What does your body eat first when starving

Abstract

Starvation is a process that begins after a meal is digested and extends until food is again ingested; the term is often used interchangeably with fasting, which implies a voluntary cessation of food intake. Major metabolic adaptations occur to deal with starvation, most notable a switch in the fuel that is used. All mammals, including humans, have relatively little carbohydrate reserves; a 70-kg man has approximately 900 kcal of carbohydrate stored as glycogen in skeletal muscle and liver, but has 141 000 kcal of triglyceride in adipose tissue. The brain and red blood cells use glucose as a fuel (the brain uses approximately 600 kcal d−1). The glucose that is synthesized (gluconeogenesis) during starvation uses amino acids as a source of carbon. To minimize the loss of lean body mass during starvation, a major adaptation must occur to allow the use of fatty acids and their oxidative product, ketone bodies, as the major sources of fuel. This article details the metabolic adaptations that occur during starvation and the methods used to assess these changes.

Protein turnover

While considerable amounts of body fat may be lost during starvation, the main danger comes from the breakdown of protein. The obvious general muscle wasting is an ominous feature that points to the parallel loss of functional proteins in heart, liver, kidneys, and other tissues.

About 150g essential amino acids, and a similar quantity of non-essential amino acids is needed daily for the synthesis of proteins in a healthy male of average weight (Munro, 1975). Much of this can be derived from the breakdown of body proteins.

When energy intakes cease to be adequate in a previously well-nourished person and the one-day supply of glycogen is used up, cellular free amino acids, regular protein turnover, and increased mobilization of a small pool of proteins with particularly rapid turnover (‘labile protein’) can cover glucose needs during the first hours of fasting. It is mainly the brain's heavy reliance on a steady supply of glucose that makes gluconeogenesis from amino acids so important.

Increasing secretion of glucagon in response to declining blood glucose levels promotes the mobilization of protein in skeletal muscle and other tissues. Most of the hydrolyzed protein reaches blood as alanine and glutamine. The liver and kidneys can use these non-essential amino acids for gluconcogenesis and send the glucose out into circulation again for use by brain, muscle, and other glucose-dependent tissues. The liver also secretes glutamine into blood as a nitrogen and fuel carrier for other tissues (Watford et al., 2002). The term alanine cycle alludes to the use of alanine as a shuttle for nitrogen and carbon transfer between muscle and liver. The increased breakdown of tissue protein and oxidation of the released amino acids is evident from the doubling of urea production during the first days of fasting (Giesecke et al., 1989). Hormones (adrenaline, Cortisol) and cytokines (e.g. interleukin 6) that increase in circulation after traumatic stress and infection rapidly draw on intracellular free amino acids (Hammarqvist et al., 2001) and accelerate protein catabolism (Smeets et al., 1995).

If starvation continues, the body's fat store needs can meet an increasing proportion of the energy. Even brain adapts increasingly to the use of the fatty acid metabolites acetoacetate and β-hydroxybutyrate. It has been suggested, however, that tissue protein must be mobilized to replenish the Krebs cycle intermediates α-ketoglutarate and oxaloacetate (Owen et al., 1998). The unusually large glucose needs of the human brain, which may account for as much as half of a child's total energy use, causes a constant drain on Krebs cycle intermediates. Glycerol from mobilized triglycerides can meet the needs for glucose synthesis of other small-brained mammals, but in humans this is not enough. Nonetheless, obese people lose tissue protein during starvation only half as fast as lean people (Elia et al., 1999). Availability of glycerol from fat may make the difference.

Sustained starvation changes the activity of key enzymes of protein and amino acid metabolism (Young and Marchini, 1990). Overall, there is a decline in the activity of enzymes involved in irreversible degradation, and an increase in enzymes for amino acid recycling and utilization.

As a result of starvation the oxidation of amino acids from protein turnover drops to less than 10% (Tomkins et al., 1983). The activities of amino acid dehydrogenases in muscle and of the urea cycle in liver and kidneys decline. In the absence of dietary intakes, the ammonia uptake from portal blood greatly exceeds aspartate uptake. The consequence is that liver proteins have to be mobilized to provide aspartate for the detoxification of the ammonia as urea (Brosnan et al., 2001).

