EFFECT OF DIETARY PROTEINS AND AMINO ACIDS ON THE SUSCEPTIBILITY OF MICE TO BACTERIAL INFECTIONS

Young mice were maintained for periods of 1 to 6 weeks on experimental diets containing all known growth factors, but differing in their protein and amino acid contents. All diets were supplemented with L-cystine. The effect of the nutritional regimen on infection was tested by inoculating the animals with either one of four pathogens (Mycobacterium tuberculosis var. bovis, Mycobacterium fortuitum, Staphylococcus aureus, Klebsiella pneumoniae type C), and by observing the survival time. The infective dose was administered by either one of three routes: intravenous, intraperitoneal, or air-borne (aerosol). In some experiments, the animals were maintained in groups of five throughout the tests. In other experiments they were housed in individual cages. This difference in housing did not affect the results in a detectable manner. Mice fed diets containing 5 or 8 per cent casein as sole source of amino acid (except for cystine supplementation) proved more susceptible to the experimental diseases than did mice fed diets containing 15 or 20 per cent of the same protein. Susceptibility to infection developed when wheat gluten, or soybean α-protein, was substituted for casein—even in high concentrations (15 or 20 per cent). In one experiment, mice were fed a diet containing as sole source of amino acids a mixture of soybean and rice flour, so designed as to provide a protein concentration of 15 per cent, with an amino acid pattern similar to that of casein. These animals gained weight at the same rate as those fed a diet containing 15 per cent casein and they exhibited a satisfactory level of resistance to bacterial infection. The infection-enhancing effect of low casein concentration (5 and 8 per cent) could be corrected by supplementing the diet with the proper mixture of amino acids. This could be done using either synthetic or natural amino acids. In contrast, susceptibility to infection developed when low casein diets were supplemented with unbalanced mixtures of amino acids. The infection-enhancing effect of gluten diets could not be corrected by supplementing the latter with lysine even though this supplementation markedly improved weight gains in uninfected animals. It appears in conclusion that the relative proportion of the various amino acids in the diet is as important a factor as their total amount in conditioning resistance to bacterial infections. This effect of nutrition on resistance can be detected irrespective of the route of infection: intravenous, intraperitoneal, or air-borne. Moreover, the effect has been observed with two strains of mice differing markedly in their natural resistance to bacterial infection.     

Effect of dietary proteins and amino acids on the susceptibility of mice to bacterial infections

Groups of young albino mice were fed continuously four different types of diets and were compared with regard to (1) rate of weight gain; (2) resistance to experimental bacterial infections. The protein content of the four diets was as follows: (a) pellets: a minimum of 21 per cent "crude" protein (according to the manufacturer); (b) diet 20 C: 20 per cent casein; (c) diet 8 C: 8 per cent casein; (d) diet 8 C + AA: 8 per cent casein supplemented with 12 per cent of a mixture of essential amino acids. All diets provided an adequate supply of minerals and vitamins. They were administered ad lib. Three strains of pathogens virulent for mice were used for the infection tests, namely: Staphylococcus aureus, Mycobacterium fortuitum, and Mycobacterium tuberculosis bovis. The bacteria were injected by the intravenous route. The experimental regimens were begun at different times before infection, and were continued until death of the animal, or until termination of the experiment. It was found that mice on the 8 C diet exhibited much greater susceptibility to infection than did mice on the 20 C diet; mice receiving pellets were intermediate between these two groups. The infection-enhancing effect of the 8 C diet could be entirely corrected by amino acid supplementation (diet 8 C + AA). Indeed, mice fed diet 8 C + AA proved the most resistant to infection. The fact that animals fed pellets (which contain a minimum of 21 per cent protein) consistently died faster following infection than did animals fed diets 20 C or 8 C + AA suggests that qualitative characteristics of the protein in the regimen are as important as the quantity of protein fed in determining susceptibility to infection. The differences in susceptibility exhibited by the mice on the four experimental diets were the same whatever the species of bacterial pathogen used for the infection test, the size of the infective dose, and the duration of the disease. There was no apparent relation between the effects of the diets on the weight curves of the animals, and on resistance to infection. Mice on diet 8 C (which were most susceptible) gained weight as rapidly as those on 20 C and more rapidly than those fed 8 C + AA (which were most resistant). All the tests reported in the present paper were carried out with young mice, which were placed on experimental diets within 1 to 2 weeks after weaning. Preliminary experiments suggest that the relation between dietary factors and susceptibility to infection was more difficult to bring out in older animals. There was evidence also that this relation was most apparent during the first weeks that the animals were fed the experimental diets, and became less striking after several weeks.     

