How do exercise, fasting, and other lifestyle factors impact AMPK, autophagy, and metabolic health?

Exercise, Fasting, and Metabolic Health: Molecular Mechanisms and Clinical Benefits

Exercise and fasting activate powerful cellular pathways that enhance autophagy, mitochondrial function, and metabolic health through AMPK, mTORC1, and SIRT1 signaling, providing significant benefits for preventing and treating metabolic diseases.

AMPK Activation and Autophagy Regulation

• Exercise, particularly high-intensity exercise, is one of the most potent activators of AMPK (AMP-activated protein kinase), which phosphorylates ULK1 at Ser555 to initiate autophagy and mitophagy (removal of damaged mitochondria) 1, 2
• AMPK activation during exercise promotes catabolic processes while suppressing anabolic pathways, helping to maintain energy homeostasis during periods of increased energy demand 2, 3
• Treadmill running in mice causes mitochondrial oxidative stress at 3-12 hours post-exercise and mitophagy at 6 hours post-exercise, demonstrating the direct connection between exercise and mitochondrial quality control 2
• The relationship between AMPK and autophagy is context-dependent - while AMPK typically promotes autophagy during exercise, it may suppress excessive autophagy during prolonged amino acid deprivation to prevent cell death 4, 5

mTORC1 Inhibition and Autophagy

• Fasting and early time-restricted eating (eTRE) decrease insulin and amino acid levels, which inhibits mTORC1 signaling and removes its suppression of autophagy 6
• The inhibition of mTORC1 is necessary for ketogenesis during fasting, activating the PPARα-FGF-21 pathway that regulates fat metabolism and ketone body production 6
• Daily changes in glucose, amino acids, and insulin cause rhythmic mTORC1 signaling, which regulates nucleotide synthesis, ribosomal biogenesis, protein translation, and DNA replication 6
• The transition from fed to fasted state reorganizes nutrient flux, inducing catabolic pathways such as lipolysis, fatty acid oxidation, amino acid breakdown, and gluconeogenesis 6

SIRT1 and Metabolic Regulation

• Fasting increases NAD+ levels, which activates SIRT1, a deacetylase that modifies PGC-1α and FOXO transcription factors to enhance antioxidant defenses and mitochondrial function 6
• SIRT1 activation through fasting contributes to the beneficial effects of ketogenic diets and intermittent caloric restriction (ICR) on non-alcoholic fatty liver disease (NAFLD) by improving PPARα signaling 6
• Caloric restriction and fasting drastically reduce insulin/IGF-1 signaling (IIS) and mTOR signaling, which has been shown to increase lifespan in many species from worms to primates 6
• In humans, long-term caloric restriction is associated with improved cardiometabolic parameters and a reduction of atherosclerosis and diastolic dysfunction 6

Sleep and Circadian Rhythms in Metabolic Health

• Sleep promotes glymphatic clearance and circadian alignment, which improves insulin action the following day 6
• Circadian rhythms in behavior and physiology cause rhythms in 20-50% of metabolites across tissues, with daily rhythms in gene expression, protein levels, and metabolites driving the compartmentalization of catabolic and anabolic processes 6
• Daily rhythms in hormones like insulin, glucagon, cortisol, adiponectin, and ghrelin are modulated by the circadian clock and affect metabolic processes throughout the day 6
• Disruption of these rhythms through irregular eating patterns or sleep disturbances can contribute to metabolic disorders 6

Clinical Applications for Metabolic Diseases

• Exercise and dietary interventions combined lead to greater improvement of metabolic parameters and intrahepatic lipid content (IHLC) in patients with NAFLD than either intervention alone 6
• Ramadan fasting (time-restricted eating) has been shown to improve liver steatosis, lipid profiles, and oxidative stress markers in patients with NAFLD 6
• Intermittent fasting (consuming up to 75% fewer calories on fasting days) improves cardiovascular markers such as LDL cholesterol and insulin sensitivity 6
• For patients with NAFLD, lifestyle modifications including diet and physical activity to achieve weight loss are the cornerstone of treatment 6

Exercise-Induced IL-6 and GLP-1 Crosstalk

• Exercise stimulates the production of IL-6 from skeletal muscle, which promotes GLP-1 secretion from intestinal L cells and pancreatic alpha cells 6
• This exercise-induced IL-6/GLP-1 crosstalk supports post-exercise insulin secretion and glucose control, contributing to the metabolic benefits of regular physical activity 6
• The gut exhibits substantial time-of-day variation in multiple processes, including hormone secretion, which affects this crosstalk 6
• Exercise intensity matters - high-intensity exercise appears more effective at activating autophagy in human skeletal muscle than low-intensity exercise, regardless of nutritional status 1

Practical Recommendations

• Combine exercise (particularly high-intensity) with fasting or time-restricted eating for maximal metabolic benefits, as they activate complementary pathways (AMPK and mTORC1 inhibition) 6, 1
• Aim for at least 150 minutes of moderate-intensity exercise per week, with some high-intensity sessions to maximize AMPK activation and autophagy 6, 1
• Consider intermittent fasting or early time-restricted eating to enhance autophagy and metabolic flexibility 6
• Align eating patterns with circadian rhythms by avoiding late-night eating to improve metabolic health 6
• For patients with metabolic conditions like NAFLD, a combination of dietary intervention and exercise is more effective than either alone 6

Cautions and Considerations

• Excessive antioxidant supplementation may counteract the beneficial effects of exercise-induced mitohormesis by downregulating cellular stress resistance proteins 6
• The relationship between AMPK and autophagy is complex and context-dependent - AMPK can both promote and inhibit autophagy depending on the specific nutrient stress 4, 5
• Patients with advanced liver disease, especially those with sarcopenia, require specialized dietary and activity management to avoid excessive protein catabolism 6
• Fasting may not be appropriate for all individuals, particularly those with certain medical conditions or those taking medications that require food 6
• The timing of exercise and meals should be considered in relation to circadian rhythms for optimal metabolic benefits 6