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The Journal of Nutrition Vol. 128 No. 2 February 1998, pp. 390S-393S

Effects of Under- and Overnutrition on Lactation in Laboratory Rats1,2

Kathleen Maher Rasmussen

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853

    ABSTRACT
Abstract
Introduction
References

To study the effects of maternal nutritional status on lactational performance, the diets of laboratory rats were manipulated with food restriction or increases in fat concentration. Compared with rats fed control diets ad libitum, conception rate, milk production and litter growth decreased and milk fat concentration increased in both chronically food restricted and obese animals. Chronically food restricted rats mobilized body fat and reduced their energy expenditure for maintenance and activity. Differences in suckling pattern between control and food-restricted rats affected hormone concentrations important for successful lactation. Obese rats experienced greater difficulty than controls in delivering their pups and more of their pups died in the first days of life. Milk production among obese rats may be constrained by poor appetite and the high heat production that characterizes lactation in litter-bearing species. There are many parallels as well as important differences between results obtained from these models and findings in nursing women. Nevertheless, these models provide useful information about the possible mechanisms by which maternal nutritional status affects lactational performance.

KEY WORDS: undernutrition · obesity · rats · lactation · milk

    INTRODUCTION
Abstract
Introduction
References

It has long been recognized that women who are extremely thin or fat have difficulty conceiving and that this problem can be cured by modifying their weight to a more normal value (Mitchell and Rogers 1953). This suggests that there is a body weight and/or composition associated with optimal reproductive success. Researchers have focused on body fatness as the key aspect of body composition meriting investigation. The specific optimum body characteristics may differ for each reproductive outcome. This principle has not been applied previously to lactation, particularly with data from states of both under- and overnutrition.

    MODELS OF UNDERNUTRITION DURING LACTATION

Animal models of protein-energy malnutrition differ primarily in the severity and timing of the deficiency. The most common approach is to offer animals a reduced proportion of the usual diet. In studies of lactation, this dietary treatment is usually imposed at parturition (acute food restriction) or several weeks before mating (chronic food restriction). Acute food restriction is a model in which dietary inadequacy is imposed during an established reproductive state and, because the animal has a reduced ability to adapt to this condition, it simulates famine conditions in a previously well-nourished population. In contrast, chronic food restriction is a model in which the stress of reproduction is imposed on an animal previously adapted to chronic food insufficiency. As such, it is a model for the conditions commonly seen in developing countries in which women of reproductive age are stunted in response to a condition of inadequate food intake that has existed since childhood.

Compared with control rats, acute food restriction (to 50% of ad libitum intake) during lactation causes a 37% reduction in mammary gland mass, a 50% reduction in milk volume (Brigham et al. 1992) and a 32% reduction in litter weight (Kliewer and Rasmussen 1987) at d 14 of lactation. The primary change in milk composition is a reduction in lactose concentration (Brigham et al. 1992, Kliewer and Rasmussen 1987). Dams subjected to acute food restriction lose weight during lactation (Brigham et al. 1992, Kliewer and Rasmussen 1987) and have higher concentrations of plasma corticosterone than control animals (Kliewer and Rasmussen 1987). The proportion of cardiac output that is directed to the mammary glands, and both absolute and relative blood flow to the mammary glands are reduced in these rats (Sakanashi et al. 1987).

Chronic food restriction compromises reproductive performance beginning at conception: compared with control rats, fewer corpora lutea are formed, fewer blastocysts implant, fewer fetuses are viable at d 18 of pregnancy (Alexander et al. 1988) and fewer liveborn pups are delivered (Young and Rasmussen 1985); dams gain less weight during pregnancy (Young and Rasmussen 1985). Carrying fewer pups to term permits food-restricted dams to protect the weight of individual pups (Rasmussen and Fischbeck 1987, Young and Rasmussen 1985).


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Fig 1. Effect of chronic dietary treatment on carcass fat concentration at d 20 of pregnancy (P) and d 14 of lactation (L). Sources: Young and Rasmussen (1985), Wallace, M. H. and Rasmussen, K. M., unpublished data.

