Intermittent fasting (IF) describes various eating patterns with recurring periods of no or few calories, ranging from 12 hours to several days. It has gained popularity as a weight loss strategy and potential health-enhancing approach. Proponents suggest IF programs are easier to maintain than traditional calorie-controlled diets. This article examines the science behind popular IF methods, including the 12-10-8-4 diet, and provides tips for maintaining this dietary approach.
Understanding the Metabolic Switch
At the heart of intermittent fasting lies the "metabolic switch." This term describes the body's shift from using glucose (derived from glycogen) to fatty acids and ketones as its primary fuel source. This preferential shift occurs when liver glycogen stores are depleted, typically 12-36 hours after stopping food intake, and fatty acids are mobilized. Ketones become the preferred fuel for the brain and body during fasting and extended exercise. This switch from lipid synthesis and fat storage to fat mobilization (free fatty acids and ketones) is relevant to weight management.
The metabolic switch typically occurs in the third phase of fasting when glycogen stores in hepatocytes are depleted and accelerated adipose tissue lipolysis produces increased fatty acids and glycerol. The metabolic switch typically occurs between 12 to 36 hours after cessation of food consumption depending on the liver glycogen content at the beginning of the fast, and on the amount of the individual’s energy expenditure/exercise during the fast. The lipids in adipocytes (triacylglycerol and diacylglycerol) are then metabolized to FFAs, which are released into the blood (Figure 1). Simultaneously, other cell types may also begin generating ketones, with astrocytes in the brain being one notable example.
How the Metabolic Switch Preserves Muscle
A shift to fatty acid and ketone oxidation, relative to glucose oxidation, may preserve muscle mass through several potential mechanisms. Muscle cells store triglycerides in lipid droplets providing a local source of fatty acids that are utilized for β-oxidation and ketone generation during periods of prolonged fasting and extended exercise. The transcriptional regulator PPAR-α induces the expression of genes that mediate fatty acid oxidation in muscle cells, and also regulates muscle cell mitochondrial biogenesis and glucose metabolism. PPAR-α gene targets that mediate a shift in muscle cell fuel preference from glucose to fatty acids during fasting and endurance exercise include the fatty acid translocase CD36, fatty acid binding protein 3, mitochondrial uncoupling protein 3, PGC-1α, pyruvate kinase dehydrogenase 4 and forkhead box O1A.
Types of Intermittent Fasting
There are various methods of intermittent fasting, and people will prefer different styles. Each person’s experience of intermittent fasting is individual, and different styles will suit different people.
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12-Hour Fast: This involves fasting for 12 hours every day. According to some researchers, fasting for 12 to 14 hours can cause the body to turn its fat stores into energy, which releases ketones into the bloodstream, encouraging weight loss. This plan may be suitable for beginners.
16/8 Method: Also known as time-restricted eating, this involves eating all meals during an 8-hour period and fasting for 16 hours. For example, eating between 10 am and 6 pm. Short-term studies suggest that people stick to intermittent fasting diets better than low-carb diets. "The 16/8 schedule is often easier to follow, since you sleep for about half of the fasting period,"
5:2 Diet: This involves eating standard amounts of healthful food for 5 days and reducing calorie intake on the other 2 days. During the 2 fasting days, men generally consume 600 calories and women 500 calories. Typically, people separate their fasting days in the week. For example, they may fast on a Monday and Thursday and eat regularly on the other days. There should be at least 1 nonfasting day between fasting days. A 2021 randomized controlled trial found that adults with obesity who tried the 5:2 fasting method with group support experienced a greater weight loss at 6 weeks and rated the diet highly.
Alternate Day Fasting: This involves fasting every other day. Some people completely avoid solid foods on fasting days, while others allow up to 500 calories. On feeding days, people often choose to eat as much as they want. Alternate day fasting is an extreme form of intermittent fasting, and it may not be suitable for beginners or those with certain medical conditions.
