lowering blood insulin levels and improving insulin sensitivity than in lowering blood glucose levels. This is likely explained by the fact that most studies were conducted with relatively healthy or overweight individuals but not individuals with T2DM, and not all participants in these studies had elevated FBG levels. In contrast, in our study, TRE intervention improved insulin levels as well as blood glucose levels, and furthermore, the combination of LCD and TRE significantly reduced fasting glucose, insulin, and HbA1c levels in MetS patients. In addition, compared with baseline, TRE with and without LCD reduced UA levels, while compared with changes among treatments, combination treatment caused more prominent reduction on UA. High UA is a strong and independent predictor of MetS and is associated with impaired fasting glucose and insulin resistance.A recent 6-h TRE trial in overweight individuals with prediabetes revealed an improvement in insulin sensitivity and β cell responsiveness but no reduction in FBG.Fasting might improve glycemic control as a result of metabolic switch from liver-derived glucose to adipose cell-derived ketones, occurring when switching from a fed to a fasted state, and it might induce ketoplasia, decrease fat accumulation, and increase insulin sensitivity.However, further studies need to be performed in participants with elevated FBG, prediabetes, or T2DM to better define the effects of LCD versus TRE on glucose regulation. Whether TRE with or without LCD has independent effects on visceral fat and metabolic outcomes or is simply an epiphenomenon of greater weight loss could not be addressed in this study. It is noted that a previous RCT indicated that TRE that induced mild body weight reduction (∼3%) without changing visceral fat mass was accompanied with improvements of insulin resistance and oxidative stress,while another study showed that although there were no effects on body weight reduction, TRE could still improve those cardiometabolic parameters in prediabetic men.

19 Sutton E.F.

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Early K.S.

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Peterson C.M. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. , 39 Gabel K.

Hoddy K.K.

Haggerty N.

Song J.

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Varady K.A. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: a pilot study. , 51 Bowen J.

Brindal E.

James-Martin G.

Noakes M. Randomized trial of a high protein, partial meal replacement program with or without alternate day fasting: similar effects on weight loss, retention status, nutritional, metabolic, and behavioral outcomes. , 52 Moro T.

Tinsley G.

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Marcolin G.

Pacelli Q.F.

Battaglia G.

Palma A.

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Paoli A. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. , 53 Harvie M.N.

Pegington M.

Mattson M.P.

Frystyk J.

Dillon B.

Evans G.

Cuzick J.

Jebb S.A.

Martin B.

Cutler R.G.

et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. , 54 Wood R.J.

Volek J.S.

Liu Y.

Shachter N.S.

Contois J.H.

Fernandez M.L. Carbohydrate restriction alters lipoprotein metabolism by modifying VLDL, LDL, and HDL subfraction distribution and size in overweight men. , 55 Volek J.S.

Fernandez M.L.

Feinman R.D.

Phinney S.D. Dietary carbohydrate restriction induces a unique metabolic state positively affecting atherogenic dyslipidemia, fatty acid partitioning, and metabolic syndrome. 56 Westman E.C.

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Olsen M.K.

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Guyton J.R. Effect of a low-carbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. , 57 Bhanpuri N.H.

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McCarter J.P.

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Volek J.S. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. 58 Trepanowski J.F.

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Klempel M.C.

Bhutani S.

Hoddy K.K.

Gabel K.

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et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. 51 Bowen J.

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et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. 19 Sutton E.F.

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Ravussin E.

Peterson C.M. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. , 39 Gabel K.

Hoddy K.K.

Haggerty N.

Song J.

Kroeger C.M.

Trepanowski J.F.

Panda S.

Varady K.A. Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: a pilot study. , 51 Bowen J.

Brindal E.

James-Martin G.

Tinsley G.

Bianco A.

Marcolin G.

Pacelli Q.F.

Battaglia G.

Palma A.

Gentil P.

Neri M.

Snel M.

Jonker J.T.

Hammer S.

Lamb H.J.

de Roos A.

Meinders A.E.

Pijl H.

Romijn J.A.

Smit J.W.A.

et al. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases plasma CETP and increases apolipoprotein AI levels without improving the cholesterol efflux properties of HDL. 60 Kim J.Y.

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Kim S.J.

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Kim J.R.

Cho K.H. Consumption of policosanol enhances HDL functionality via CETP inhibition and reduces blood pressure and visceral fat in young and middle-aged subjects. The effects of LCD and TRE on dyslipidemia are highly variable between studies.We observed that LCD alone and combined with TRE adversely increased LDL-c after 3-month intervention, which is consistent with several studies showing that LCD increases cholesterol levels within the large LDL subfractions.In this study, while TRE treatment did not impact HDL-c, TRE and combination treatment, but not LCD, significantly reduced plasma TG levels. In fact, TRE was generally reported not to affect HDL-c, although one study reported a minor improvement.Yet, the effects of TRE on TG levels are still controversial. For instance, some TRE studies demonstrated a reduction in TG,whereas others showed no significant effects.In addition, we observed that TRE and combination treatment reduced the TG/HDL-c ratio, which could be partly due to reduced VFA by these treatments, but not by LCD alone. Indeed, VFA but not SFA strongly correlates with the TG/HDL-c ratio ( Figure S2 C). The TG/HDL-c ratio is a well-known predictor for CVD. A reduced TG/HDL-c ratio may be attributed to decreased cholesteryl ester transfer protein (CETP) activity, as CETP mediates the net transfer of CE from HDL to TG-rich lipoproteins in exchange for TG. Previous studies have demonstrated that weight loss induced by a very low calorie diet was correlated with reduced CETP concentration,and CETP inhibition was associated with the improvement of visceral fat.Therefore, TRE, with or without restricted carbohydrate consumption, could significantly improve visceral obesity and reduce TG level and TG/HDL-c ratio, as well as decrease CETP concentration.

