Intermittent Fasting and Its Metabolic Effects

Intermittent fasting is a nutrition method that we have started to hear about a lot today and whose practices are becoming more common.

It appears as a medical nutrition method used in many chronic diseases and for healthy aging. Is all this popularity in vain? Or let's see if he deserves it.

First of all, let's get to know hunger;

Hunger is a state of stopping eating for approximately 4-6 hours. The satiety that begins with the meal continues for up to 4 hours. At the end of this period, which is considered the satiety period, the person begins to feel hungry. The state of hunger begins 4 hours after the meal and is fully formed within 6 hours.  Hunger that lasts more than 12 hours is a prolonged hunger period.

During the developmental process, organisms have developed mechanisms that can adapt according to the amount of food available. A decrease in the amount of nutrients causes mechanisms and cellular responses to be activated to maintain cellular energy levels. Hormonal changes that occur in response to decreasing levels of glucose and amino acids in the blood manage these complex responses.

Within 1-2 hours after the meal, the food eaten begins to be broken down in the stomach and intestines and absorbed into glucose and amino acids. Fats are first packaged into chylomicrons and pass into the arterial blood via the lymphatic route. Glucose, amino acids and triglycerides increase in the blood. Meanwhile, insulin release increases due to the increase in glucose and parasympathetic activity in pancreatic Beta cells. Insulin lowers blood levels by introducing these increased molecules into the tissues and allowing them to be used or stored.

With the decrease in blood glucose level and insulin, the increase in glucagon comes into play. Here, the blood glucose level is tried to be kept around 80 mg/dl. There are three main mechanisms why this happens:

• The release of glucose into the blood from the liver
• Release of fatty acids from fatty tissue into the blood
• Increased use of fatty acids instead of glucose as an energy source in the liver and muscle tissue.

There are glut proteins that allow glucose to enter the cell.  Transport of glucose in organs occurs with different glut molecules. While glut 1-2-3 is independent of insulin, glut 4 is insulin dependent, that is, it does not work actively during prolonged fasting when the amount of insulin in the blood is low.

Glucose formed from glycogen breakdown cannot be used adequately by muscle and fat tissue, which uses insulin-dependent glut 4 when the insulin level is low. The glucose here is used by erythrocytes, brain cells, and kidney medulla cells that work independently of insulin.  In the meantime, muscles and liver use fatty acids. During prolonged fasting, liver glycogen stores begin to be depleted, and gluconeogenesis continues from lactic acid and alanine. During the burning of fat in muscle tissue, triglycerides are converted into fatty acids and glycerol. The remaining glucose requirement is obtained from amino acids obtained by hydrolysis of proteins in muscle tissue. If starvation lasts for a long time, the organism starts to use fatty acids by reducing the use of glucose to prevent protein breakdown. It does this by producing ketone bodies (b-hydroxybutyrate, acetoacetate, acetone) from fatty acids and by using the glycerol released from fats in the production of glucose. The primary important thing is to keep the blood glucose level around 80 mg / dL and not to drop it below 40 mg / dL.

To briefly summarize what happens in our body during hunger;

• Glucose and fatty acids are the main nutritional sources for cells. After meals, glucose is used for energy consumption and fatty acids are stored in adipose tissue in the form of triglycerides. During fasting, triglycerides in adipose tissue are converted into fatty acids and glycerol and used as an energy source. Again, the energy needs of the brain and central nervous system, which cannot use fatty acids as an energy source during the fasting process, are met by converting fatty acids into ketone bodies in the liver. Fasting for 10 to 14 hours or more causes liver glycogen stores to be depleted and triglycerides in adipocytes  to free fatty acids  causes hydrolysis. FFAs released into the circulation transport ketone bodies such as acetoacetate and β-hydroxybutyrate to hepatocytes, where they are produced.
• Ketone bodies are not only used as fuel but also regulate the expression and activity of many proteins (SIRT, BDNF, FGF21) and molecules known to affect health and aging.
• In studies conducted in the past years, intermittent fasting and its metabolic effects were attributed only to the decreased formation of oxygen radicals that developed due to weight loss and calorie restriction. However, recent studies have shown that intermittent fasting without calorie restriction in humans and animals is accompanied by metabolic improvement, indicating evolutionarily preserved adaptive cellular responses integrated between and within organs.
• During fasting, cells improve glucose regulation and increase stress resistance.It activates pathways that suppress inflammation and inflammation, increasing internal defenses against oxidative and metabolic stress and eliminating or repairing them. The most important of these ways is autophagy. Let's see what this autophagy is;

