At present, more and more people in the world are suffering from metabolic diseases and obesity . IF, a popular dietary strategy, has become increasingly popular among citizens as more and more people around the world are suffering from metabolic diseases and obesity. Although IF was considered to be related to undesired outcomes, such as gout, arrhythmia, and peptic ulcer , it is still widely believed that IF could reduce weight, relive rheumatoid arthritis, and slow down aging [57, 58], even if they still disagreed on cancer [12, 59]. In this study, IF was compared with normal diet and CR. In addition, subgroup analysis was conducted based on the pattern of IF, gender, and additionally considered the situation of narrowing to overweight or obese population.
In our study, IF was found to have significant benefits in regulating weight, FM, insulin, and blood lipids compared to normal diet (non-intervention diet). These results were similar to previous studies [6, 57, 59], indicating that IF can result in desirable weight loss and better health. However, there was no difference in blood glucose level between them in this study. It might be due to the fact that the included population was mostly non-diabetic patients, so the basal glucose level was relatively low, resulting in slight fluctuations in participants. As for the outcomes of insulin and HOMA-IR, IF was proved to be potentially beneficial in reliving insulin resistance. Here, IF was about as effective as CR, only slightly better than CR in reducing WC. Although some researchers believed that, comparing with CR, IF had better compliance and benefited more in the reduction of FM [11, 58], other studies showed that long-term compliance of IF was limited due to the high drop-out rate .
As for the comparison between ADF and CR, the subgroup analysis based on the dietary pattern of IF found that ADF showed no differences with CR, but other studies showed a superior compliance, FM, and FFM in the ADF group [11, 61]. Furthermore, ADF is more preferable in having no burden of chronic poor feeding and other adverse outcomes compared to CR . However, some investigators believed that ADF might not be a viable public health intervention because of the considerably and continuously reported hunger by Patterson et al [8, 62]. In addition, comparing to ADF, weekly TRF exerted significant advantages on the regulation of WC, FM, and DBP. Another meta-analysis also reported that besides weight, DBP, and insulin regulation, TRF was also more effective in FFM reduction .
In addition, IF might play a small role in women, because FM was the only parameter that was found to be significantly reduced after IF. Comparatively, IF was found to significantly reduce weight and TG in male. The reason for the difference based on gender was still currently not clear. We assumed that it might be related to the gender-depending fat distribution and sex hormones . Estrogen was considered to suppress appetite and reduce the accumulation of belly fat, while androgen promot food intake. However, research on the relationship between IF and human sex hormones is lacking. Moreover, our subgroup analysis against overweight and obese patients showed that IF could not provide more benefit to this particular population. This was at odds with previous studies by researchers who believed that IF is functional in regulating blood pressure, TC, and TG, especially more than CR did, in overweight or obese patients [31, 64]. One theory we speculated was the insufficient quantity of included studies, another might be that the intervention time was relatively short, which is a median follow-up of only 3 months in our study, thus no appearance of IF efficacy.
In many ways, the effects of IF and CR overlapped significantly . The essence of both IF and CR was to reduce energy intake. The difference was that CR maintained a normal eating frequency, while IF was no or small amounts of energy intake during fasting . In this study, although most of the included studies did not perform energy intake interventions during non-fasting periods, there were still some studies that restricted energy intake during feeding periods, and certain eating patterns of IF also shaped a certain degree of energy restriction [19, 49]. Thus, while IF was discovered to be superior to the non-intervention diet here, it was unclear whether time restriction or energy restriction played a greater role. On the other hand, in our study, IF and CR had few differences in their effects on participants, and the previous studies showed that CR could promote weight loss, relive insulin resistance, improve insulin sensitivity, lower TG and TC, and elevate HDL . Although IF did not restrict calories in some of the included studies , it is suspected here that CR may be dominant as time restriction did not seem to play a role.
The researchers suggested that weight loss after CR was due to the adaptation to metabolically induced reductions in FM and FFM [65, 66]. The weight loss resulted from IF was also due to the reduction of FM and FFM. However, the difference was that human body, in addition to metabolic adaptations, consumed the stored hepatic glycogen 10–12 hours after fasting, and then generated massive ketone bodies through the oxidation of fatty acids in adipose tissue, which would be used as the energy source of the whole body [67, 68]. Therefore, an increase in blood ketones was found after IF, but not after CR alone . Unfortunately, this investigation was not included in this study. The decrease in blood TG might also be due to the oxidative breakdown of fat and the restriction of fat intake . Although previous studies attributed weight loss after IF and CR to the reduction of FM and FFM [65, 68], it was an important discovery in our study that IF preserved FFM better. This finding contributes to further recognition of IF, which is that IF does not damage lean tissue, dissipating the concern of IF being the potential cause of osteoporosis and sarcopenia .
One of the mechanisms by which CR mediated was that CR could cause decreased levels of anabolic hormones including insulin, leptin, estrogen, and testosterone . CR in corporating with weight loss can further improve insulin sensitivity, which might lead to decreased insulin secretion . In addition to the above possible mechanisms, IF might also be due to the ketone produced by fat metabolism acting on the nerve center, enhancing the effect of leptin and insulin on the central nervous system, which normally regulates food intake and insulin sensitivity as well as resistance . Herein, insulin levels decreased and insulin resistance was relieved after IF with no significance. Both CR and IF lowered TC . This probably due to the mechanistic target of rapamycin (mTOR) pathway [56, 69]. Reduction in TC production was induced by a complex intracellular reaction between mTOR complex 1(mTORC1) and sirtuins [56, 71]. IF might lower TC through inhibiting TC production via supressing this pathway. Since this pathway could also be activated by CR, it is resonable to discover no difference in TC levels between the two intervention groups.
Researchers have proposed three possible mechanisms for IF: circadian rhythms, gastrointestinal microbiota, and modifiable lifestyle behaviors . Some researchers argued that the human body clock was affected by, but not limited to, metabolic hormones, nutrients, intracellular metabolism, and intestinal flora . The human circadian rhythms regulate eating, sleep, hormonal and physiological processes, and coordinated metabolism and energetics. Certain patterns of IF might affect the body clock by revising the time humans eat, thus realigning metabolism and energy allocation to ensure human health . Sutton's study of daily TRF, a six-hour daily eating during a five-week period, showed that TRF improved cardio-metabolic health . Unfortunately, due to the limited number of studies, we were unable to conduct a comparative analysis between daily TRF and CR or normal diet. In contrast, the feeding window of the non-fasting period for weekly TRF and ADF was not addressed in the viewed RCTs [46, 73], so it was unknown whether circadian rhythms plays a role in these two patterns of IF. Irregular and inappropriate diet might lead to metabolic disorders and other adverse consequences . Although current IF was actually accompanied with energy restriction, it was undeniable that IF limited daytime hours of feeding, which might contribute to improved parameters . Both of the two other hypotheses lacked human clinical trials and could not be confirmed in the relation to IF here.
So far, this study is the first systematic meta-analysis based on RCTs of IF. However, it must be pointed out that there are still considerable limitations in this study. Firstly, this study mixed various patterns of IF, which might reduce the reliability. Secondly, part of the outcomes such as hip circumference, and waist to hip ratio could not be analysed in this study due to insufficient data, which might produce publication bias. Moreover, although subgroup analysis was conducted, the role of various factors such as the long-term effect of IF was not thoroughly analyzed in detail due to the limited quantity of studies. Finally, only studies that were published in English were included, which might create publication bias.