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M. ELIA* * Dunn Clinical Nutrition Centre, 100 Tennis Court Road, Cambridge, CB2 1QL, U.K.



A detailed comparison is made of the metabolic response to starvation (up to several weeks) between lean and obese subjects. Early starvation (1-3 days) is frequently associated with a transient increase in basal metabolic rate (BMR) and protein oxidation. As starvation progresses and lean body mass decreases, both BMR and protein oxidation decrease. However, lean subjects, with their smaller lean body mass than obese subjects, maintain a higher daily N excretion in absolute terms, in relation to weight loss and in relation to energy expenditure. Indeed, in lean individuals the contribution of protein oxidation to BMR does not decrease as starvation progresses (up to 45 weeks) but in obese individuals it does, reaching values that are more than two-fold lower than in lean subjects. The proportion of energy derived from protein oxidation is inversely related to the body mass index (BMI) and percent body fat. Such differences are considered to be of major importance to survival, which can be several-fold longer in obese individuals than lean individuals. In subjects ingesting hypocaloric diets, the effect of initial adiposity on protein oxidation and composition of weight loss is discussed in relation to other confounding variables (e g., composition of diet, duration of dieting, exercise, etc.). Recommendations are made for nutritional support.







Although starvation and hypocaloric dieting are often considered to produce a progressive reduction in basal metabolic rate (BMR) and N loss, there is little information as to the extent to which these changes depend on initial body composition. This paper critically evaluates the protein-energy interrelationships which occur during total starvation and hypocaloric feeding, evaluates the physiological significance of the differences that exist between lean and obese subjects, and considers the implication for nutritional support for those receiving very low calorie diets.







Although prolonged total starvation is associated with an absolute reduction in basal metabolic rate (BMR), during the first 2 days of starvation there is often a small absolute increase in BMR relative to values obtained after an overnight fast (Figure 1). Since this change occurs while there is loss of body weight and lean tissue ( � 2%), the increment is greater when expressed in relation to body weight or lean body mass. As early as 1907, VAN NOORDEN wrote "during the first few days of acute starvation the general metabolism of the body suffers no diminution". However, a transient increase in metabolic rate may have been missed, because the results were often compared to measurement made at the end of the first day of starvation (36 hours since the last meal).

In other studies it may have been missed because the first of a series of measurements were made after a meal, as in the case of Cetti who was first studied one hour after breakfast (LEHMANN et al., 1983). The classic fast reported by BENEDICT in 1915 was associated with a small increase in metabolic rate compared to values obtained after an overnight fast (Figure 1), and so were a number of other classic starvation studies in individual subjects. Four of the five lean subjects studied by TAKAHIRA (1925) (not shown in Figure 1) also showed an increase of up to 6% in BMR during early starvation. The subject who did not show an increase did not have a measurement made on day 2 of starvation. More recent studies in groups of individuals have confirmed a transient early increase in BMR (Figure 1). The rise in BMR could be due to either an increase in the energy equivalent of ATP gained as the body reduces the proportion of energy derived from glycogen (73.3 kJ/mole ATP gained) increases and the proportion derived from fat (79.2 kJ/mole ATP gained) decreases (ELIA and LIVESEY, 1988; 1992), or an increase in the requirement for ATP.

An increased requirement may occur as a result of the increased gluconeogenesis (ERIKSSON et al., 1988; FELIG et al., 1969), increased triglyceride-fatty acid cycling (ELIA et al., 1987; KLEIN et al., 1989), which is considered to account for 1-2% of the BMR during early starvation, increased protein-amino cycling, which has been reported to increase during the first 3 days of starvation (NAIR et al., 1987), and increased acetyl CoA-ketone body cycling. This last cycle occurs because the liver synthesises ketone bodies from acetyl Coa (AcCoA), while other tissues such as brain and muscle convert ketone bodies back to AcCoA before final oxidation. This cycling (from AcCoA to ketone bodies and back to AcCoA) has an energy cost of 1 ATP. Based on the rate of ketone body production and utilisation during early starvation (ELIA, 1991) and the energy equivalent of ATP (ELIA and LIVESEY, 1988; 1992), it is estimated that such cycling could contribute to about 1-2% of the BMR during early starvation.