Protein Catabolism during Starvation

During starvation, following depletion of hepatic glycogen, amino acids become the major source for glucose homeostasis because of the decrease in plasma insulin level and the rise in glucocorticoid level. The pattern of amino acids released by skeletal muscle during starvation does not reflect the composition of muscle protein. Alanine and glutamine account for over half of the amino acids released. Alanine is taken up by liver, its carbon chain converted to glucose, and the nitrogen to urea. In early starvation, the principal site of glutamine metabolism is the gut. One product is alanine. The special role of glutamine in gut may be due to the high demand for glutamine in purine synthesis because of the active shedding of intestinal cells. In long-term starvation, a major site of glutamine metabolism is the kidney, since the excretion of ketone bodies requires NH4+ as a counterion formed from ammonia produced by glutaminase. The resulting glutamate is utilized for renal gluconeogenesis, the activity of which is quantitatively equivalent to that of liver. The change in location of glutamine metabolism with long-term starvation has been termed the acid-base metabolic switch. Figure 22-24 summarizes the organ interrelationships in amino acid fluxes postprandially and during extended starvation. Figure 22-25 shows the sources and sites of glucose production during starvation. In early starvation, hepatic glycogen becomes depleted as gluconeogenesis increases. As starvation progresses, gluconeogenesis diminishes in the liver but increases in the kidney as the need for ammonia excretion increases. This switch is reflected by the nitrogen excretion products. In the fed state, urea predominates. In fasting, the total nitrogen excreted decreases, and as starvation progresses, urea excretion decreases while ammonia excretion increases, coinciding with the increased rate of renal gluconeogenesis.

Starvation in Healthy Animals

Starvation in an unstressed (i.e., not ill or injured) animal, also called uncomplicated starvation, initially results in utilization of the body's carbohydrate stores, especially hepatic glycogen. In dogs this reservoir may last for several days, compared with approximately 24 hours in humans.5 Energy consumption then shifts primarily to fat and some protein metabolism. Both skeletal and visceral body proteins are used to provide gluconeogenic precursors, but liver structural proteins are used for gluconeogenesis before skeletal muscle.6 As all body protein is functional, the primary adaptive shift is to fat utilization. Fatty acids are readily oxidized by the kidney and muscle tissues. Fatty acids are also converted to ketones in the liver which may then be used by the central nervous system. Several tissues, for example, adrenal medulla, red blood cells, and brain, have an obligate requirement for glucose, but the brain can adapt to ketone metabolism during periods of starvation. Glycerol resulting from the breakdown of triglycerides can be converted to glucose. Full adaptation to starvation with minimal protein oxidation can take up to 2 weeks in humans. At that time the respiratory quotient (RQ), a determination of the fuels being used by the body, is usually 0.6 to 0.7, indicating fat oxidation primarily.7,8 If uncomplicated starvation lasts for longer than several days, metabolic rate is decreased as a consequence of a loss of tissue mass, a decreased metabolic rate of the remaining tissues, and decreased physical activity.9

2.31.3.1 Starvation Stress

Starvation is an ecologically relevant stressor, as food availability is a dynamic aspect of most environments. Therefore, one might assume that the accompanying behavioral and physiological responses to food deprivation have come under significant selective pressure, and that the mechanisms underlying starvation responses might be similar in a wide range of organisms. In insects, the most commonly used metric to determine starvation responses is life span, and there are essentially two factors that will determine how long an organism can survive a starvation challenge. The first is the size of the energy stores (i.e., fuel tank), and the second is how that energy is utilized (i.e., miles per gallon).

The energetic capacity can be affected by prior feeding history as well as by the relative efficiency of nutrient transformation into stored reserves. Energy utilization is likewise impacted by a variety of different biological factors, including metabolic demands, the conversion of stores into an available energetic currency, and the relative efficiency of utilization (oxidative capacity) by active tissues. The redistribution of energetic demands is a critical aspect of fueling stress responses, and such responses reflect biological priorities to alleviate homeostatic challenges.