61 Zomer E.

Gurusamy K.

Leach R.

Trimmer C.

Lobstein T.

Morris S.

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Finer N. Interventions that cause weight loss and the impact on cardiovascular risk factors: a systematic review and meta-analysis. In addition, only combination intervention significantly decreased blood pressure in our study. Generally, moderate (5%–10%) weight loss caused by interventions is expected to lead to larger reductions in SBP of 5 mmHg and DBP of 3 mmHg than that of mild (0–5%) weight loss over 6–12 months as shown in a systematic review and meta-analysis.We observed that the mean reduction in DBP (5 mmHg) by combination intervention that produced a moderate weight loss of 5.8% was apparently higher and not accompanied by a reduction in SBP. It should be noted though that our study was not properly powered to observe a significant change in blood pressure, and larger studies are obviously needed to further address the effects of LCD and TRE on blood pressure in MetS patients.

19 Sutton E.F.

Beyl R.

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Peterson C.M. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. 17 Cienfuegos S.

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Peterson C.M. Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes. 17 Cienfuegos S.

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Varady K.A. Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity. 62 Lowe D.A.

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et al. Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: the TREAT randomized clinical trial. , 63 Xie Z.

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Mao Y. Randomized controlled trial for time-restricted eating in healthy volunteers without obesity. 64 Morris C.J.

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Scheer F.A.J.L. The human circadian system has a dominating role in causing the morning/evening difference in diet-induced thermogenesis. , 65 Poggiogalle E.

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Shea S.A. Adverse metabolic and cardiovascular consequences of circadian misalignment. 64 Morris C.J.

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Scheer F.A.J.L. The human circadian system has a dominating role in causing the morning/evening difference in diet-induced thermogenesis. , 65 Poggiogalle E.

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Peterson C.M. Circadian regulation of glucose, lipid, and energy metabolism in humans. , 66 Scheer F.A.J.L.

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Mantzoros C.S.

Shea S.A. Adverse metabolic and cardiovascular consequences of circadian misalignment. , 67 Morris C.J.

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Scheer F.A.J.L. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. 68 Ravussin E.

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Peterson C.M. Early time-restricted feeding reduces appetite and increases fat oxidation but does not affect energy expenditure in humans. In this study, eTRE shows greater effects on reducing abdominal fat area (both SFA and VFA) than lTRE, while eTRE and lTRE showed comparable benefits on body weight, glycemic control, dyslipidemia, and blood pressure. Nevertheless, participants were not randomly assigned to eTRE or lTRE, and sample sizes were relatively small, so the comparison of eTRE and lTRE was exploratory. Previous studies showed that both eTREand lTREimproved multiple indicators of cardiovascular health. Sutton et al.conducted a 5-week study comparing eTRE (6-h eating window before 3:00 p.m.) with a control condition (conventional 12-h eating window) and found better glycemic control and improvement of blood pressure by eTRE without significant body weight changes. Furthermore, Cienfuegos et al.found that both 4- and 6-h lTRE caused mild body weight reduction (∼3%) over 2 months when compared with the control. However, several studies on lTRE demonstrated conflicting results regarding body weight.Moreover, the thermic effect of food, insulin sensitivity, and β cell function is better in early morning than nightbecause the body is optimized to ingesting food in early morning.Thus, an 8 a.m. to 4 p.m. eating window may be applied as a more effective intervention to improve insulin sensitivity. Besides, lipids were also affected by meal timing, which might be due to an increase of fat oxidation in eTRE.However, for participants who find it easier to skip breakfast than dinner, the latter being a more social meal in most cultures, a 12 p.m. to 8 p.m. eating window is an alternative. Thus, it is important to consider participants’ individual schedule and personal preference and allow them to choose the suitable TRE eating window in order to increase efficacy and adherence.

Conclusions In conclusion, compared with baseline, all three treatments after a 3-month intervention reduce body weight and SFA, as well as some cardiometabolic outcomes, including fasting insulin, C-peptide, and insulin sensitivity index, but only TRE, with and without LCD, significantly reduces abdominal visceral fat, FBG, UA, TG, and TG/HDL-c ratio. More importantly, compared with changes of LCD, TRE and combination treatment further decrease body weight and VFA. Taken together, without changing physical activity, TRE with and without LCD significantly improves glycemic control, atherogenic dyslipidemia, and UA, thus largely improves metabolic disease risk, with TRE being superior over LCD with respect to reducing body weight and abdominal visceral obesity. Therefore, we anticipate that an 8-h TRE without and with LCD can serve as an effective intervention for MetS.