The effects of moderate exercise on secretory IgA production in mice depends on dietary carbohydrate intake

Secretory immunoglobulin A (sIgA) is produced from intestinal mucosa and is essential in preventing infection. We analyzed the influence of moderate exercise on intestinal sIgA production and antioxidative function under different carbohydrate nutritional conditions. Thirty-six mice were fed an experimental diet for 10 weeks—a high-carbohydrate (HC) diet, a low-carbohydrate (LC) diet, or a control (C) diet. After 1 week on the experimental diets, mice were divided into sedentary and exercise groups (n = 6/group), where the exercise consisted of treadmill running for 30 min/day at 11 m/min for 6 days/week in 9 consecutive weeks. Intestinal sIgA levels in the exercise groups fed C or LC diets were significantly lower compared with the parallel sedentary groups, or exercise-group mice fed HC diet. Expression of the polymeric immunoglobulin receptor (pIgR) in the small intestine was significantly higher in the exercise group fed a HC diet. Superoxide dismutase activity in the small intestine was higher in the exercise group than in the sedentary group, with no effects resulting from intake carbohydrate levels. Our results indicated that moderate exercise reduced the levels of intestinal sIgA depending on decreasing of carbohydrate intake, which is connected with the expression of pIgR.     

Reversible changes in the susceptibility of mice to bacterial infections. II. Changes brought about by nutritional disturbances

A study has been made of the time variations in the susceptibility of albino mice to experimental infections with Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium tuberculosis. Susceptibility to infection was determined by two criteria: (a) mortality rates following intravenous injection of a known infective dose; (b) numbers of bacterial colonies that could be recovered from the tissues of the infected animals at various times after infection. When measured in terms of either one of these two criteria, susceptibility was consistently modified by temporary deprivation of food, and by various changes in the composition of the diet. Increase in susceptibility to infection could be detected within a few hours to a few days depending upon the nature and intensity of the nutritional disturbance imposed upon the animal. Under the proper conditions, return to a normal state of resistance could also occur within a very short time. There was commonly observed an explosive bacterial multiplication in mice receiving the infective dose shortly after being subjected to nutritional disturbances. In the case of infection with Klebsiella pneumoniae, however, this phase of increased susceptibility was often followed a few hours later by one during which the numbers of living bacteria that could be recovered from the various organs fell to a very low level. Many of the animals which had exhibited severe but transient bacteriemia recovered rapidly and survived the infection. Mice rendered more susceptible to infection by being fed deficient diets progressively recovered their normal resistance while being kept on the same inadequate regimens. This adaptation occurred even though the weight of the animals on these regimens remained much lower than the weight of the animals fed a complete diet ad lib. The weight of the animal at the time of infection appeared to have little bearing on susceptibility. However, susceptibility consistently increased during the periods while the animals were losing weight—whatever the cause of the weight loss. The facts disclosed in the present study, as well as findings reported by other investigators, make clear that profound changes in susceptibility to infection can be brought about by varied non-specific procedures. These changes can occur within very short periods of time and are often rapidly reversible.     

