Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges.

Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8-9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia.

[1]  S. Lewis,et al.  Metabolic imprinting, programming and epigenetics – a review of present priorities and future opportunities , 2010, British Journal of Nutrition.

[2]  C. Glass,et al.  Inflammation and lipid signaling in the etiology of insulin resistance. , 2012, Cell metabolism.

[3]  P. Mayes,et al.  Intermediary metabolism of fructose. , 1993, The American journal of clinical nutrition.

[4]  Karl Kornacker,et al.  JTK_CYCLE: An Efficient Nonparametric Algorithm for Detecting Rhythmic Components in Genome-Scale Data Sets , 2010, Journal of biological rhythms.

[5]  S. Panda,et al.  Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression , 2009, Proceedings of the National Academy of Sciences.

[6]  Stuart Maudsley,et al.  VennPlex–A Novel Venn Diagram Program for Comparing and Visualizing Datasets with Differentially Regulated Datapoints , 2013, PloS one.

[7]  Arya M. Sharma,et al.  Peroxisome Proliferator-Activated Receptor γ and Adipose Tissue—Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism , 2007 .

[8]  B. Brewer,et al.  Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. , 2003, The Journal of clinical investigation.

[9]  K. Gamble,et al.  Circadian clock control of endocrine factors , 2014, Nature Reviews Endocrinology.

[10]  F. Marlowe,et al.  Hunter-Gatherer Energetics and Human Obesity , 2012, PloS one.

[11]  R. Ritchie,et al.  Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. , 2011, Journal of molecular and cellular cardiology.

[12]  Arya M. Sharma,et al.  Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism. , 2007, The Journal of clinical endocrinology and metabolism.

[13]  James W. Anderson,et al.  Long-term weight-loss maintenance: a meta-analysis of US studies. , 2001, The American journal of clinical nutrition.

[14]  Satchidananda Panda,et al.  Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. , 2012, Cell metabolism.

[15]  Kathryn Moynihan Ramsey,et al.  High-fat diet disrupts behavioral and molecular circadian rhythms in mice. , 2007, Cell metabolism.

[16]  Steven A. Brown,et al.  The human circadian metabolome , 2012, Proceedings of the National Academy of Sciences.

[17]  E. Mercken,et al.  Metformin improves healthspan and lifespan in mice , 2013, Nature Communications.

[18]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[19]  G. Aldini,et al.  Physiology and pathophysiology of carnosine. , 2013, Physiological reviews.

[20]  James D. Johnson,et al.  Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. , 2012, Cell metabolism.

[21]  K. Stanhope Role of fructose-containing sugars in the epidemics of obesity and metabolic syndrome. , 2012, Annual review of medicine.

[22]  Corey D. DeHaven,et al.  Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. , 2009, Analytical chemistry.

[23]  Mengwei Zang,et al.  AMPK exerts dual regulatory effects on the PI3K pathway , 2010, Journal of molecular signaling.

[24]  G. Bray,et al.  Update on obesity pharmacotherapy , 2014, Annals of the New York Academy of Sciences.

[25]  Jana Husse,et al.  Circadian Desynchrony Promotes Metabolic Disruption in a Mouse Model of Shiftwork , 2012, PloS one.

[26]  B. Manning Balancing Akt with S6K , 2004, The Journal of cell biology.

[27]  Pierre Baldi,et al.  Coordination of the transcriptome and metabolome by the circadian clock , 2012, Proceedings of the National Academy of Sciences.

[28]  Pierre Baldi,et al.  Reprogramming of the Circadian Clock by Nutritional Challenge , 2013, Cell.

[29]  B. H. Miller,et al.  Coordinated Transcription of Key Pathways in the Mouse by the Circadian Clock , 2002, Cell.

[30]  B. Neuschwander‐Tetri,et al.  Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[31]  N. Timchenko,et al.  Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis. , 2013, Cell reports.

[32]  Maria M. Mihaylova,et al.  AMPK and PPARδ Agonists Are Exercise Mimetics , 2008, Cell.

[33]  R. Wolfe,et al.  Exercise, protein metabolism, and muscle growth. , 2001, International journal of sport nutrition and exercise metabolism.

[34]  Xianlin Han,et al.  Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. , 2014, Cell metabolism.

[35]  V. Samuel Fructose induced lipogenesis: from sugar to fat to insulin resistance , 2011, Trends in Endocrinology & Metabolism.

[36]  Mark P Mattson,et al.  Fasting: molecular mechanisms and clinical applications. , 2014, Cell metabolism.

[37]  Chao-Yung Wang,et al.  A mouse model of diet-induced obesity and insulin resistance. , 2012, Methods in molecular biology.

[38]  H. Roche,et al.  Mechanisms of Obesity-Induced Inflammation and Insulin Resistance: Insights into the Emerging Role of Nutritional Strategies , 2013, Front. Endocrinol..

[39]  D. Bessesen Update on obesity. , 2008, The Journal of clinical endocrinology and metabolism.

[40]  M. Bray,et al.  Time-of-Day-Dependent Dietary Fat Consumption Influences Multiple Cardiometabolic Syndrome Parameters in Mice , 2010, International Journal of Obesity.

[41]  B. Swinburn,et al.  The global obesity pandemic: shaped by global drivers and local environments , 2011, The Lancet.

[42]  A. Saltiel Insulin resistance in the defense against obesity. , 2012, Cell metabolism.