Starvation response

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Starvation response in animals (including humans) is a set of adaptive biochemical and physiological changes, triggered by lack of food or extreme weight loss, in which the body seeks to conserve energy by reducing metabolic rate and/or non-resting energy expenditure to prolong survival and preserve body fat and lean mass. [1]

Contents

Equivalent or closely related terms include famine response, starvation mode, famine mode, starvation resistance, starvation tolerance, adapted starvation, adaptive thermogenesis, fat adaptation, and metabolic adaptation.

In humans

Ordinarily, the body responds to reduced energy intake by burning fat reserves and consuming muscle and other tissues. Specifically, the body burns fat after first exhausting the contents of the digestive tract along with glycogen reserves stored in liver cells via glycogenolysis, and after significant protein loss. [2] After prolonged periods of starvation, the body uses the proteins within muscle tissue as a fuel source, which results in muscle mass loss. [3]

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 similar physical characteristics. On average, the starvation response of the individuals after isolation was a 750-kilojoule (180-kilocalorie) reduction in daily total energy expenditure. 250 kJ (60 kcal) of the starvation response was explained by a reduction in fat-free mass and fat mass. An additional 270 kJ (65 kcal) was explained by a reduction in fidgeting. The remaining 230 kJ (55 kcal) was statistically insignificant. [4]

General

The energetic requirements of a body are composed of the basal metabolic rate (BMR) and the physical activity level (ERAT, exercise-related activity thermogenesis). This caloric requirement can be met with protein, fat, carbohydrates, or a mixture of those. Glucose is the general metabolic fuel, and can be metabolized by any cell. Fructose and some other nutrients can be metabolized only in the liver, where their metabolites transform into either glucose stored as glycogen in the liver and in muscles, or into fatty acids 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 daily intake of 7,500 kJ (1,800 kcal), this equates to 1,360 kJ (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 skeletal muscle. [5]

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 turned into glucose in the liver via the gluconeogenesis pathway.

When even the glucose made from glycerol reserves start declining, the liver starts producing ketone bodies. Ketone bodies are short-chain derivatives of the free fatty acids mentioned in the previous paragraph, and can cross the blood–brain barrier, meaning they 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, but are themselves too ionized to cross the blood–brain barrier[ contradictory ].

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 4 days, this goes up to 75%. [6]

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). This still leaves a deficit of about 10 g of glucose per day that must come from some other source. This deficit is supplied via gluconeogenesis from amino acids from proteolysis of body 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 the human body's muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation.

However, the body can selectively decide which cells break down protein and which do not.[ citation needed ] About 2–3 g of protein must 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, to conserve protein, this number may decrease the longer the fasting.

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.[ citation needed ] (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.

In the very obese, it has been shown that proteins can be depleted first. Accordingly, death from starvation is predicted to occur before fat reserves are used up. [7]

Biochemistry

During starvation, less than half of 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. [8]

Initially, the level of insulin in circulation drops and the levels of glucagon, epinephrine and norepinephrine rise. [9] 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 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 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 stores over 400,000 kilojoules of triglycerides (mostly in adipose tissue). [10] 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 triglyceride 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. [11]

Fatty acids 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. The body invests some of this ATP in gluconeogenesis to produce more glucose. [12]

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. [13]

After prolonged fasting,[ clarification needed ] the body begins to degrade its own skeletal muscle. To keep the brain functioning, gluconeogenesis continues 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. [14]

Autophagy then occurs at an accelerated rate. In autophagy, cells cannibalize critical molecules to produce amino acids for gluconeogenesis. This process distorts the structure of the cells, [15] and a common cause of death in starvation is due to diaphragm failure from prolonged autophagy.[ citation needed ]

In bacteria

Bacteria become highly tolerant to antibiotics when nutrients are limited. Starvation contributes to antibiotic tolerance during infection, as nutrients become limited when they are sequestered by host defenses and consumed by proliferating bacteria. [16] [17] One of the most important causes of starvation induced tolerance in vivo is biofilm growth, which occurs in many chronic infections. [18] [19] [20] 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. [21] Biofilm bacteria shows extreme tolerance to almost all antibiotic classes, and supplying limiting substrates can restore sensitivity. [22]

See also

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Ketone bodies</span> Chemicals produced during fat metabolism

Ketone bodies are water-soluble molecules or compounds that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA —which then enters the citric acid cycle and is oxidized for energy. These liver-derived ketone groups include acetoacetic acid (acetoacetate), beta-hydroxybutyrate, and acetone, a spontaneous breakdown product of acetoacetate.