THE EFFECT OF THE INTESTINAL FLORA ON THE GROWTH RATE OF MICE, AND ON THEIR SUSCEPTIBILITY TO EXPERIMENTAL INFECTIONS

Mice delivered by Caesarian section were used to develop a new mouse colony which has been maintained in an environment protected from contact with common mouse pathogens, but not in the germ-free state. These mice, designated as NCS, were compared with animals of the same sex and age coming from the parent colony maintained under ordinary conditions. The NCS mice grew more rapidly than ordinary mice on complete diets; moreover, they continued to gain weight—although at a slower rate—when fed deficient diets which caused ordinary mice to stop growing, or to lose weight. The NCS mice proved much more susceptible than ordinary mice to certain experimental bacterial infections. In contrast, they were much more resistant than ordinary mice to the lethal effect of large doses of endotoxins. However, they responded to injection of minute amounts of these endotoxins by a marked increase in susceptibility to staphylococcal infection. Bacteriological studies revealed striking qualitative differences between the intestinal flora of NCS and ordinary mice. When NCS mice were contaminated—either by contact or by feeding—with a strain of Escherichia coli recovered from the intestine of ordinary mice, they acquired the characteristics of the latter animals with regard to weight gain on various diets, and to response to bacterial pathogens and endotoxins. NCS mice have been found well suited to the study of several nutritional, bacteriological, and immunological problems and it appears that their production on a large scale will not present unsurmountable difficulties.     

DIET AND TISSUE GROWTH : I. THE REGENERATION OF LIVER TISSUE ON VARIOUS ADEQUATE DIETS.

1. The toxicity of chloroform varies according to the diets used in these experiments in the following order of decreasing susceptibility of the animals: high fat > standard > high carbohydrate > high protein diets. 2. On the high fat and high carbohydrate diets there may be a more or less marked proliferation of the endothelium and the connective tissue stroma in the necrotic area producing in some instances scars resembling the picture of an early cirrhosis. 3. On the diets studied, standard, high carbohydrate, high protein, and high fat, the most active and rapid repair is observed on the standard balanced diet. On the high fat diet the reparative process is definitely delayed in comparison with the others. There are only slight differences between the high carbohydrate and high protein diets which suggest but do not conclusively show a more rapid repair with the latter diet.     

THE EFFECT OF DIET ON THE FECAL BACTERIAL FLORA OF MICE AND ON THEIR RESISTANCE TO INFECTION

A study was made of the effect of certain dietary regimens on the lactobacillus flora in the stools of mice and on their resistance to infection. Semi-synthetic diets with purified casein or wheat gluten as sole source of protein, gave rise to much smaller numbers of viable lactobacilli in the stools than did other diets containing unidentified natural products—as present for example in mixtures of whole wheat and whole milk, or in certain commercial pellets. Furthermore, one of the lactobacillus types with rhizoid morphology disappeared completely from the stools of animals fed the semi-synthetic diet. The change in the lactobacillus flora became apparent within a very few days after the animals had been shifted from the complex to the synthetic diet Moreover, this change was not completely reversible. Whereas the total numbers of lactobacilli increased when the animals were shifted back from the synthetic to the complex diets, the rhizoid lactobacilli which had disappeared completely from the stools reappeared only slowly or not at all. In twelve consecutive experiments the three diets which gave rise to the large numbers of lactobacilli in the stools also conferred on the mice a much higher resistance to experimental infection with Staphylococcus aureus and Klebsiella pneumoniae, than did the semi-synthetic diets. However, direct evidence has not yet been obtained that the two kinds of phenomena were causally related. Following administration of endotoxin there was a rapid and very large increase in the numbers of enterococci and coliform bacilli in mice fed the semi-synthetic casein diet, but not in those fed the pellets. In two preliminary experiments carried out with another colony of mice, not pathogen-free, it was also found that the rhizoid type of lactobacilli disappeared from animals fed the semi-synthetic casein diet while enterococci and coliform bacilli progressively increased in numbers under the same conditions. The dietary effects on the lactobacillus flora, and on resistance to experimental infection, were equally pronounced whether the mice were housed in individual cages on wire grids, or grouped in larger cages with wood shavings as litter. This was true even if the bedding was changed only once weekly and became therefore grossly soiled.     

Low-carbohydrate diets adversely impact the skin of a mouse model of photoaging exposed to ultraviolet B radiation

The study results regarding the effects of low-carbohydrate (LC) diets remain controversial; hence further research is required to assess their safety. Here, we examined whether LC diets cause skin damage in C57BL/6J mice. Six-week-old female mice (n = 20) were fed an LC (protein/fat/carbohydrate energy ratio = 35:45:20) or control diet ad libitum for eight weeks, after which their backs were shaved, and a subset of the mice were exposed to ultraviolet B radiation thrice per week. Ultraviolet B irradiation induced wrinkle formation on the skin surface, and thickening of the epidermis, which was also noticeable in the LC diet-fed mice in the absence of ultraviolet B radiation. Meanwhile, the number of epidermal melanocytes and degree of horny layer keratosis increased in the LC diet-fed mice following ultraviolet B irradia­tion. mRNA expression analysis of the liver and skin showed decreased levels of the antioxidant enzyme superoxide dismutase 1 following ultraviolet B irradiation only in the LC diet-fed mice. Alternatively, the expression of pro-inflammatory cytokines, tumor necrosis factor-α and interleukin-1β, increased in response to ultraviolet B radiation and LC diet intake. Hence, LC diets may adversely affect skin morphology and exacerbate the effects of ultraviolet B irradiation, which may be associated with anti­oxidant dysfunction.     

