Starvation response
Encyclopedia
Starvation response in animals is a set of adaptive biochemical and physiological changes that reduce metabolism
in response to a lack of food.
Equivalent or closely related terms include famine response, starvation mode, famine mode, starvation resistance, starvation tolerance, adapted starvation, adaptive thermogenesis and metabolic adaptation.
Ordinarily, the body responds to reduced caloric intake by burning fat reserves first, and only consumes muscle and other tissues when those reserves are exhausted. Specifically, the body burns fat after first exhausting the contents of the digestive tract along with glycogen reserves stored in muscle and liver cells. After prolonged periods of starvation, the body will utilize the proteins within muscle tissue as a fuel source. People who practice fasting
on a regular basis, such as those adhering to caloric restricted diets, can prime their bodies to abstain from food without burning lean tissue.. Resistance training (such as weight lifting) can also prevent the loss of muscle mass while a person is caloric restricted.
as its main metabolic fuel if it is available. About 25% of the total body glucose consumption occurs in the brain
, more than any other organ. The rest of the glucose consumption fuels muscle tissue and red blood cells.
Glucose can be obtained directly from dietary sugars and carbohydrates. In the absence of dietary sugars and carbohydrates, it is obtained from the breakdown of glycogen
. Glycogen is a readily-accessible storage form of glucose, stored in small quantities in the liver and muscles. The body's glycogen reserve can provide glucose for about 6 hours.
After the glycogen reserve is used up, glucose can be obtained from the breakdown of fats. Fats from adipose tissue
are broken down into glycerol
and free fatty acids. Glycerol can then be used by the liver as a substrate for gluconeogenesis
, to produce glucose.
Fatty acids can be used directly as an energy source by most tissues in the body, except the brain, since fatty acids are unable to cross the blood-brain barrier
. After the exhaustion of the glycogen reserve, and for the next 2-3 days, fatty acids are the principal metabolic fuel. At first, the brain continues to use glucose, because, if a non-brain tissue is using fatty acids as its metabolic fuel, the use of glucose in the same tissue is switched off. Thus, when fatty acids are being broken down for energy, all of the remaining glucose is made available for use by the brain.
However, the brain requires about 120 g of glucose per day (equivalent to the sugar in 3 cans of soda), and at this rate the brain will quickly use up the body's remaining carbohydrate stores. However, the body has a "backup plan," which involves molecules known as ketone bodies. Ketone bodies
are short-chain derivatives of fatty acids. These shorter molecules can cross the blood-brain barrier and can be used by the brain as an alternative metabolic fuel.
After 2 or 3 days of fasting, the liver begins to synthesize ketone bodies from precursors obtained from fatty acid breakdown. The brain uses these ketone bodies as fuel, thus cutting its requirement for glucose. After fasting for 3 days, the brain gets 30% of its energy from ketone bodies. After 4 days, this goes up to 70%.
Thus, the production of ketone bodies cuts the brain's glucose requirement from 120 g per day to about 30 g per day. Of the remaining 30 g requirement, 20 g per day can be produced by the liver from glycerol (itself a product of fat breakdown). But this still leaves a deficit of about 10 g of glucose per day that must be supplied from some other source. This other source will be the body's own proteins.
After several days of fasting, all cells in the body begin to break down protein
. This releases amino acids into the bloodstream, which can be converted into glucose by the liver. Since much of our muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation
.
However, the body is able to selectively decide which cells will break down protein and which will not. About 2–3 g of protein has to be broken down to synthesise 1 g of glucose; about 20–30 g of protein is broken down each day to make 10 g of glucose to keep the brain alive. However, this number may decrease the longer the fasting period is continued in order to conserve protein.
Starvation ensues when the fat reserves are completely exhausted and protein is the only fuel source available to the body. Thus, after periods of starvation, the loss of body protein affects the function of important organs, and death results, even if there are still fat reserves left unused. (In a leaner person, the fat reserves are depleted earlier, the protein depletion occurs sooner, and therefore death occurs sooner.)
The ultimate cause of death is, in general, cardiac arrhythmia or cardiac arrest
brought on by tissue degradation and electrolyte
imbalances.
to function. During starvation, less than half the energy used by the brain comes from metabolized glucose. Because the human brain can use ketone bodies
as major fuel sources, the body is not forced to break down skeletal muscles at a high rate, thereby maintaining both cognitive function and mobility for up to several weeks. This response is extremely important in human evolution
and allowed for humans to continue to find food effectively even in the face of prolonged starvation.