Eat-Stop-Eat: This involves fasting completely for 1 or 2 days a week, eating no food for 24 hours at a time. People following this diet plan can have water, tea, and other calorie-free drinks during the fasting period. People should return to regular eating patterns on nonfasting days.
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The Warrior Diet: This involves eating very little, usually just a few servings of raw fruit and vegetables, during a 20-hour fasting window, then eating one large meal at night. The eating window is usually only around 4 hours. Supporters of the Warrior Diet claim that humans are natural nocturnal eaters and that eating at night allows the body to gain nutrients in line with its circadian rhythms.
Tips for Maintaining Intermittent Fasting
It can be challenging to stick to an intermittent fasting program. The following tips may help people stay on track and maximize the benefits of intermittent fasting:
- Staying hydrated: Drink lots of water and calorie-free drinks, such as herbal teas, throughout the day. This can help ensure you get enough electrolytes, sodium, and potassium chloride.
- Avoiding thinking about food: Plan plenty of distractions on fasting days to avoid thinking about food, such as catching up on paperwork or going to see a movie.
- Resting and relaxing: Avoid strenuous activities on fasting days, although light exercise such as yoga may be beneficial.
- Making every calorie count: If the chosen plan allows some calories during fasting periods, select nutrient-dense foods that are rich in protein, fiber, and healthful fats. Examples include beans, lentils, eggs, fish, nuts, avocado, and unprocessed meats.
- Eating high volume foods: Select filling yet low calorie foods, which include popcorn, raw vegetables, and fruits with high water content, such as grapes and melon.
- Increasing the taste without the calories: Season meals generously with garlic, herbs, spices, or vinegar. These foods are extremely low in calories yet are full of flavor.
- Choosing nutrient-dense foods after the fasting period: Eating foods that are high in fiber, vitamins, minerals, and other nutrients helps to keep blood sugar levels steady and prevent nutrient deficiencies. A balanced diet will also contribute to weight loss and overall health.
Potential Benefits of Intermittent Fasting
Intermittent fasting has been linked with various health benefits, such as reducing cardiovascular disease risk factors, such as obesity, high blood sugar, high blood pressure, and high cholesterol. Research has also suggested it may be linked to a healthier gut microbiome, with possible improved digestion and protection against infections.
Calorie restriction (CR), a reduction in caloric intake without malnutrition, has consistently been found to produce reductions in body weight and extend healthy life span across a variety of species, including non-human primates. Studies conducted in overweight humans indicate short-term CR (6-months) can significantly improve several cardiovascular risk factors, insulin-sensitivity, and mitochondrial function.
Compared to control animals fed ad libitum, rats or mice maintained on ADF and/or IF exhibit reduced plasma glucose, insulin and leptin levels, and elevated ketone and adiponectin levels, which are most pronounced on the fasting days. Mice fed a high fat diet ad libitum develop obesity, elevated plasma glucose, insulin and leptin levels, and impaired glucose tolerance; TRF mostly normalizes these adverse effects of the high fat diet. Compared to mice fed ad libitum, mice on the 4:3 IF diet also exhibit reductions in plasma glucose levels and elevations of ketone levels, which are most pronounced at the end of the fasting period.
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In mice fed a high fat diet, TRF normalizes the expression of genes involved in fatty acid metabolism (Fasn), β-oxidation (Pparγ) and antioxidant defenses (Sod1) in the liver. TRF accentuates diurnal rhythms in the expression of many different genes in liver cells including those encoding Per2, Bmal1 and Cry1. TRF also completely prevents the adverse effects of a high fat diet on the circadian rhythm of phosphorylation CREB (cyclic AMP response element-binding protein), a transcription factor that plays a critical role in gluconeogenesis during fasting. TRF also completely prevents the accumulation of lipids in the liver that occurs in mice maintained on a high fat diet. Moreover, multiple markers of inflammation (TNF-α, IL-6 and IL-1β) are reduced in livers of mice on TRF, and metabolomic analyses indicate multiple alterations in liver metabolites (palmitate, oleate and palmitoleate), bioenergetic pathway molecules (glucose-6-phosphate, citrate and opthalmate), and the antioxidant reduced glutathione, caused by a high fat diet are reversed by TRF.
