Intermittent fasting (IF) plays a critical role in mitigating obesity, yet the precise biological mechanisms require further elucidation. Here Orosomucoid 2 (Orm2) is identified as an IF-induced hepatokine that stimulates adipose browning. IF induced Orm2 expression and secretion from the liver through peroxisome proliferator-activated receptor alpha (PPARα). In adipose tissue, Orm2 bound to glycoprotein 130/interleukin 23 receptor (GP130/IL23R) and promoted adipose browning through the activation of p38 mitogen-activated protein kinases (p38-MAPK). In obese mice, Orm2 led to a significant induction of adipose tissue browning and subsequent weight loss, an effect that is not replicated by a mutant variant of Orm2 deficient in GP130/IL23R binding capability. Crucially, genetic association studies in humans identified an obesity-associated Orm2 variant (D178E), which shows decreased GP130/IL23R binding and impaired browning capacity in mice. Overall, the research identifies Orm2 as a promising therapeutic target for obesity, mediating adipose browning through the GP130/IL23R-p38 signalling pathway.

OBJECTIVE: The impact of dietary habits on cognitive function is increasingly gaining attention. The review is to discuss how caloric restriction (CR) and intermittent fasting (IF) can enhance cognitive function in healthy states through multiple pathways that interact with one another. Secondly, to explore the effects of CR and IF on cognitive function in conditions of neurodegenerative diseases, obesity diabetes and aging, as well as potential synergistic effects in combination with exercise to prevent cognitively related neurodegenerative diseases.
RESULTS: With age, the human brain ages and develops corresponding neurodegenerative diseases such as Alzheimer\'s disease, Parkinson\'s disease, and epilepsy, which in turn trigger cognitive impairment. Recent research indicates that the impact of diet and exercise on cognitive function is increasingly gaining attention. The benefits of exercise for cognitive function and brain plasticity are numerous, and future research can examine the efficacy of particular dietary regimens during physical activity when combined with diet which can prevent cognitive decline.

Intermittent fasting (IF) is an intervention that involves not only dietary modifications but also behavioral changes with the main core being a period of fasting alternating with a period of controlled feeding. The duration of fasting differs from one regimen to another. Ramadan fasting (RF) is a religious fasting for Muslims, it lasts for only one month every one lunar year. In this model of fasting, observers abstain from food and water for a period that extends from dawn to sunset. The period of daily fasting is variable (12-18 hours) as Ramadan rotates in all seasons of the year. Consequently, longer duration of daily fasting is observed during the summer. In fact, RF is a peculiar type of IF. It is a dry IF as no water is allowed during the fasting hours, also there are no calorie restrictions during feeding hours, and the mealtime is exclusively nighttime. These three variables of the RF model are believed to have a variable impact on different liver diseases. RF was evaluated by different observational and interventional studies among patients with non-alcoholic fatty liver disease and it was associated with improvements in anthropometric measures, metabolic profile, and liver biochemistry regardless of the calorie restriction among lean and obese patients. The situation is rather different for patients with liver cirrhosis. RF was associated with adverse events among patients with liver cirrhosis irrespective of the underlying etiology of cirrhosis. Cirrhotic patients developed new ascites, ascites were increased, had higher serum bilirubin levels after Ramadan, and frequently developed hepatic encephalopathy and acute upper gastrointestinal bleeding. These complications were higher among patients with Child class B and C cirrhosis, and some fatalities occurred due to fasting. Liver transplant recipients as a special group of patients, are vulnerable to dehydration, fluctuation in blood immunosuppressive levels, likelihood of deterioration and hence observing RF without special precautions could represent a real danger for them. Patients with Gilbert syndrome can safely observe RF despite the minor elevations in serum bilirubin reported during the early days of fasting.

