Starvation response

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.

Starvation contributes to tolerance during infection, as nutrients become limited when they are sequestered by host defenses and consumed by proliferating bacteria. One of the most important causes of starvation induced tolerance in vivo is biofilm growth, which occurs in many chronic infections. Starvation in biofilms is due to nutrient consumption by cells located on the periphery of biofilm clusters and by reduced diffusion of substrates through the biofilm. Biofilm bacteria shows extreme tolerance to almost all antibiotic classes, and supplying limiting substrates can restore sensitivity.

In humans
Starvation mode is a state in which the body is responding to prolonged periods of low energy intake levels. During short periods of energy 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 energy 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 energy restricted diets, can prime their bodies to abstain from food while reducing the amount of muscle burned. Resistance training (such as weight lifting) can also prevent the loss of muscle mass while a person is energy-restricted.

Magnitude and composition
The magnitude and composition of the starvation response (i.e. metabolic adaptation) was estimated in a study of 8 individuals living in isolation in Biosphere 2 for two years. During their isolation, they gradually lost an average of 15% (range: 9–24%) of their body weight due to harsh conditions. On emerging from isolation, the eight isolated individuals were compared with a 152-person control group that initially had had similar physical characteristics. On average, the starvation response of the individuals after isolation was a 180 kcal reduction in daily total energy expenditure. 60 kcal of the starvation response was explained by a reduction in fat-free mass and fat mass. An additional 65 kcal was explained by a reduction in fidgeting, and the remaining 55 kcal was statistically insignificant.

General
The energetic requirements of a body are composed of the basal metabolic rate and the physical activity level. This caloric requirement can be met with protein, fat, carbohydrates or a mixture of them. Glucose is the general metabolic fuel, which can be metabolized by any cell. Fructose and some other nutrients can only be metabolized in the liver, where their metabolites are transformed either into glucose and stored as glycogen, both in the liver and in the muscles; or into fatty acids which are stored in adipose tissue.

Because of the blood–brain barrier, getting nutrients to the human brain is especially dependent on molecules that can pass this barrier. The brain itself consumes about 18% of the basal metabolic rate: on a total intake of 1800 kcal/day, this equates to 324 kcal, or about 80 g of glucose. About 25% of total body glucose consumption occurs in the brain.

Glucose can be obtained directly from dietary sugars and by the breakdown of other carbohydrates. In the absence of dietary sugars and carbohydrates, glucose is obtained from the breakdown of stored glycogen. Glycogen is a readily-accessible storage form of glucose, stored in notable quantities in the liver and in small quantities in the muscles. The body's glycogen reserve is enough to provide glucose for about 24 hours.

When the glycogen reserve is depleted, glucose can be obtained from the breakdown of fats from adipose tissue. Fats are broken down into glycerol and free fatty acids, with the glycerol being utilized in the liver as a substrate for gluconeogenesis.

When even the glycerol reserves are depleted, or sooner, the liver will start producing ketone bodies. Ketone bodies are short-chain derivatives of fatty acids, which, since they are capable of crossing the blood–brain barrier, can be used by the brain as an alternative metabolic fuel. Fatty acids can be used directly as an energy source by most tissues in the body.

Timeline
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.

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 40 days, this goes up to 75%.

Thus, the production of ketone bodies cuts the brain's glucose requirement from 80 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 synthesize 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.

Timeline
0 hours:        Glucose still used as primary fuel.

0 – 6 hours:      Glycogen is broken down to produce glucose for the body.

6 – 72 hours:     Glycogen stores are used up and the body breaks down fatty acids. Ketone bodies are produced to help feed the brain.

The body's rate of protein loss is greatest during the first 72 hours. After several days of starvation the body adapts and starts to conserve protein.

Biochemistry
The human starvation response is unique among animals in that human brains do not require the ingestion of glucose 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, epinephrine and norepinephrine rise. . At this time, there is an up-regulation of glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. The body’s glycogen stores are consumed in about 24 hours. In a normal 70 kg adult, only about 8,000 kilojoules 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 energy 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 8,000 kilojoules of stored glycogen, lipid fuels are much richer in energy content, and a 70 kg adult will store over 400,000 kilojoules 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 and long-chain fatty acids are too hydrophobic to cross into brain cells, so the liver must convert them into short-chain fatty acids and ketone bodies 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.

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