Increasing the fat-to-carbohydrate ratio in a high-fat diet prevents the development of obesity but not a prediabetic state in rats

Metabolic disorders induced by high-fat feeding in rodents evoke some, if not all, of the features of human metabolic syndrome. The occurrence and severity of metabolic disorders, however, varies according to rodent species, and even strain, as well as the diet. Therefore, in the present study, we investigated the long-term obesogenic and diabetogenic effects of three high-fat diets differing by their fat/carbohydrate ratios. Sprague-Dawley rats were fed a control high-carbohydrate and low-fat diet [HCD; 3:16:6 ratio of fat/carbohydrate/protein; 15.48 kJ/g (3.7 kcal/g)], a high-fat and medium-carbohydrate diet [HFD1; 53:30:17 ratio of fat/carbohydrate/protein; 19.66 kJ/g (4.7 kcal/g)], a very-high-fat and low-carbohydrate diet [HFD2; 67:9:24 ratio of fat/carbohydrate/protein; 21.76 kJ/g (5.2 kcal/g)] or a very-high-fat and carbohydrate-free diet [HFD3; 75:0:25 ratio of fat/carbohydrate/protein; 24.69 kJ/g (5.9 kcal/g)] for 10 weeks. Compared with the control diet (HCD), rats fed with high-fat combined with more (HFD1) or less (HFD2) carbohydrate exhibited higher BMI (body mass index; +13 and +10% respectively; P<0.05) and abdominal fat (+70% in both HFD1 and HFD2; P<0.05), higher plasma leptin (+130 and +135% respectively; P<0.05), lower plasma adiponectin levels (-23 and -30% respectively; P<0.05) and impaired glucose tolerance. Only the HFD1 group had insulin resistance. By contrast, a very-high-fat diet devoid of carbohydrate (HFD3) led to impaired glucose tolerance, insulin resistance and hypoadiponectinaemia (-50%; P<0.05), whereas BMI, adiposity and plasma leptin did not differ from respective values in animals fed the control diet. We conclude that increasing the fat-to-carbohydrate ratio to the uppermost (i.e. carbohydrate-free) in a high-fat diet prevents the development of obesity, but not the prediabetic state (i.e. altered glucose tolerance and insulin sensitivity).     

MICROBIC VIRULENCE AND HOST SUSCEPTIBILITY IN PARATYPHOID-ENTERITIDIS INFECTION OF WHITE MICE : XII. THE EFFECT OF DIET ON HOST RESISTANCE. FURTHER STUDIES.

When 5 per cent of butter fat or cod liver oil is added to a bread and milk diet, in itself adequate to promote the breeding and rearing of a healthy stock of mice through a period of years, the resistance of these mice to per os infection with the paratyphoid mouse typhoid bacillus (B. pestis caviæ), as compared to that of mice on the unmodified diet, is definitely increased. A similar effect may be obtained with a McCollum "complete" diet, even when the butter fat is omitted, and with a bread and milk diet in which the milk used has been rayed with a mercury vapor lamp. When an inactive fat like Crisco is added to the bread and milk diet, the results obtained are not very clear-cut. While seasonal fluctuations in resistance to mouse typhoid were not completely eliminated by the various modified diets, they were nevertheless reduced, the modified diets tending to stabilize the death rate at a point lower than that usually reached by the mice on the control diet.     

Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice

Deficiency of the membrane protein FAT/CD36 causes a marked defect in fatty acid uptake by various tissues and is genetically linked to insulin resistance in rats and humans. Here, we examined insulin responsiveness of CD36-/- mice. When fed a diet high in complex carbohydrates and low (5%) in fat, these animals cleared glucose faster than the wild-type. In vivo, uptake of 2-fluorodeoxyglucose by muscle was increased severalfold, and in vitro, insulin responsiveness of glycogenesis by the soleus was enhanced. Null mice had lower glycogen levels in muscle and liver, lower muscle triglyceride levels, and increased liver triglyceride content--all findings consistent with increased insulin-sensitivity. However, when the chow diet was switched to one high in fructose, CD36-/- mice but not wild-type mice developed marked glucose intolerance, hyperinsulinemia, and decreased muscle glucose uptake. High-fat diets impaired glucose tolerance equally in both groups, although CD36 deficiency helped moderate insulin-responsive muscle glucose oxidation. In conclusion, CD36 deficiency enhances insulin responsiveness on a high-starch, low-fat diet. It predisposes to insulin resistance induced by high fructose and partially protects from that induced by high-fat diets. In humans, CD36 deficiency may be an important factor in the metabolic adaptation to diet and in susceptibility to some forms of diet-induced pathology.     

INHERITANCE OF RESISTANCE OF MICE TO ENTERIC BACTERIAL AND NEUROTROPIC VIRUS INFECTIONS

Under the conditions specified, there may be selected promptly from a hybrid stock of mice, of which 40 to 50 per cent die following a standard dose of B. enteritidis or St. Louis encephalitis virus, lines in which as high as 95 per cent and as low as 15 per cent succumb. Three lines,—one bacteria-susceptible-virus-susceptible, one bacteria-susceptible-virus-resistant, and one bacteria-resistant-virus-susceptible,—are regarded as remaining relatively stable after approximately twelve generations of selection and brother to sister or line inbreeding. Crossing susceptible with resistant lines and testing F₁, F₂, F₃, and backcross progeny resulted in mortality percentages in the neighborhood of those expected on the basis that resistance to B. enteritidis and to encephalitis virus is each inherited independently on a single factor basis with resistance dominant over susceptibility. A bacteria-resistant-virus-resistant line is being developed from a cross between bacteria-susceptible-virus-resistant and bacteria-resistant-virus-susceptible lines. All selected lines proved uniformly susceptible to a strain of mouse passage rabies virus.     

THE CORRELATION OF A BIPHASIC METABOLIC RESPONSE WITH A BIPHASIC RESPONSE IN RESISTANCE TO TUBERCULOSIS IN RABBITS

We have found a phase of susceptibility associated with a reduced metabolic activity on the part of peritoneal mononuclear phagocytes taken from BCG-vaccinated rabbits. A second stage of heightened resistance to infection was found to be associated with a heightened metabolic activity. The period of susceptibility in BCG vaccination is primarily concerned with initiation of the infection and not with the progression of the disease, which in both stages is increased. These reactions are discussed in relation to other conditions, such as nonspecific protein therapy and the administration of endotoxin, which also have similiar biphasic stages of resistance. Of incidental interest is the fact that rabbits who received 400 roentgen units are two years later still unable to respond to BCG vaccination with an increase in resistance. We conclude that there is a relationship between the level of certain metabolic activities of reticuloendothelial cells and resistance to tuberculosis.     

INFLUENCE OF DIETARY FACTORS AND SEX ON THE TOXICITY OF CARBON TETRACHLORIDE IN RATS

Six groups of rats on different diets were exposed to the inhalation of carbon tetrachloride (about 300 p. p. m.) for 150 days. Food intake and changes in weight were followed throughout the experiment. Animals fed a diet low in protein showed greater susceptibility than rats on a diet high in protein. Methionine was a good substitute for protein (casein) in the diet. Increase in fat intake with correspondingly lower carbohydrate intake exerted a harmful effect, especially evident in combination with a low protein diet. In this change of the fat: carbohydrate ratio, whether the increased fat or the lowered carbohydrate is the specific factor must remain unanswered at the present time. Necrotizing nephrosis was the presenting sign of the intoxication caused by carbon tetrachloride, in addition to hepatic changes, such as hydropic degeneration, necrosis, and cirrhosis. Dietary factors (methionine and methionine-containing protein, as well as low fat intake) more consistently prevented renal injury than cirrhosis of the liver. Under identical dietary conditions, especially with higher fat intake, male rats appeared to evince greater susceptibility to carbon tetrachloride than female rats. The significance of this observation and its wider applicability has been discussed.     