Figure 1. Changes in resting energy expenditure during early starvation expressed as a percentage of overnight fasted value (indicated as 100% at 12 hours)

In addition to the early increase in energy expenditure, there is also some loss of energy in the form of ketone bodies in both breath (acetone) and urine (3-hydroxybutyrate and acetoacetate and acetone). During early starvation in lean subjects this loss corresponds to about 3 % BMR (ELIA et al., 1984a; REICHARD et al., 1979). In obese subjects, the loss is less, but as the circulating concentration of ketone bodies increases during more prolonged starvation, the loss also increases (REICHARD et al., 1979).

After the first 2-3 days of starvation, the BMR becomes lower than after an overnight fast. This reduction is partly due to loss of the metabolically active lean tissues (during the first 3 days of starvation there is a loss of about 30-35 g N; about 1.5-2% of the total body N in a lean subject), and partly to changes in metabolic rate per kg fat-free issue, by mechanisms which are poorly understood.

Figure 2. Changes in urine N excretion in groups of lean and obese subjects (solid lines = lean subjects; n = 12 men, n = 12 women; dotted lines = obese subjects, n = 12 men, n = 12 women). Based on data provided by GOSCHKE et al. (1975).



Although the rate of protein oxidation (reflected in the rate of urine N excretion) is frequently considered to decrease during prolonged starvation, especially in the obese (see below), several studies have shown that there is often a transient early increase. Examples in lean and obese subjects are shown in Figure 2, but similar changes have been noted by a variety of workers (e.g., VAN NOORDEN, 1907; BENEDICT, 1915; ELIA et al., 1984a; TAKAHIRA, 1925). In the study of ELIA et al. (1984a), the increase in N excretion could not be explained by loss of preformed urea, because the circulating urea concentration showed a tendency to increase rather than decrease (ELIA et al., 1984a).

It would therefore appear that there is often genuine transient increase in amino acid oxidation during early starvation. TAKAHIRA (1925) suggested that this increased oxidation of protein was responsible for the temporary increase in energy expenditure that he observed in his starving subjects. This suggestion was based on the premise that the specific dynamic action of catabolized proteins is greater than that for fat or carbohydrate. It is also of interest that the energy equivalent of ATP for protein is greater than that of fat or carbohydrate (ELIA and LIVESEY, 1988; 1992).

Not all of the N found in the urine during early starvation reflects protein catabolism, since some of it is due to catabolism of free amino acids, particularly glutamine. This amino acid has a greater concentration in the circulation ( � 0.5-0.7 mmol/L) and muscle (20-25 mmol/L intracellular water) than any other alpha amino acid, and its release from muscle (as well as that of several other amino acids), increases significantly during early starvation (36-72 hours) (ELIA and LUNN, 1989; POZEFSKY et al., 1976).

The pool of free glutamine in muscle, estimated to be about 45 g or 15 g glutamine nitrogen in a 70 kg man, almost halves between 12 and 72 hours of starvation (MAGNUSSON et al., 1987; ELWYN et al., 1981). Since during this period there is a loss from the body of about 28 g N (9-13 g N/d), the loss of free glutamine from muscle corresponds to about 25% of the urine N excretion. There is also a general tendency for other amino acids to be lost from the free amino acid pool in muscle during short-term starvation (MAGNUSSON et al., 1987) (although some amino acids such as the branched-chain amino acids, which have only a small pool size, may actually accumulate in muscle). However, the absolute changes of these other amino acids are small, relative to the loss of glutamine.

After the first 2-3 days of starvation, urine N excretion begins to decrease and generally continues to do so for most of the subsequent period of starvation (although a premortal rise frequently occurs).







The ratio of N excretion (as an index of protein oxidation) to BMR is variable during short-term starvation, but calculations based on the results of several studies suggest a tendency for this ratio to transiently increase during the first 2-3 days of starvation.