Not surprisingly, a longer period of food restriction produces even more severe compromises in lactational performance. Compared with control rats, chronic food restriction (also to 50% of ad libitum intake) begun before mating and continuing throughout pregnancy and lactation causes a 62% reduction in mammary gland mass, a 69% reduction in milk volume (Brigham et al. 1992) and a 61% reduction in litter weight (Kliewer and Rasmussen 1987) at d 14 of lactation. Milk lactose concentration decreases and fat concentration increases in dams subjected to chronic food restriction; as a result, the caloric density of their milk tends to increase (Brigham et al. 1992, Kliewer and Rasmussen 1987), but not enough to compensate for the large reduction in milk volume. Body weight decreases minimally during lactation in dams subjected to chronic food restriction. Their plasma corticosterone concentrations are increased and prolactin concentrations decreased compared with controls (Kliewer and Rasmussen 1987).

Rats restricted to 60% of ad libitum intake during pregnancy and lactation expend less energy on activity and maintenance during lactation (Roberts and Coward 1984). When dietary restriction begins before conception, food-restricted dams are smaller than controls, and some of their reduced energy expenditure for maintenance during lactation results from their smaller body size (Sadurskis et al. 1991). Food-restricted rats mobilize more body fat and produce less milk than controls (Sadurskis et al. 1991).

The majority of these changes parallel those observed in poorly nourished women, but their magnitude is greater. This is likely because the chronically food-restricted rats are subjected to a more severe degree of food restriction than is the case in most human populations. In addition, lactation is much more energetically demanding in rodents than in women. This reduces the applicability of the specific findings from this model (Prentice and Prentice 1988), but has the advantage of revealing effects that might otherwise be too small to detect in reasonable numbers of human subjects.

The major exception to these parallel findings is plasma prolactin values, which are decreased in this model and are increased in poorly nourished women (Lunn et al. 1980). This likely results from differences between women and these rats in the severity of food restriction. At 50% of ad libitum intake, rat dams search for food instead of nursing their pups. In contrast, rats restricted to 70% of ad libitum intake have increased prolactin values (McGuire et al. 1995). This lesser degree of food restriction is more similar to that characteristic of poorly nourished human populations.

    MODELS OF OVERNUTRITION DURING LACTATION

Two different dietary approaches for producing obesity in laboratory rats have been used to study the effects of maternal overnutrition on lactational performance. With "cafeteria feeding," rats are offered a selection of high fat, highly palatable foods in addition to their usual closed-formula diet. This is a reasonable model for human dietary patterns, but it is difficult to know exactly what the rats have consumed, and they may choose a diet that may not contain sufficient protein for reproduction.

In the other approach, rats are offered a high fat version of their usual open-formula diet. This is also a reasonable model for human dietary patterns; however, rats are offered a higher proportion of dietary energy derived from fat so as to produce obesity as rapidly as possible. It is easier to quantify the animal's nutrient intake with this approach, but care must still be taken to ensure consumption of adequate protein to meet their needs for reproduction.


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Fig 2. Effect of chronic dietary treatment on pup weight at birth (left) and daily gain from birth to d 14 (right). HF is high fat and C* (AIN-76) and C** (AIN-93) are different control dietary treatment groups; ***, significantly different (P < 0.05) from C** group. Sources: Young and Rasmussen (1985), Wallace and Rasmussen, unpublished data.


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Fig 3. Effect of chronic dietary treatment on milk production (left) and lipid concentration at d 14 of lactation (right). HF is high fat and C* (AIN-76) and C** (AIN-93) are different control dietary treatment groups. Sources: Young and Rasmussen (1985), Wallace and Rasmussen, unpublished data.