Energy stores are obviously first and foremost impacted by the availability of nutrients. While we cannot give specific subjects such as food drive and metabolic conversion the proper treatment they deserve, we highlight critical features of feeding behaviors and metabolism and how these impact longevity during starvation. First, what makes an insect eat? An understanding of the mechanisms that underlie food drive in the insects is far from complete. However, recent findings show that the neuropeptide F (NPF) regulates hunger-driven behaviors in Drosophila larvae (Wu et al., 2005). This is significant, as the NPF shows homology to the mammalian neuropeptide Y (NPY) system (Wu et al., 2003), which mediates feeding behaviors in mammals (Valassi et al., 2008). Thus, it appears that the neuroendocrine factors that regulate feeding behaviors in the vertebrates and insects are conserved and that the NPY system is a component of the circuitry that is responsive to starvation conditions. While it is unclear what the sensory signals are that modulate NPF, it was recently shown that in Drosophila the presence of olfactory cues expedites death during nutrient deprived conditions (Libert et al., 2007). This suggests that there are multimodal sensory inputs relaying nutrient status, olfactory and/or gustatory cues about the presence of food in the environment, as well as other internal sensory systems.

In Drosophila, as well as in many other metazoans, starvation induces hyperactive behaviors. This change in locomotion is of general adaptive significance, as it facilitates the removal of the organism from the source of stress, or, in the specific case of starvation, promotes foraging behaviors. Obviously, starvation also leads to a depletion of energy stores, which is exacerbated by increased activity levels and concomitant higher metabolic demand. Clearly, heightened activity precipitates the loss of energy reserves, but the converse may also be true – that is, that the amount of locomotion is ultimately controlled by energy availability. If this is the case, then one might speculate that peripheral tissues relay sensory information to central regions that control locomotor behaviors. Alternatively, starvation may induce independent changes in energy mobilization and locomotion.

Recently, it was found that when cells within the Drosophila fat body were prevented from undergoing programmed autophagy, starvation longevity increased (Aguila et al., 2007). These results implicate developmental origins to starvation-induced phenotypes. These stored reserves may fuel gonadal maturation, as female ovarian development requires significant investment of energy. The observation that starvation inhibits egg-laying behaviors, female receptivity, and ovarian development is consistent with the general notion of energy redistribution during starvation conditions. It is also thought that the energy vested in the ovaries may be available to females via resorbtion, which may explain sexual dimorphisms of starvation survival (Terashima et al., 2005). It is of note that the reproductive history of Drosophila females impacts the sensitivity to starvation conditions, with mating leading to an increase in longevity under starvation conditions (Rush et al., 2007). Furthermore, transcripts involved in reproduction, for example, yolk proteins, are also significantly decreased during starvation conditions (Harbison et al., 2005). Collectively, these observations suggest an acute modulation of reproductive output during stress and are consistent with resource allocation models stating that energy under limiting conditions is shunted away from growth and reproduction and toward physiologies that maximize maintenance (McNamara and Buchanan, 2005).

The behaviors and physiologies enumerated above, which are targets of starvation modulation, have also been investigated in strains derived from selection experiments for starvation resistance in a number of different insects. In Drosophila, starvation resistant lines have higher ovariole numbers than unselected lines, but produce fewer eggs (Wayne et al., 2006). In general, the number of ovarioles positively correlates with female reproductive output (Wayne et al., 1997). Therefore, the reproductive potential of a female is not thought to represent an absolute confine determining starvation resistance, but rather a critical element is the early allocation of resources to either reproduction or survival (Wayne et al., 2006). Also in Drosophila, some starvation resistant lines have higher lipid content, demonstrating plasticity in energy storage capacities (Djawdan et al., 1998; Harshman et al., 1999). These lines also have lower basal metabolic rates as measured by O2 consumption (Harshman et al., 1999). The underlying traits that selection is then thought to act upon include lower rates of energy utilization and increased energy storage. Notably, many of these starvation resistant lines are resistant to a number of different heterotypic stressors, including oxidative and desiccation challenges (Rion and Kawecki, 2007), suggesting that the traits being selected might represent general mechanisms leading to stress resistance. It is unclear if locomotor activity, which is clearly heightened during starvation, is likewise impacted in these selected lines.

Selection analysis also provides insight into underlying genetic components, which can be readily investigated through quantitative trait loci (QTL) or microarray analysis. Transcript analysis of animals subjected to starvation conditions demonstrates a general decrease in the abundance of transcripts of genes functioning in immunity (Harbison et al., 2005). In support of these results, parasitized Drosophila are hypersensitive to starvation and desiccation stresses (Hoang, 2001). This suggests that the failure to divert energies away from immune-related functions adversely impacts survivorship under these conditions. This is also supported by the observation that chronic stimulation of the immune system in Drosophila reduces life span (Libert et al., 2006). Likewise, microarray analysis demonstrates increased expression in various transcripts functioning within the metabolic processes of energy mobilization (Harbison et al., 2005). These results support the central role of energy stores and usages as a critical target of starvation-induced modification.