BACKGROUND: In the face of the growing global burden of cancer, there is increasing interest in dietary interventions to mitigate its impacts. Pre-clinical evidence suggests that time-restricted eating (TRE), a type of intermittent fasting, induces metabolic effects and alterations in the gut microbiome that may impede carcinogenesis. Research on TRE in cancer has progressed to human studies, but the evidence has yet to be synthesized.
OBJECTIVE: The objective of this study was to systematically evaluate the clinical and/or metabolomic effects of TRE compared with ad libitum eating or alternative diets in people with cancer.
METHODS: Ovid MEDLINE, Ovid Embase, CINAHL, Ovid Cochrane Central Register of Control Trials (CENTRAL), Web of Science Core Collection (ESCI, CPCI-SSH, CPCI-S), and SCOPUS were searched up to January 4, 2023, using the core concepts of \"intermittent fasting\" and \"cancer.\" Original study designs, protocols, and clinical trial registries were included.
METHODS: After evaluating 13 900 results, 24 entries were included, consisting of 8 full articles, 2 abstracts, 1 published protocol and 13 trial registries. All data were extracted, compared, and critically analyzed.
METHODS: There was heterogeneity in the patient population (eg, in tumor sites), TRE regimens (eg, degree of restriction, duration), and clinical end points. A high rate (67-98%) of TRE adherence was observed, alongside improvements in quality of life. Four articles assessed cancer markers and found a reduction in tumor marker carcinoembryonic antigen, reduced rates of recurrence, and a sustained major molecular response, following TRE. Five articles demonstrated modified cancer risk factors, including beneficial effects on body mass index, adiposity, glucoregulation, and inflammation in as short a period as 8 weeks. None of the completed studies assessed the effect of TRE on the microbiome, but analysis of the microbiome is a planned outcome in 2 clinical trials.
CONCLUSIONS: Preliminary findings suggest that TRE is feasible and acceptable by people with cancer, may have oncological benefits, and improves quality of life.
BACKGROUND: PROSPERO registration No. CRD42023386885.

The aim of this secondary analysis was to compare the effects of time-restricted eating (TRE) versus calorie restriction (CR) and controls on sleep in adults with type 2 diabetes (T2D). Adults with T2D (n = 75) were randomized to 1 of 3 interventions for 6 months: 8 h TRE (eating only between 12 and 8 pm daily); CR (25% energy restriction daily); or control. Our results show that TRE has no effect on sleep quality, duration, insomnia severity, or risk of obstructive sleep apnea, relative to CR and controls, in patients with T2D over 6 months.

Intermittent fasting has drawn significant interest in the clinical research community due to its potential to address metabolic complications such as obesity and type 2 diabetes mellitus. Various intermittent fasting regimens include alternate-day fasting (24 h of fasting followed by 24 h of eating), time-restricted fasting (fasting for 14 h and eating within a 10 h window), and the 5:2 diet (fasting for two days and eating normally for the other five days). Intermittent fasting is associated with a reduced risk of type 2 diabetes mellitus-related complications and can slow their progression. The increasing global prevalence of type 2 diabetes mellitus highlights the importance of early management. Since prediabetes is a precursor to type 2 diabetes mellitus, understanding its progression is essential. However, the long-term effects of intermittent fasting on prediabetes are not yet well understood. Therefore, this review aims to comprehensively compile existing knowledge on the therapeutic effects of intermittent fasting in managing type 2 diabetes mellitus and prediabetes.

Intermittent religious fasting increases the risk of hypo- and hyperglycemia in individuals with diabetes, but its impact on those without diabetes has been poorly investigated. The aim of this preliminary study was to examine the effects of religious Bahá\'í fasting (BF) on glycemic control and variability and compare these effects with time-restricted eating (TRE). In a three-arm randomized controlled trial, 16 subjects without diabetes were assigned to a BF, TRE, or control group. Continuous glucose monitoring and food intake documentation were conducted before and during the 19 days of the intervention, and the 24 h mean glucose and glycemic variability indices were assessed. The BF and TRE groups, but not the control group, markedly reduced the daily eating window while maintaining macronutrient composition. Only the BF group decreased caloric intake (-677.8 ± 357.6 kcal, p = 0.013), body weight (-1.92 ± 0.95 kg, p = 0.011), and BMI (-0.65 ± 0.28 kg, p = 0.006). Higher maximum glucose values were observed during BF in the within-group (+1.41 ± 1.04, p = 0.039) and between-group comparisons (BF vs. control: p = 0.010; TRE vs. BF: p = 0.022). However, there were no alterations of the 24 h mean glucose, intra- and inter-day glycemic variability indices in any group. The proportions of time above and below the range (70-180 mg/dL) remained unchanged. BF and TRE do not exhibit negative effects on glycemic control and variability in subjects without diabetes.

