System-wide Benefits of Intermeal Fasting by Autophagy

• Published in: Cell metabolism Vol. 26; no. 6; pp. 856 - 871.e5
• Main Authors: Martinez-Lopez, Nuria, Tarabra, Elena, Toledo, Miriam, Garcia-Macia, Marina, Sahu, Srabani, Coletto, Luisa, Batista-Gonzalez, Ana, Barzilai, Nir, Pessin, Jeffrey E., Schwartz, Gary J., Kersten, Sander, Singh, Rajat
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2017
• Subjects: Adiposity; Age Factors; Aging; Animals; Autophagy; Blood Glucose - analysis; Caloric Restriction; Circadian; Circadian Rhythm; Fasting; Fatty liver; Feeding Behavior; Female; Gluconeogenesis; Humans; Insulin - blood; Lipids - analysis; Liver - metabolism; Male; Metabolic syndrome; Metabolic Syndrome - prevention & control; Mice; Mice, Knockout; Muscle Development; Myogenic progenitors; POMC; Twice-a-day feeding; metabolic syndrome; POMC; circadian; autophagy; caloric restriction; fatty liver; aging; gluconeogenesis; twice-a-day feeding; myogenic progenitors
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2017.09.020

Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount as ad libitum controls but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin. ITAD feeding decreases adiposity and, unlike CR, enhances muscle mass. ITAD feeding drives energy expenditure, lowers lipid levels, suppresses gluconeogenesis, and prevents age/obesity-associated metabolic defects. Using liver-, adipose-, myogenic-, and proopiomelanocortin neuron-specific autophagy-null mice, we mapped the contribution of tissue-specific autophagy to system-wide benefits of ITAD feeding. Our studies suggest that consuming two meals a day without CR could prevent the metabolic syndrome. [Display omitted] •Isocaloric twice-a-day (ITAD) feeding impacts autophagy in multiple tissues•ITAD feeding promotes diverse metabolic benefits in multiple tissue systems•ITAD feeding prevents age- and obesity-associated metabolic defects•Tissue-specific autophagy contributes to distinct benefits of ITAD feeding Our studies suggest that consuming two meals a day with complete food restriction in between the meals is sufficient to lower blood glucose and lipid levels. This simple dietary approach activates a cell “cleansing system” called autophagy in liver, fat, brain, and muscle that helps prevent obesity and diabetes.