Center for Clinical and Translational Science

Time Restricted Feeding (TRF) is a form of intermittent fasting that confines food intake to active daytime hours and involves fasting for 12 to 14 hours. Circadian misalignment caused by changes in sleeping and eating behaviors has emerged as having a detrimental impact on weight, glucose metabolism, and other cardiovascular disease-related outcomes. Feeding during active periods appears to be advantageous for weight, glucose metabolism and related outcomes whereas feeding during the inactive period confers deleterious effects on these outcomes. Therefore, TRF shows great promise as a novel intervention for addressing obesity and related cardiovascular outcomes. To address this potential, we are conducting a randomized 7-day isocaloric crossover feeding study titled “The Time-Restricted-feeding effects on Inflammation and Obesity” (TRIO), in humans with prediabetes and obesity. We will study the effect of restricting the timing of caloric intake to earlier in the day (TRF) versus later in the day (usual feeding pattern, UFP) on glucose levels and inflammation.

In the TRIO study Dr. Jose Aleman, a graduate of the Clinical Scholars program who is now Assistant Professor of Medicine at NYU, will explore the impact of TRF on systemic inflammation and shifts in glucose metabolism over 1 week, as well as its effects on surrogate markers of diabetes and cardiovascular disease while weight remains stable. Dr. Jan Breslow, Head of the Laboratory of Biochemical Genetics and Metabolism, will serve as Co-PI.

Animal studies suggest that timing of feeding, including intermittent fasting or TRF, decreases inflammation and causes ketosis. We are unaware of any data in humans on these potential mechanisms. Dr. Aleman’s independent work at NYU aims to understand the role of inflammation in fat towards causing the complications of excess weight. His team is pursuing this goal by obtaining detailed phenotyping of subjects with obesity undergoing bariatric surgery and observing how metabolic and inflammatory phenotypes change with one form of bariatric surgery called sleeve gastrectomy. The overall hypothesis is that obesity is associated with activation of inflammatory signaling pathways, the most notable of which is the Receptor for Advanced Glycation End-Products (RAGE) signaling pathway, and treating obesity will decrease this form of inflammation. However, we lack interventions to decrease this form of systemic inflammation when weight is stable, such as when maintaining weight after bariatric surgery. Activation of the RAGE pathway can be assessed by measurements of soluble RAGE (sRAGE), an inhibitor of the pathway. We hypothesize that the downstream consequences of RAGE activation are reductions in energy expenditure and glucose tolerance, increased white blood cell (WBC) counts and inflammatory gene expression, and greater levels of circulating cytokines. Low levels of sRAGE are associated with long-term risk of diabetes, cardiovascular disease, and premature mortality.

This collaborative research project integrates the Rockefeller University Hospital’s expertise in conducting sophisticated nutritional studies with Dr. Aleman’s group’s expertise in obesity, dietary interventions,.. exercise, and metabolic studies (Popp et al. 2016, Vanegas et al. 2017). Systemic and adipose tissue inflammation are known to decrease with long-term weight loss and maintenance, but the dynamics of sRAGE within each circadian rhythm are not well understood. We hypothesize that decreased glucose and AGEs would decrease signaling through the RAGE pathway, and over 7 days lead to a reduction in sRAGE with TRF, which has not been tested previously in the context of a detailed feeding study. Through the proposed metabolomic analysis, we will be able to measure AGEs in the context of this detailed dietary intervention, linking timing of feeding directly to RAGE signaling.

The study will enroll 10 persons with obesity (BMI>30 kg/m2) and prediabetes (HbA1c 5.7-6.4%) and randomize them TRF or UFP. In the TRF arm, participants consume all food between 8 am and 2 pm, producing a 16-hour fast each day, and eat 80% of their calories prior to 1 pm. In the UFP arm, participants consume their calories between 8 am and midnight and eat 50% of their calories after 4 pm. In both arms, participants consume diets with the same macro- and micronutrients based on their home diet, analyzed by Bionutritonists in the Rockefeller Bionutrition Department, using the validated Vioscreen Food Frequency Questionnaire (that captures the participants usual intake within the last 3 months). The study has crossover design, with subjects switching to the other intervention arm after completing the first 7 day intervention. Subjects will act as their own control, and we will be able to monitor compliance with the TRF intervention by monitoring continuous glucose monitoring (CGM) tracings. CGM technology is widely used in the care of patients with diabetes, and the TRIO study will be the first application of CGM at Rockefeller Hospital.

We know that glycemic variation decreases with TRF interventions, but will test sRAGE, clinical markers of inflammation such as high sensitivity C-reactive protein (CRP), plasma metabolomic profiles by liquid chromatography/mass spectrometry, in addition to collecting urine and stool for future analyses. with the TRF intervention by monitoring continuous glucose monitoring (CGM) tracings. CGM technology is widely used in the care of patients with diabetes, and the TRIO study will be the first application of CGM at Rockefeller Hospital. We know that glycemic variation decreases with TRF interventions, but will test sRAGE, clinical markers of inflammation such as high sensitivity C-reactive protein (CRP), plasma metabolomic profiles by liquid chromatography/mass spectrometry, in addition to collecting urine and stool for future analyses.

 As part of Drs. Aleman and Breslow’s commitment to training the next generation of obesity and cardiovascular researchers, nutritionist clinical fellows from the NYU American Heart Association Obesity Center, Dr. Collin Popp and Dr. Sally Vanegass, will participate in the deployment and execution of the TRIO study in collaboration with Rockefeller Bionutrition Department. We hope the TRIO study will yield new connections between metabolism and inflammation, while testing for additional benefits of this creative dietary intervention in the clinical setting. with the TRF intervention by monitoring continuous glucose monitoring (CGM) tracings. CGM technology is widely used in the care of patients with diabetes, and the TRIO study will be the first application of CGM at Rockefeller Hospital. We know that glycemic variation decreases with TRF interventions, but will test sRAGE, clinical markers of inflammation such as high sensitivity C-reactive protein (CRP), plasma metabolomic profiles by liquid chromatography/mass spectrometry, in addition to collecting urine and stool for future analyses.