Potential Risks and Considerations
Recent research from the American Heart Association (AHA) has suggested a link between intermittent fasting and cardiovascular disease. One 2024 study involving over 20,000 adults from across the United States found that people who restricted their eating to an 8-hour eating schedule - otherwise known as the 16:8 method - had a 91% higher risk of death from cardiovascular disease. However, it is important to note that the study was observational, so it does not show cause and effect, only a link between two factors.
IF diets have not always resulted in improvements in health indicators.
People who lose weight very quickly are much more likely to regain the weight over time than people who lose weight slowly through less drastic diet changes and physical activity. Losing more than 1 or 2 lb (0.5 to 1 kg) a week is not safe for most people. It can cause you to lose muscle, water, and bone density. Rapid weight loss can also cause some side effects including:Gallstones Gout Fatigue Constipation Diarrhea Nausea People who lose weight quickly are also more likely to gain back the weight quickly. This can lead to other health problems.
It is also important for people with health conditions such as diabetes to consult a healthcare professional before fasting. Low blood sugar levels from not eating for so long could cause problems.
Fasting might not be a good idea for certain groups or people with some health problems.
These forms of dieting may not be suitable for everyone. If a person is prone to disordered eating, these approaches may exacerbate their irregular relationship with food. People with health conditions, including diabetes, should speak with a doctor before attempting any form of fasting.
The Role of Sirtuins
The transition in transcriptional programs that occurs in liver cells in response to the metabolic switch is regulated, in part, by sirtuins. SIRT1 suppresses glucose production through inhibiting CRTC2 -mediated gluconeogenesis. Time-course analyses during the fasting period showed SIRT1 is activated during the metabolic switch from glycogenolysis to ketone production, which leads to deacetylation and degradation of CRTC2. In addition, SIRT1 represses lipolysis and cholesterol synthesis by regulating the activity of cholesterol catabolic pathways. SIRT1 acts as a positive regulator of liver oxidation of fatty acids. It increases the rate of fatty acid oxidation by deacetylating PGC-1α and by activating peroxisome proliferators-activated receptor α (PPARα). PPARα promotes fatty acid β oxidation in both the mitochondria and peroxisomes.
Mitochondrial SIRT3 is critical for fatty acid oxidation and ketogenesis during fasting. It directly regulates the acetylation state and activity of mitochondrial enzymes involved in the metabolic switch including acetyl CoA synthetase 2, long chain acyl-CoA dehydrogenase, ornithine transcarbamoylase and a subunit of Complex 1 in the mitochondrial electron transport chain.
Intermittent Fasting and Muscle Tissue
Given that skeletal muscle is a major consumer of energy and utilizes ketones during prolonged fasting, there have been surprisingly few studies in which the effects of IF on muscle tissue have been evaluated at any level, from molecular and biochemical to functional. Accumulating evidence suggests some organ systems exhibit similar cellular and molecular responses to aerobic exercise and IF (e.g., suppression of mTOR, stimulation of autophagy, and mitochondrial biogenesis).
IF and exercise stimulate mitochondrial biogenesis and mitochondrial stress resistance in muscle cells by mechanisms involving the second messenger Ca2+ and an increase of the AMP/ATP ratio. The elevation of cytoplasmic Ca2+ levels that mediates muscle contraction also activates Ca2+ /calmodulin-dependent protein kinase IV which, in turn, activates the transcription factor CREB. The increase in the AMP/ATP ratio activates AMPK. Both CREB and AMPK up-regulate expression of PGC-1α, a master regulator of the transcription of multiple genes which encode proteins that mediate the division and growth of mitochondria. As in liver cells, fasting induces the expression of SIRT3 in skeletal muscle cells, and SIRT3 knockout mice exhibit reduced activities of AMPK and CREB, and reduced expression of PGC-1α. SIRT3 also protects muscle cells against oxidative stress by deacetylating and activating SOD2.