One of the most consistent autopsy findings of animals and humans who died of 'pure' starvation, is the virtual absence of depot fat, both subcutaneously and internally (KEYS et al., 1950). In some studies, fat was found to be replaced by a translucent gelatinous material. In the autopsy of a man who refused all food until his death, MEYERS (1917) confirmed the absence of storage fat from most parts of the body, and noted that in those areas where small amounts of fat persisted (e.g., pericardial fat), the boundaries of the fat cells were maintained, but the cells which had become small, were often completely filled with granular protoplasm rather than fat. Therefore, individuals dying of starvation only have a small amount of storage fat and a small amount of structural fat, mainly in cell membranes and the brain and nerves. Since body fat is the major store reserve of energy which disappears during starvation, it is reasonable to suggest that the initial amount of body fat is a major determinant of the length of survival during starvation. Most of the weight loss during starvation in lean individuals is due to loss of lean body mass. A variety of autopsy studies in humans have shown that 25-50% of most lean tissues and organs are lost during starvation. However, the brain, gonads and skeleton appear to be preferentially preserved. Examples of the changes occurring in humans and non-human species (cats, dogs and pigeons) during 'total' starvation are shown in Table 1.

Table 1. Percentage loss of fresh organs during starvation

Pigeons

Cats

Rats

Dogs*

Man

Skeleton

3

10.4

14

5

-

Muscle

42

57.9

31

42

40.7











(Whole body)

Brain and cord

1

2.2

3

22

6.9











(Brain)

Heart

45

34.0

3

16

40.4

Spleen

71

68.5

-

57

18.4

Liver

53

59.8

54

50

28.6

Pancreas

64

55.1

-

62

48.8

Kidney

32

50.9

-

55

49.2

Lungs

32

20.5

-

29

28.6

Fat

-

-

97

-

-



* Loss of fresh fat-free organs.

Based on work by Chossat (pigeons), Sedlmair (cats), Voit (cats), Voit (dogs) and Meyers (man) (summarized by MEYERS, 1917).

Table 2. Some examples of massive successful weight reduction during fasting in gross obesity

Weight

Subject No.

Gender

Initial Kg

Final kg

Loss kg

% Loss

Year

Period of dieting (months)

1

M

636

216

419

66

1979

24

2

M

410.5

984

312.1

76

1987

<24

3

M

216

59

162

75

1985

7

4

M

304

91

213

70

1967

23

5

F

262

84.8

177.2

68

1951

22

6

F

251

69

182

73

1967

14







50+

201+

80+





7

F

200

69.8

130.2

65

1973

18



+ 16 years later.

Based on BORTZ et al., 1967 (subject 4) and MacFARLAN, 1991 (other subjects).

In the 19th century and early part of the 20th century, various authors believed in the concept of a lethal level of loss of body weight. For example, KRIEGER (1921) suggested that the lethal level of weight loss in adults was about 40% for acute starvation and 50% for semi-starvation. This concept may have originated from CHOSSAT (1843), who reported that animals dying of starvation had lost 40-50% of their body weight. Death was considered inevitable beyond these limits. However, even Krieger's own data demonstrated substantial variation in the weight loss of subjects dying of starvation. Other workers disagreed with the concept of a critical lethal weight loss, and, as should become apparent later in this paper, both the extent of weight loss and survival time depend on the initial degree of adiposity (see Table 2 for some remarkable world records of weight loss in fasting obese subjects). Therefore, Krieger's figures can only be regarded as an approximate guide.

The subject studied by MEYERS (1917) who died 63 days after refusing food, lost about 41% of his body weight. The mean weight of the Northern Ireland festers at the time of death was 45 kg. Unfortunately, it has proved difficult to establish their initial body weight. However, if they had lost 40% of their body weight their initial weight would have been 75 kg. In contrast, there are several reports of successful total fasts in obese individuals who have lost more than 50% of their body weight (e.g., STEWART and FLEMING, 1973; COLLINSON, 1967; BARNARD et al., 1969; FORBES, 1970; FORBES and DRENICK, 1979). If starvation had continued until death, the weight loss could have been substantially more.

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