Fasting can affect the body\'s inflammatory response, and this has been linked to potential health benefits, including improvements for people with rheumatic diseases. In this work, we evaluated, in vitro, how changes in nutrient availability alter the inflammatory response of macrophages. Macrophage-differentiated THP1 cells were cultured, deprived of FCS or subjected to cycles of FCS deprivation and restoration to mimic intermittent fasting. Changes in the macrophage phenotype, the cells\' response to inflammatory stimuli and the level of mitochondrial alteration were assessed. The results indicate that while periods of serum starvation are associated with a decrease in IL1β and TNFα expression, consistent with an anti-inflammatory response, intermittent serum starvation cycles promote a pro-inflammatory phenotype. Rapid changes in reducing capacity and mitochondrial response were also observed. Of note, while some changes, such as the production of oxygen free radicals, were reversed with refeeding, others, such as a decrease in reducing capacity, were maintained and even increased. This study shows that different fasting protocols can have diverging effects and highlights that time-limited nutrient changes can significantly affect macrophage functions in cell cultures. These findings help elucidate some of the mechanisms by which specific fasting dietary interventions could help control inflammatory diseases.

Obesity and type 2 diabetes (T2D) are associated with metabolic inflexibility, characterized by an impaired ability to switch between substrate storage and utilization pathways. Metabolic inflexibility during obesity is typified by lower engagement of fatty acid metabolism despite an ample supply of stored lipids. Intermittent fasting (IF) can promote metabolic flexibility. However, it is not clear how obesity and T2D alter metabolic flexibility after repeated IF. Male obese db/db and control db/+ mice were fasted for 24 hours twice a week for 10 weeks. This 5:2 IF regimen did not alter body mass, body composition, food intake, or physical activity in db/db or db/+ mice. After IF, db/db mice had lower fatty acid oxidation and higher carbohydrate oxidation in the fed state, indicating metabolic inflexibility to metabolize lipids. After IF, control db/+ mice had higher fatty acid oxidation and lower carbohydrate oxidation in the fed state, characteristic of metabolic flexibility and increased engagement of lipid metabolism. In the fasted state, IF lowered carbohydrate oxidation and increased fatty acid oxidation in control db/+ mice but not in obese db/db mice. After IF, db/db mice also had lower serum β-hydroxybutyrate than control db/+ mice. 10 weeks of IF decreased adipocyte size in visceral adipose tissue of control db/+ mice, but this IF regimen did not change adipocyte size in obese db/db mice. Therefore, IF increases fatty acid oxidation and metabolic flexibility in lean mice, but this adaptation is absent in a mouse model of obesity and type 2 diabetes.

OBJECTIVE: Time-restricted eating (TRE) which consists of restricting the eating window to typically 4-8h (while fasting for the remaining hours of the day) has been proposed as a non-pharmacological strategy with cardio-metabolic benefits but little is known about its metabolic impact in type 2 diabetes (T2DM). We evaluated whether TRE can improve pancreatic beta-cell function and metabolic status in overweight individuals with early T2DM.
METHODS: In a randomized cross-over trial, 39 participants [mean 2.9 years of diabetes duration, baseline glycated hemoglobin (HbA1c) 6.6% ± 0.7% and body mass index (BMI) 32.4 ± 5.7 kg/m2] were randomized to either an initial intervention consisting of 6-weeks of TRE (20h-fasting/4h-eating) or standard lifestyle. The primary outcome of beta-cell function was assessed by Insulin Secretion-Sensitivity Index-2 (ISSI-2) derived from an oral glucose tolerance test. Trial registration: clinicaltrials.gov NCT05717127.
RESULTS: As compared to standard lifestyle, TRE induced a 14% increase in ISSI-2 (+14.0 ± 39.2%, p = 0.03) accompanied by 14% reduction of hepatic insulin resistance as evaluated by HOMA-IR [-11.6% (-49.3-21.9), p = 0.03]. Fasting glucose did not differ between interventions, but TRE yielded a significant reduction in HbA1c (-0.32 ± 0.48%, p <0.001). These metabolic improvements were coupled by a reduction of body weight of 3.86% (-3.86 ± 3.1%, p <0.001) and waist circumference of 3.8 cm (-3.8 ± 7.5 cm, p = 0.003).
CONCLUSIONS: TRE improved beta-cell function and insulin resistance in overweight patients with early diabetes, accompanied by beneficial effects on adiposity.