System-wide Benefits of Intermeal Fasting by Autophagy

Abstract

Summary Autophagy failure associates 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.

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…In a variation of time-restricted feeding paradigm, Martinez-Lopez et al tested the effect of feeding two times a day during two fixed 2 hour-long windows to institute two mandatory periods of fasting every day. Mice fed chow diet twice a day ingested similar calories per day as ad-lib fed mice, whereas mice fed a high fat diet twice a day were resistant to weight gain (128); mimicking prior observations with every other day fasting regimens in young adult mice on similar diets in our hands (72, 119). Importantly, twice a day time-restricted feeding led to reduced fat mass with commensurate increase in lean body mass, and a twice a day peak in autophagic flux in the liver versus the typical circadian pattern of highest autophagic flux observed at mid-day in ad-lib fed mice during their ‘sleep’ cycle (128).…”

“…Mice fed chow diet twice a day ingested similar calories per day as ad-lib fed mice, whereas mice fed a high fat diet twice a day were resistant to weight gain (128); mimicking prior observations with every other day fasting regimens in young adult mice on similar diets in our hands (72, 119). Importantly, twice a day time-restricted feeding led to reduced fat mass with commensurate increase in lean body mass, and a twice a day peak in autophagic flux in the liver versus the typical circadian pattern of highest autophagic flux observed at mid-day in ad-lib fed mice during their ‘sleep’ cycle (128). This was accompanied by increased anti-inflammatory signaling in adipose tissue macrophages, and salutary global metabolic effects as improved glucose tolerance, reduced hepatic gluconeogenesis, reduced hepatic lipogenesis and increased lipophagy under high fat diet conditions.…”

“…In fact, mTOR appears to regulate BMAL1 via S6K1 mediated phosphorylation, (118) and control the central circadian clock via regulating the activity of the translational repressor, eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1) (32) Intriguingly, restricting food intake to the active period (for 8 hours, at night time) in mice simultaneously restored circadian variations in TOR activity and prevented the dampening of circadian gene oscillations in mice fed high fat diet, with complete prevention of adverse metabolic consequences (85), and these findings recapitulate independent observations by other groups in murine models with varying dietary composition and timing of feeding (158, 221). Indeed, time-restricted feeding activated circadian cycling of autophagic flux in various tissues (128) and the associated metabolic effects were critically dependent on autophagy. Given prior observation that fasting induced AMPK-activation targets circadian repressor CRY for degradation (111), while feeding-induced TOR activation modulates Per gene expression (70) these observations point to intricate counter-regulation of lysosome function with circadian rhythm in driving metabolic consequences.…”

Autophagy: clocking in for the night shift

“…On the other hand, autophagy is compromised in aging and dampened autophagic flux is correlated with chronic diseases. Isocaloric twice‐a‐day feeding led to sustained diurnal autophagy in aged mice, rescuing age‐associated metabolic perturbations (Martinez‐Lopez et al , ). These findings demonstrate the influence of nutrient availability on clock‐independent diurnal gene expression patterns of metabolic genes through mTORC1 signaling and autophagy.…”

Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

“…The seahorse assay cycles were: mix for 3 minutes, wait for 2 minutes, measure for 3 minutes, repeated 5 times for baseline measurements before injecting with oligomycin. For muscle and iWAT baseline OCR measurements, we adopted previously established protocols as reported in 78, 79 . Briefly, muscle and iWAT were collected after sacrifice and washed with Krebs-Henseleit buffer (KHB) (111 mM NaCl, 4.7 mM KCl, 2 mM MgSO4, 1.2 mM Na2HPO4, 0.5 mM carnitine, 2.5 mM glucose and 10 mM sodium pyruvate).…”