Autophagy

• The 2016 Nobel Prize in Medicine was awarded to Japanese scientist Yoshinori Ohsumi, who discovered and elucidated the mechanisms underlying autophagy, a fundamental process of degradation and recycling of cellular components.
• Autophagy is a destruction pathway that functions in all nucleated cells, from yeast to humans, and is of critical importance in maintaining intracellular balance. Under basic conditions, autophagy plays a role in breaking down waste within the cell and delivering it to the cell for recycling.
• In conditions that may be harmful to the cell, such as starvation, inflammation, hypoxia, oxygen stress and endoplasmic reticulum stress; It provides alternative building blocks and energy sources to cell metabolism by recycling nutrients. In this way, it plays a role in the survival of cells by adapting to difficult conditions.
• In order to perform its cellular function, it requires more than 30 autophagy proteins to work in harmony. The degradation of intracellular fat, sugar, long-lived proteins, and proteins that are misfolded or precipitated due to a disease-related mutation depends on autophagy.
• In addition, autophagy provides the digestion and quality control of intracellular bacteria, viruses and parasites, and the digestion and quality control of organelles such as mitochondria and endoplasmic reticulum.
• The main molecule regulating autophagy is MTOR Protein. This protein prevents the onset of autophagic destruction when there is sufficient amount of nutrients in the intracellular environment.

In cases where the amount of nutrients is insufficient, autophagy is initiated. Energy is obtained by breaking down damaged molecules in the body, meaning the body becomes a recycling factory on its own.

If we look at the studies;

• Rothchild et al. in their meta-analysis study; 3-4, 7-8 and 10-12 hour time-restricted feeding studies conducted with humans and animals were examined. The results obtained from animal studies show that time-restricted feeding (intermittent fasting); It has been determined that it positively affects decreases in body weight, total cholesterol, triglyceride, glucose, insulin, IL-6 and TNF-α concentrations and improvements in insulin sensitivity.
• While it was emphasized in the study that these metabolic effects are probably due to body weight loss, although the reasons are not fully known, in the study conducted by Sutton et al., the effect of time-restricted nutrition on cardiometabolic parameters in individuals without loss of body weight was investigated, and for this purpose, it provides individuals with the daily energy requirement to maintain their body weight. diet was given. As a result of the study, a decrease was observed in fasting insulin, insulin resistance, systolic and diastolic blood pressure values of individuals with prediabetes, regardless of body weight.
• In the study conducted by Moro et al. with endurance athletes, individuals were ensured to receive their daily energy needs in three meals, at certain times and within eight hours, thus eliminating the differences that the number of meals would create in the evaluated parameters. As a result of the study, a decrease in IL-6, TNF-alpha, leptin values and an increase in adiponectin values were observed in the TRF group. In addition, there was a significant decrease in fat mass in people in the TRF group compared to the ND group, and it was observed that the fat-free mass of both groups was preserved.
• In the proteomic study conducted by Mindikoğlu et al. Fourteen healthy subjects fasted from dawn to dusk for more than 14 hours per day. During this period, no calorie restriction was applied and there was no weight loss. The fasting period was 30 consecutive days. Serum samples were taken before 30-day intermittent fasting, at the end of the 4th week of 30-day intermittent fasting, and one week after 30-day intermittent fasting. increases key regulatory proteins such as remodeling; Serum proteomes have been shown to regulate the immune system, cognitive function, protecting against cancer, obesity, diabetes, metabolic syndrome, inflammation, Alzheimer's disease, and various neuropsychiatric disorders.

As a result, intermittent fasting;

• Insulin resistance,
• Obesity,
• Diabetes,
• Metabolic syndrome,
• In the prevention and treatment of chronic inflammatory diseases, Alzheimer's, Neuropsychiatric diseases and cancer  It is a nutritional model that can be used.

References;

Rothschild J, Hoddy KK, Jambazian P, Varady KA. Timerestricted feeding and risk of metabolic disease: a review of human and animal studies. Nutr Rev 2014; 72(5): 308–18. Doi: 10.1111/nure.12104.

Moro T, Tinsley G. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med. 2016;14(1):290.

Mindikoglu A, Abdulsada M. Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects. J Proteomics. 2020 Apr 15;217:103645. doi: 10.1016/j.jprot.2020.103645