Initially, the level of insulin
in circulation drops and the levels of glucagon
and epinephrine
rise, releasing high levels of glycogen
and upregulating gluconeogenesis
, lipolysis
, and ketogenesis
. The body’s glycogen stores are consumed in about 24 hours. In a normal 70 kg adult, only about 2,000 kilocalories of glycogen are stored in the body (mostly in the striated muscles
).The body also engages in gluconeogenesis in order to convert glycerol and glucogenic amino acids into glucose for metabolism. Another adaptation is the Cori cycle
, which involves shuttling lipid-derived calories in glucose to peripheral glycolytic tissues, which in turn send the lactate
back to the liver
for resynthesis to glucose. Because of these processes, blood glucose levels will remain relatively stable during prolonged starvation.
However, the main source of energy during prolonged starvation is derived from triglycerides. Compared to the 2,000 kilocalories of stored glycogen, lipid fuels are much richer in caloric content, and a 70 kg adult will store over 100,000 kilocalories of triglycerides (mostly in adipose tissue). Triglycerides are broken down to fatty acids via lipolysis. Epinephrine precipitates lipolysis by activating protein kinase A, which phosphorylates hormone sensitive lipase (HSL)
and perilipin
. These enzymes, along with CGI-58 and adipose triglyeride lipase (ATGL), complex at the surface of lipid droplets. The concerted action of ATGL and HSL liberates the first two fatty acids. Cellular monoacylglycerol lipase (MGL)
, liberates the final fatty acid. The remaining glycerol enters gluconeogenesis.
Fatty acids by themselves cannot be used as a direct fuel source. They must first undergo beta oxidation
in the mitochondria (mostly of skeletal muscle, cardiac muscle, and liver cells). Fatty acids are transported into the mitochondria as an acyl-carnitine
via the action of the enzyme CAT-1. This step controls the metabolic flux of beta oxidation. The resulting acetyl-CoA enters the TCA cycle and undergoes oxidative phosphorylation
to produce ATP
. Some of this ATP is invested in gluconeogenesis in order to produce more glucose.
Triglycerides are too hydrophobic to cross into brain cells, so the liver must convert fatty acids into ketones through ketogenesis. The resulting ketone bodies, acetoacetate and β-hydroxybutyrate, are amphipathic and can be transported into the brain (and muscles) and broken down into acetyl-CoA
for use in the TCA cycle. Acetoacetate
breaks down spontaneously into acetone, and the acetone is released through the urine and lungs to produce the “acetone breath” that accompanies prolonged fasting. The brain also uses glucose during starvation, but most of the body’s glucose is allocated to the skeletal muscles and red blood cells. The cost of the brain using too much glucose is muscle loss. If the brain and muscles relied entirely on glucose, the body would lose 50% of its nitrogen content in 8-10 days.
After prolonged fasting, the body begins to degrade its own skeletal muscle. In order to keep the brain functioning, gluconeogenesis will continue to generate glucose, but glucogenic amino acids, primarily alanine, are required. These come from the skeletal muscle. Late in starvation, when blood ketone levels reach 5-7 mM, ketone use in the brain rises, while ketone use in muscles drops.
Autophagy
then occurs at an accelerated rate. In autophagy, cells will cannibalize critical molecules to produce amino acids for gluconeogenesis. This process distorts the structure of the cells, and a common cause of death in starvation is due to diaphragm
failure from prolonged autophagy.
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in response to a lack of food.
Equivalent or closely related terms include famine response, starvation mode, famine mode, starvation resistance, starvation tolerance, adapted starvation, adaptive thermogenesis and metabolic adaptation.
In humans
Starvation mode is a state in which the body is responding to prolonged periods of low caloric intake levels. During short periods of caloric abstinence, the human body will burn primarily free fatty acids from body fat stores. After prolonged periods of starvation the body has depleted its body fat and begins to burn lean tissue and muscle as a fuel source.Ordinarily, the body responds to reduced caloric intake by burning fat reserves first, and only consumes muscle and other tissues when those reserves are exhausted. Specifically, the body burns fat after first exhausting the contents of the digestive tract along with glycogen reserves stored in muscle and liver cells. After prolonged periods of starvation, the body will utilize the proteins within muscle tissue as a fuel source. People who practice fasting
Fasting
Fasting is primarily the act of willingly abstaining from some or all food, drink, or both, for a period of time. An absolute fast is normally defined as abstinence from all food and liquid for a defined period, usually a single day , or several days. Other fasts may be only partially restrictive,...
on a regular basis, such as those adhering to caloric restricted diets, can prime their bodies to abstain from food without burning lean tissue.. Resistance training (such as weight lifting) can also prevent the loss of muscle mass while a person is caloric restricted.