Dietary restriction extends longevity in different organisms, and such is the case in the insects. The mechanism that increases life span is thought to be a reduction of the prooxidants, thus limiting the damage caused by reactive oxygen species (ROS) (Sohal and Weindruch, 1996). Whether the mechanism of extended longevity is strictly related to the number of calories in Drosophila is somewhat controversial, and it appears that the source of calories (protein or carbohydrate) determine life span rather than absolute caloric intake (Mair et al., 2005; Min et al., 2006; Lee et al., 2008b). In the context of stress, we note that dietary restriction is fundamentally different from starvation or nutrient deprivation stress. Dietary restriction is defined as a state that does not lead to malnourishment (Piper et al., 2005). While dietary restriction clearly is not defined as a stress, it does exemplify the intricate connections between reproduction, metabolism, diet, and aging. Furthermore, dietary restriction in and of itself leads to enhanced starvation resistance (Chippindale et al., 1993), although it is unclear if this phenomenon represents a hormetic response to limited diet or occurs through independent life-span-lengthening pathways. In addition, fecundity is altered under dietary restriction conditions, and thus reduced egg production is clearly subject to nutritional status. However, dietary restriction does not alter metabolic rate (Hulbert et al., 2004), and suggests that activity may be unaffected by dietary restriction.

Low T3 States

Starvation, and more precisely carbohydrate deprivation, appears to rapidly inhibit deiodination of T4 to T3 by type 1 iodothyronine deiodinase in the liver, thus inhibiting generation of T3 and preventing metabolism of reverse T3 (rT3).10 Consequently, there is a drop in serum T3 and elevation of reverse T3. Since starvation induces a decrease in basal metabolic rate,11 it has been argued, teleologically, that this decrease in thyroid hormone represents an adaptive response by the body to spare calories and protein by inducing some degree of hypothyroidism. Patients who have only a drop in serum T3, representing the mildest form of the NTIS, do not show clinical signs of hypothyroidism. Nor has it been shown that this decrease in serum T3 (in the absence of a drop in T4) has an adverse physiologic effect on the body or that it is associated with increased mortality.

2.2.3 σE and Starvation Stress

Carbon starvation and nutrient limitation are amongst the most common stresses experienced by bacteria. Induction of rpoE is seen following shifts from the utilization of glucose to alternative carbon sources (such as succinate, citrate and maltose), specifically substrates that require an OM and/or periplasmic component for their utilization (Kenyon, Thomas, Johnson, Pallen, & Spector, 2005). The initial stages of C-starvation (the first∼4–5 h postnutrient limitation) see an increase in activity and quantity of RpoE, with rpoE mutants showing severe defects in the long-term starvation survival (Humphreys et al., 1999; Kenyon et al., 2002, 2005).

The peptidyl-prolyl isomerases SurA and FkpA are both σE-regulated, but are also important for carbon starvation induced cross-resistance to numerous other stresses (e.g. acid, thermal and AP stress) and survival of Salmonella during long-term carbon stress (Kenyon, Humphreys, Roberts, & Spector, 2010). Despite this, Kenyon et al. (2010) showed that although surA and fkpA expression occurs in C-starved cells and they have an important role in cell survival, both are not directly induced by C-starvation and are not under the control of σE during starvation stress. This highlights key differences between the heat shock and C-starvation inducible σE regulons.

Long-term starvation stress survival requires global metabolic remodeling, providing a more flexible and efficient energy regulation and resulting in morphological and physiological differences when compared to growing cells (Kenyon et al., 2002). The vast majority of genes responsible for this long-term survival are regulated by the cAMP:CRP complex, with an array of other loci under the control of the alternative sigma factor σS. Both σS and cAMP:CRP are required to establish full infection of mice, and null strains of each are emerging as potential and useful vaccines (Chen et al., 2010; Karasova et al., 2009). σE also has a role in the virulence of S. Typhimurium, and along with σS and the cAMP:CRP complex, it provides further evidence linking the SSR to the full virulence of Salmonella (Kenyon et al., 2002).

CpxAR is not required for the Salmonella SSR; however its involvement in the response to P pilus mislocalization, hydrophobic surface interactions, antibiotic stress and virulence are discussed below.