The effect of malnutrition on the susceptibility of the host to viral infection

The effect of progressive long term dietary protein depletion on viral susceptibility was investigated in 2 host-virus systems: (1) swine influenza in the male CF₁ mouse, and (2) Rous sarcoma virus in the New Hampshire red chicken. Data are presented demonstrating a relationship between host protein nutrition and susceptibility to virus infection. This relationship is shown to be cyclic in character, involving phases of increased and decreased viral susceptibility. The relative resistance of the host on low protein intake is a function of the duration on incomplete diet administration before virus inoculation, and consequently a function of the host's state of depletion. As illustrated in Fig. 6, the cyclic susceptibility change demonstrated by these animals on low protein diet was characterized by an initial phase of increased susceptibility, a secondary phase of increased resistance, and a final phase of increased susceptibility. It is proposed that these alterations in relative viral susceptibility result from metabolic changes occurring within the host during the process of dietary protein depletion. The resistance changes are roughly correlated to periods of depot fat utilization (increased susceptibility), reserve protein utilization (decreased susceptibility), and tissue breakdown subsequent to protein starvation (increased susceptibility). Many previously published concepts of the interplay of viral susceptibility and host nutrition maintained that host malnourishment led to increased host resistance. The cyclic change in resistance, reported herein, is given as evidence that the effect of host deficiency cannot be explained simply on the basis of an inhibition of virus growth due to retarded cellular metabolism in the host. Protein deficiency is shown not to produce an "all-or-none" effect, but a series of reproducible phases of increased and decreased resistance. From the aforementioned results it is proposed that the phases of viral susceptibility seen in the protein-deficient host are demonstrative of the dynamic interrelationship between the physiologic state and the resistance of the host. Dietary influences in the normal host, by producing similar metabolic changes, could have analogous implications on innate resistance. It is believed that the foregoing leads to a more clear and dynamic concept of viral resistance in the normal individual.     

HEMOGLOBIN AND PLASMA PROTEIN PRODUCTION : VARIOUS PROTEINS,CONCENTRATES, AND DIGESTS INFLUENCE BLOOD PROTEIN PRODUCTION IN ANEMIA AND HYPOPROTEINEMIA

Given healthy dogs, fed abundant iron and protein-free or low protein diets, with sustained anemia and hypoproteinemia due to bleeding, we can study the capacity of these animals to produce simultaneousiy new hemoglobin and plasma protein. The reserve stores of blood protein-producing materials in this way are largely depleted, and levels of 6 to 8 gm. per cent for hemoglobin and 4 to 5 gm. per cent for plasma protein can be maintained for considerable periods of time. These dogs are very susceptible to infection and to injury by many poisons. Dogs tire of these diets and loss of appetite terminates many experiments. These incomplete experiments are not recorded in the present paper but give supporting evidence in harmony with those tabulated. Under these conditions (double depletion) the dogs use effectively the proteins listed above—egg, lactalbumin, meat, beef plasma, and digests of various food proteins and hemoglobin. Egg protein at times seems to favor slightly the production of plasma protein when compared with the average response (Tables 1 and 2). Various digests and concentrates compare favorably with good food proteins in the production of new hemoglobin and plasma protein in these doubly depleted dogs. Whole beef plasma by mouth is well utilized and the production of new hemoglobin is, if anything, above the average—certainly plasma protein production is not especially favored. "Modified" beef plasma by vein causes fatal anaphylaxis (Table 4). Hemoglobin digests are well used by mouth to form both hemoglobin and plasma protein. Supplementation by amino acids is recorded. Methionine in one experiment may have been responsible for a better protein output and digest utilization (Table 7).     

The effect of nutritional disturbances on the susceptibility of mice to staphylococcal infections

The susceptibility of mice to intravenous injection of coagulase-positive hemolytic staphylococci was estimated by (a) observing the extent and time of mortality of infected animals; (b) determining the number of colonies of cocci that could be recovered from the liver and spleen at various intervals of time after infection. Complete deprival of food for 36 to 48 hours immediately before infection was found to increase susceptibility. This infection-enhancing effect was further increased by allowing the animals to drink a 5 per cent glucose solution instead of water or saline during the fasting period. In contrast, sodium lactate partially corrected the effect of fasting. The infection-enhancing effect of fasting was reversible. Mice prevented from gaining weight for several weeks either by restricting their daily food intake, or by feeding them ad lib. an inadequate diet, appeared just as resistant to staphylococcal infection as did mice that gained weight rapidly on an unrestricted, complete diet.     