Process
The body uses glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
as its main metabolic fuel if it is available. About 25% of the total body glucose consumption occurs in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, more than any other organ. The rest of the glucose consumption fuels muscle tissue and red blood cells.
Glucose can be obtained directly from dietary sugars and carbohydrates. In the absence of dietary sugars and carbohydrates, it is obtained from the breakdown of glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
. Glycogen is a readily-accessible storage form of glucose, stored in small quantities in the liver and muscles. The body's glycogen reserve can provide glucose for about 6 hours.
After the glycogen reserve is used up, glucose can be obtained from the breakdown of fats. Fats from adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
are broken down into glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
and free fatty acids. Glycerol can then be used by the liver as a substrate for gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, to produce glucose.
Fatty acids can be used directly as an energy source by most tissues in the body, except the brain, since fatty acids are unable to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. After the exhaustion of the glycogen reserve, and for the next 2-3 days, fatty acids are the principal metabolic fuel. At first, the brain continues to use glucose, because, if a non-brain tissue is using fatty acids as its metabolic fuel, the use of glucose in the same tissue is switched off. Thus, when fatty acids are being broken down for energy, all of the remaining glucose is made available for use by the brain.
However, the brain requires about 120 g of glucose per day (equivalent to the sugar in 3 cans of soda), and at this rate the brain will quickly use up the body's remaining carbohydrate stores. However, the body has a "backup plan," which involves molecules known as ketone bodies. Ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...
are short-chain derivatives of fatty acids. These shorter molecules can cross the blood-brain barrier and can be used by the brain as an alternative metabolic fuel.
After 2 or 3 days of fasting, the liver begins to synthesize ketone bodies from precursors obtained from fatty acid breakdown. The brain uses these ketone bodies as fuel, thus cutting its requirement for glucose. After fasting for 3 days, the brain gets 30% of its energy from ketone bodies. After 4 days, this goes up to 70%.
Thus, the production of ketone bodies cuts the brain's glucose requirement from 120 g per day to about 30 g per day. Of the remaining 30 g requirement, 20 g per day can be produced by the liver from glycerol (itself a product of fat breakdown). But this still leaves a deficit of about 10 g of glucose per day that must be supplied from some other source. This other source will be the body's own proteins.
After several days of fasting, all cells in the body begin to break down protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
. This releases amino acids into the bloodstream, which can be converted into glucose by the liver. Since much of our muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation
Starvation
Starvation is a severe deficiency in caloric energy, nutrient and vitamin intake. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death...
.
However, the body is able to selectively decide which cells will break down protein and which will not. About 2–3 g of protein has to be broken down to synthesise 1 g of glucose; about 20–30 g of protein is broken down each day to make 10 g of glucose to keep the brain alive. However, this number may decrease the longer the fasting period is continued in order to conserve protein.
Starvation ensues when the fat reserves are completely exhausted and protein is the only fuel source available to the body. Thus, after periods of starvation, the loss of body protein affects the function of important organs, and death results, even if there are still fat reserves left unused. (In a leaner person, the fat reserves are depleted earlier, the protein depletion occurs sooner, and therefore death occurs sooner.)
The ultimate cause of death is, in general, cardiac arrhythmia or cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
brought on by tissue degradation and electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
imbalances.
Biochemistry
The human starvation response is unique among animals in that human brains do not require the ingestion of glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to function. During starvation, less than half the energy used by the brain comes from metabolized glucose. Because the human brain can use ketone bodies
Ketone bodies
Ketone bodies are three water-soluble compounds that are produced as by-products when fatty acids are broken down for energy in the liver and kidney. They are used as a source of energy in the heart and brain. In the brain, they are a vital source of energy during fasting...
as major fuel sources, the body is not forced to break down skeletal muscles at a high rate, thereby maintaining both cognitive function and mobility for up to several weeks. This response is extremely important in human evolution
Human evolution
Human evolution refers to the evolutionary history of the genus Homo, including the emergence of Homo sapiens as a distinct species and as a unique category of hominids and mammals...
and allowed for humans to continue to find food effectively even in the face of prolonged starvation.
Initially, the level of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
in circulation drops and the levels of glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
rise, releasing high levels of glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
and upregulating gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
, and ketogenesis
Ketogenesis
Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.-Production:Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate...