Poor body condition (Figs. 6.21–6.23)

Starvation is a common disorder of neglected horses in all parts of the world. The metabolic consequences of significant nutritional deprivation are extensive and varied. A single animal affected in a group may suffer from effective deprivation in the presence of food for social reasons, there being no physical or medical reason for the failure to ingest the food. This is relatively common in confined herds of horses which receive all their food as preserved fodder, fed particularly at irregular intervals. One animal in a group (or on its own) having access to normal quantities of food may be metabolically deprived through inability to eat, chew, swallow or make effective use of ingested food material. Horses which are in poor condition may therefore not necessarily be starved. Cachexia associated with infectious or inflammatory conditions or neoplasia may also result in poor body condition in a single member of a herd. However, it is likely that where several horses in a herd are found in similarly poor bodily condition, the availability of nutritious food or any food may be limited. Individual horses in a group may, however, suffer from starvation when they are subjected to dominance behavior from more aggressive or dominant animals in the group. Horses suffering from starvation are able to tolerate considerable and prolonged deprivation without marked effects, and it is often only the extremes of nutritional deprivation which exert significant metabolic effect in terms of specific deficiencies of minerals, vitamins or other nutrients.

Overview and Goal

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Starvation of horse(s) may be due to a variety of factors including lack of feed availability, illness or injury, or owner factors such as economic hardship, ignorance, apathy, illness or injury, and possibly other crimes such as domestic violence.

Causes of starvation: Multifactorial including (Kronfeld, 1993):

Lack of quantity and quality of feed, especially the nutrient content and balance of energy and protein. Deficiencies or excesses of certain minerals and vitamins over the long-term can contribute to malnutrition and/or emaciation.

Seasonal declines in the primary feed source such as pasture.

Malabsorption of nutrients associated with diarrhea, poor dental function, or geriatric condition.

Parasites can be either a primary or secondary contributor to starvation/emaciation.

Cachexia

Starvation may arise from stress-induced failure to eat, provision of too little food, inappropriate foods or feeding man-agement, and diseases that affect appetite and metabolism. Like starved mammals, starved reptiles lose lean tissue (protein) and adipose (Figure 18-41). Loss of protein from skeletal muscle is readily evident as atrophied musculature. Loss of protein from heart, liver, intestines, and other organs is less evident but impairs function and threatens life.

Ectotherms have remarkable abilities to withstand fasts but are debilitated by long-term starvation. Metabolic rates may decrease by 50%. Degree of weight lost with fasting is variable. Snakes starved for up to 100 days at 82°F (28°C) lost up to 37% of their BW and catabolized their fat bodies.140 Juvenile aquatic turtles fasted for 19 days lost from 1% to 16% of BW and oxygen consumption (VO2) decreased to about one third prefast levels.141 Underfed female chameleons allocate their energy reserves to egg production, resulting in increased mortality at egg deposition, higher incidence of retained eggs, and poorer physical condition after nesting, compared with fed chameleons.142 Laboratory diagnosis of starvation may be difficult, for in at least one species, the Green Lizard (Ameiva ameiva), ketone bodies were unaltered (acetoacetate) or decreased (3-hydroxybutyrate) with starvation.143

To treat starvation, first restore fluids and electrolytes. Then, provide judicious amounts of calories and nutrients, with assist-feeding if necessary, until appetite returns. Deficiencies in management must be identified and corrected. Common husbandry errors include low temperatures, inappropriate food items, and stress from excessive crowding, noise, and light.

To initiate voluntary feeding in starved reptiles, place the patient in a warm environment, over 85°F (30°C) for most reptiles but cooler for montane species, especially Chamaeleo spp. Include a basking light and a gradient toward cooler temperatures. Many patients respond to warm (80°F [26°C]) water soaks.

Offer small amounts of food frequently. Foods should be fresh, and dead vertebrate prey should be warmed. If possible, natural food items should be offered. A low dose of metronidazole (12.5 to 25 mg/kg PO) may initiate feeding, although the likely mechanism is unknown and the drug's efficacy has not been established in controlled trials.

Some products sold for nutritional rehabilitation of veterinary patients contain too much fat and almost no protein. These products, usually in gel or paste forms, fail to meet the immediate nutritional needs of starved or hypermetabolic animals.