<span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional energy source for the brain in the form of ketones. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

<span class="mw-page-title-main">Glycogen</span> Glucose polymer used as energy store in animals

Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

<span class="mw-page-title-main">Starvation</span> Severe deficiency in caloric energy intake, below the level needed to maintain an organisms life

Starvation is a severe deficiency in caloric energy intake, below the level needed to maintain an organism's life. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death. The term inanition refers to the symptoms and effects of starvation. Starvation by outside forces is a crime according to international criminal law and may also be used as a means of torture or execution.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is an ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Lipolysis</span> Metabolism involving breakdown of lipids

Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.

<span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Fructose bisphosphatase deficiency</span> Medical condition

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.

Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Glycogen storage disease type I</span> Medical condition

Glycogen storage disease type I is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate or glucose ; however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib.

In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride synthesis, with the latter being the process by which fatty acids are esterified to glycerol before being packaged into very-low-density lipoprotein (VLDL). Fatty acids are produced in the cytoplasm of cells by repeatedly adding two-carbon units to acetyl-CoA. Triacylglycerol synthesis, on the other hand, occurs in the endoplasmic reticulum membrane of cells by bonding three fatty acid molecules to a glycerol molecule. Both processes take place mainly in liver and adipose tissue. Nevertheless, it also occurs to some extent in other tissues such as the gut and kidney. A review on lipogenesis in the brain was published in 2008 by Lopez and Vidal-Puig. After being packaged into VLDL in the liver, the resulting lipoprotein is then secreted directly into the blood for delivery to peripheral tissues.

Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In animals, these fats are obtained from food and are synthesized by the liver. Lipogenesis is the process of synthesizing these fats. The majority of lipids found in the human body from ingesting food are triglycerides and cholesterol. Other types of lipids found in the body are fatty acids and membrane lipids. Lipid metabolism is often considered as the digestion and absorption process of dietary fat; however, there are two sources of fats that organisms can use to obtain energy: from consumed dietary fats and from stored fat. Vertebrates use both sources of fat to produce energy for organs such as the heart to function. Since lipids are hydrophobic molecules, they need to be solubilized before their metabolism can begin. Lipid metabolism often begins with hydrolysis, which occurs with the help of various enzymes in the digestive system. Lipid metabolism also occurs in plants, though the processes differ in some ways when compared to animals. The second step after the hydrolysis is the absorption of the fatty acids into the epithelial cells of the intestinal wall. In the epithelial cells, fatty acids are packaged and transported to the rest of the body.

<span class="mw-page-title-main">Bioenergetic systems</span> Metabolic processes for energy production

Bioenergetic systems are metabolic processes that relate to the flow of energy in living organisms. Those processes convert energy into adenosine triphosphate (ATP), which is the form suitable for muscular activity. There are two main forms of synthesis of ATP: aerobic, which uses oxygen from the bloodstream, and anaerobic, which does not. Bioenergetics is the field of biology that studies bioenergetic systems.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

<span class="mw-page-title-main">White adipose tissue</span> Fatty tissue composed of white adipocytes

White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is mostly metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate from precursors other than glucose. Usually, glycerol 3-phosphate is generated from glucose by glycolysis, in the liquid of the cell's cytoplasm. Glyceroneogenesis is used when the concentrations of glucose in the cytosol are low, and typically uses pyruvate as the precursor, but can also use alanine, glutamine, or any substances from the TCA cycle. The main regulator enzyme for this pathway is an enzyme called phosphoenolpyruvate carboxykinase (PEPC-K), which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. Glyceroneogenesis is observed mainly in adipose tissue, and in the liver. A significant biochemical pathway regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorders such as type 2 diabetes.