. The body’s glycogen stores are consumed in about 24 hours. In a normal 70 kg adult, only about 2,000 kilocalories of glycogen are stored in the body (mostly in the striated muscles
Striated muscle
Striated muscle tissue is a form of fibers that are combined into parallel fibers. More specifically, it can refer to:* Cardiac muscle .* Skeletal muscle* Branchiomeric muscles...
).The body also engages in gluconeogenesis in order to convert glycerol and glucogenic amino acids into glucose for metabolism. Another adaptation is the Cori cycle
Cori cycle
The Cori cycle , named after its discoverers, Carl Cori and Gerty Cori, refers to the metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate.-Cycle:Muscular...
, which involves shuttling lipid-derived calories in glucose to peripheral glycolytic tissues, which in turn send the lactate
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
back to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
for resynthesis to glucose. Because of these processes, blood glucose levels will remain relatively stable during prolonged starvation.
However, the main source of energy during prolonged starvation is derived from triglycerides. Compared to the 2,000 kilocalories of stored glycogen, lipid fuels are much richer in caloric content, and a 70 kg adult will store over 100,000 kilocalories of triglycerides (mostly in adipose tissue). Triglycerides are broken down to fatty acids via lipolysis. Epinephrine precipitates lipolysis by activating protein kinase A, which phosphorylates hormone sensitive lipase (HSL)
Hormone-sensitive lipase
Hormone-sensitive lipase also previously known as cholesteryl ester hydrolase is an enzyme that, in humans, is encoded by the LIPE gene....
and perilipin
Perilipin
Perilipin, also known as lipid droplet-associated protein or PLIN, is a protein that, in humans, is encoded by the PLIN gene.- Function :Perilipin is a protein that coats lipid droplets in adipocytes, the fat-storing cells in adipose tissue...
. These enzymes, along with CGI-58 and adipose triglyeride lipase (ATGL), complex at the surface of lipid droplets. The concerted action of ATGL and HSL liberates the first two fatty acids. Cellular monoacylglycerol lipase (MGL)
Monoacylglycerol lipase
Monoacylglycerol lipase, also known as MAG lipase, MAGL, MGL or MGLL is a protein that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases...
, liberates the final fatty acid. The remaining glycerol enters gluconeogenesis.
Fatty acids by themselves cannot be used as a direct fuel source. They must first undergo beta oxidation
Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....
in the mitochondria (mostly of skeletal muscle, cardiac muscle, and liver cells). Fatty acids are transported into the mitochondria as an acyl-carnitine
Carnitine
Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
via the action of the enzyme CAT-1. This step controls the metabolic flux of beta oxidation. The resulting acetyl-CoA enters the TCA cycle and undergoes oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
to produce ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. Some of this ATP is invested in gluconeogenesis in order to produce more glucose.
Triglycerides are too hydrophobic to cross into brain cells, so the liver must convert fatty acids into ketones through ketogenesis. The resulting ketone bodies, acetoacetate and β-hydroxybutyrate, are amphipathic and can be transported into the brain (and muscles) and broken down into acetyl-CoA
Acetyl-CoA
Acetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
for use in the TCA cycle. Acetoacetate
Acetoacetic acid
Acetoacetic acid is the organic compound with the formula CH3CCH2CO2H. It is the simplest beta-keto acid group and like other members of this class is unstable.- Synthesis and properties :...
breaks down spontaneously into acetone, and the acetone is released through the urine and lungs to produce the “acetone breath” that accompanies prolonged fasting. The brain also uses glucose during starvation, but most of the body’s glucose is allocated to the skeletal muscles and red blood cells. The cost of the brain using too much glucose is muscle loss. If the brain and muscles relied entirely on glucose, the body would lose 50% of its nitrogen content in 8-10 days.
After prolonged fasting, the body begins to degrade its own skeletal muscle. In order to keep the brain functioning, gluconeogenesis will continue to generate glucose, but glucogenic amino acids, primarily alanine, are required. These come from the skeletal muscle. Late in starvation, when blood ketone levels reach 5-7 mM, ketone use in the brain rises, while ketone use in muscles drops.
Autophagy
Autophagy
In cell biology, autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance...
then occurs at an accelerated rate. In autophagy, cells will cannibalize critical molecules to produce amino acids for gluconeogenesis. This process distorts the structure of the cells, and a common cause of death in starvation is due to diaphragm
Thoracic diaphragm
In the anatomy of mammals, the thoracic diaphragm, or simply the diaphragm , is a sheet of internal skeletal muscle that extends across the bottom of the rib cage. The diaphragm separates the thoracic cavity from the abdominal cavity and performs an important function in respiration...
failure from prolonged autophagy.