FGF21 is an endocrine signal of protein restriction

Enhanced fibroblast growth factor 21 (FGF21) production and circulation has been linked to the metabolic adaptation to starvation. Here, we demonstrated that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. LP-induced increases in FGF21 were associated with increased phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the liver, and both baseline and LP-induced serum FGF21 levels were reduced in mice lacking the eIF2α kinase general control nonderepressible 2 (GCN2). Finally, while protein restriction altered food intake, energy expenditure, and body weight gain in WT mice, FGF21-deficient animals did not exhibit these changes in response to a LP diet. These and other data demonstrate that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake.     

Diet-induced obese mice develop peripheral, but not central, resistance to leptin.

Leptin administration reduces obesity in leptin-deficient ob/ob mice; its effects in obese humans, who have high circulating leptin levels, remain to be determined. This longitudinal study was designed to determine whether diet-induced obesity in mice produces resistance to peripheral and/or central leptin treatment. Obesity was induced in two strains of mice by exposure to a 45% fat diet. Serum leptin increased in proportion to body weight (P < 0.00001). Whereas C57BL/6 mice initially responded to peripherally administered leptin with a marked decrease in food intake, leptin resistance developed after 16 d on high fat diet; mice on 10% fat diet retained leptin sensitivity. In AKR mice, peripheral leptin significantly decreased food intake in both 10 and 45% fat-fed mice after 16 d of dietary treatment. However, after 56 d, both groups became resistant to peripherally administered leptin. Central administration of leptin to peripherally leptin-resistant AKR mice on 45% fat diet resulted in a robust response to leptin, with a dose-dependent decrease in food intake (P < 0.00001) and body weight (P < 0.0001) after a single intracerebroventricular infusion. These data demonstrate that, in a diet-induced obesity model, mice exhibit resistance to peripherally administered leptin, while retaining sensitivity to centrally administered leptin.     

Efficacy of a high-carbohydrate diet in catabolic illness.

OBJECTIVE: To determine within the setting of isocaloric, isonitrogenous enteral diets whether a diet that supplies most of its calories from fat or carbohydrate would be most beneficial at limiting muscle protein wasting in catabolic illness. DESIGN: Prospective, randomized, crossover trial. SETTING: Academic pediatric burn unit in tertiary medical center. PATIENTS: Fourteen severely burned (>40% total body surface area) children underwent systemic metabolic and cross-leg muscle protein kinetic studies. INTERVENTIONS: All were treated clinically in a similar manner, including early excision and grafting, antimicrobial therapy, and isocaloric, isonitrogenous enteral nutritional support. Subjects randomly received either a high-carbohydrate enteral diet (3% fat, 82% carbohydrate, 15% protein), or a high-fat enteral diet (44% fat, 42% carbohydrates, 14% protein) for 1 week and then crossed over to the other diet for a second week. MEASUREMENTS AND MAIN RESULTS: On day 5 of each diet, muscle protein kinetics were determined from femoral arterial and venous blood samples during a primed-constant d5-phenylalanine infusion. Indirect calorimetry was used to determine systemic resting energy expenditure and respiratory quotient. The seven boys and seven girls were 7.1 +/- 1.1 (mean +/- sem) years old and suffered burns over 65 +/- 4% of their bodies, with 52 +/- 6% being third-degree burns. Muscle protein degradation markedly decreased (p <.01) with administration of the high-carbohydrate diet. Protein synthesis was unaltered. Endogenous insulin concentrations increased during the high-carbohydrate feeding period. No differences in energy expenditure were seen between study diets. CONCLUSIONS: In severely burned pediatric patients, enteral nutrition supplied predominantly as carbohydrate rather than fat improves the net balance of skeletal muscle protein across the leg. This is attributable to decreased protein breakdown, suggesting a protein-sparing effect of high-carbohydrate feedings.