References

  1. ↑ Adapted from Wang et al. 2006, p 223.
  2. ↑ Therapeutic Fasting
  3. ↑ Couch, Sarah C. (7 April 2006). "Ask an Expert: Fasting and starvation mode". University of Cincinnati (NetWellness). Archived from the original on 19 July 2011.
  4. ↑ Weyer, Christian; Walford, Roy L; Harper, Inge T S; Milner, Mike A; MacCallum, Taber; Tataranni, P Antonio; Ravussin, Eric (2000). "Energy metabolism after 2 y of energy restriction: the Biosphere 2 experiment". American Journal of Clinical Nutrition. 72 (4): 946–953. doi: 10.1093/ajcn/72.4.946 . PMID   11010936.
  5. ↑ Jensen, J.; Rustad, P. I.; Kolnes, A. J.; Lai, Y. C. (2011). "The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise". Frontiers in Physiology. 2: 112. doi: 10.3389/fphys.2011.00112 . PMC   3248697 . PMID   22232606.
  6. ↑ C. J. Coffee, Quick Look: Metabolism, Hayes Barton Press, Dec 1, 2004, p.169
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  8. ↑ Cahill, George F.; Veech, Richard L. (2003). "Ketoacids? Good medicine?". Transactions of the American Clinical and Climatological Association. 114: 149–161, discussion 162–163. ISSN   0065-7778. PMC   2194504 . PMID   12813917.
  9. ↑ Zauner, C., Schneeweiss, B., Kranz, A., Madl, C., Ratheiser, K., Kramer, L., ... & Lenz, K. (2000). Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine. The American Journal of Clinical Nutrition, 71(6), 1511-1515.
  10. ↑ Clark, Nancy. Nancy Clark's Sports Nutrition Guidebook. Champaign, IL: Human Kinetics, 2008. pg. 111
  11. ↑ Yamaguchi; et al. (2004). "CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome". J. Biol. Chem. 279 (29): 30490–30497. doi: 10.1074/jbc.m403920200 . PMID   15136565.
  12. ↑ Zechner, R, Kienesberger, PC, Haemmerle, G, Zimmermann, R and Lass, A (2009) Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores, J Lipid Res, 50, 3-21
  13. ↑ McCue, MD (2010) Starvation physiology: reviewing the different strategies animals use to survive a common challenge, Comp Biochem Physiol, 156, 1-18
  14. ↑ Cahill, GF; Parris, Edith E.; Cahill, George F. (1970). "Starvation in man". N Engl J Med. 282 (12): 668–675. doi:10.1056/NEJM197003192821209. PMID   4915800.
  15. ↑ Yorimitsu T, Klionsky DJ (2005). "Autophagy: molecular machinery for self-eating". Cell Death and Differentiation. 12 (Suppl 2): 1542–1552. doi:10.1038/sj.cdd.4401765. PMC   1828868 . PMID   16247502.
  16. ↑ McDERMOTT, W (February 1958). "Microbial persistence". The Yale Journal of Biology and Medicine. 30 (4): 257–91. PMC   2603844 . PMID   13531168.
  17. ↑ McCune, Robert M.; Dineen, Paul A. Peter; Batten, John C. (August 1956). "The Effect of Antimicrobial Drugs on an Experimental Staphylococcal Infection in Mice". Annals of the New York Academy of Sciences. 65 (3): 91–102. Bibcode:1956NYASA..65...91M. doi:10.1111/j.1749-6632.1956.tb36627.x. PMID   13363203. S2CID   40134313.
  18. ↑ Fux, C.A.; Costerton, J.W.; Stewart, P.S.; Stoodley, P. (January 2005). "Survival strategies of infectious biofilms". Trends in Microbiology. 13 (1): 34–40. doi:10.1016/j.tim.2004.11.010. PMID   15639630. S2CID   10216159.
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