When either of these dietary regimens is begun at weaning or at least several weeks before mating, rat dams will be heavier at conception (Rolls et al. 1984, Shaw et al. 1997). These animals will be described as "obese" (although no formal standard exists by which to classify them this way). Obese rats suffer from estrous cycle irregularities (Glick et al. 1990), may not conceive as readily as controls (Wallace M. H. and Rasmussen K. M., unpublished data) and implant fewer embryos (Shaw et al. 1997). They gain weight less readily near term (Shaw et al. 1997) or they may gain less weight overall (Wallace and Rasmussen, unpublished data). Obese rats deliver fewer and lighter pups than controls (Wallace and Rasmussen, unpublished data) and are more likely to have difficulty delivering; their pups are much more likely to die in the first few days after birth (Rolls et al. 1980, Shaw et al. 1997, Wallace and Rasmussen, unpublished data). Inasmuch as many of the pups who die have no visible milk in their stomachs, inadequate initiation of lactation is a possible cause of death. Our observational data are inadequate to exclude inappropriate maternal behavior as an additional, contributing cause.

Although obese rats produce milk of higher fat concentrations than control rats, their milk volume is substantially reduced (Rolls et al. 1981, 1983 and 1986, Wallace and Rasmussen, unpublished data). Pups who survive do not grow as well as pups of control rats (Wallace and Rasmussen, unpublished data). Obese rats do not develop the hyperphagia that is characteristic of lactation in the rat (Rolls et al. 1980). Milk production is not limited by mobilization of maternal caloric reserves because obese dams lose more weight and fat during lactation than controls; nonetheless, they remain fatter at d 14 of lactation (Wallace and Rasmussen, unpublished data).

Little is known about the causes of the poor lactational performance observed among obese dams. Our data suggest that the metabolic transition to lactation (particularly the expected dramatic decrease in plasma insulin concentrations) is impaired (Shaw et al. 1997).

Investigators have also used these two dietary approaches over shorter time intervals. When high fat or cafeteria feeding is begun at conception or shortly thereafter, rats do not become obese. Thus, this represents a model of high fat consumption during an established reproductive state and not an effect of obesity per se. Results of recent research using this model (Del Prado et al. 1997) suggest that this supports higher milk production and pup growth. However, other investigators (Guo and Jen 1995) have identified deleterious effects of maternal high fat feeding on the metabolism of these larger pups (higher blood glucose and triglyceride concentrations).

Researchers have also fed high fat or cafeteria diets beginning after parturition. This model investigates the effect of consuming a high fat diet during lactation because the diets do not change maternal body weight or composition. Nonetheless, this dietary treatment affects maternal metabolism in ways that are not supportive of milk production. Glucose metabolic clearance rate is reduced, although other characteristics of glucose metabolism remain unchanged (Burnol et al. 1987). Lipogenesis increases in brown adipose tissue (Agius et al. 1981). Glucose uptake, and lipogenesis (Agius et al. 1980) and acetyl-CoA carboxylase activity (Munday and Williamson 1987) are reduced in isolated acini from mammary glands of rats fed a cafeteria diet. Dams fed high fat diets become ketotic (Agius et al. 1983), which decreases appetite (Friggens et al. 1993). It is also possible that their food intake is constrained because their heat production is already maximal (Friggens et al. 1993).

Taken together, findings from laboratory rats suggest that consuming a high fat diet adversely affects the dam's ability to produce milk. Even in situations in which pup growth is not decreased by this manipulation of the dam's diet, there may still be adverse metabolic consequences for the pups. When high fat diets are consumed for a period sufficient to produce excess maternal fatness, milk production and pup growth are severely compromised; in addition, the initiation of lactation is adversely affected. Studies are just beginning on the effects of obesity on lactational performance among women (Hilson et al. 1997, Rutishauser and Carlin 1992), but it appears that the laboratory rat is an adequate animal model for studying this issue because of the parallels in physiologic findings that have been identified to date.

    LINKING FINDINGS ACROSS THE SPECTRUM OF MATERNAL NUTRITIONAL STATUS

It is clear from comparison of the results from these models in laboratory rats of under- and overnutrition that maternal nutritional status both before and during lactation exerts a profound effect on lactational performance. This can be seen in the combined data on carcass fat content at d 20 of pregnancy and d 14 of lactation (Fig. 1), pup birthweight and weight gain during the first 14 d after birth (Fig. 2) and milk volume and lipid concentration at d 14 of lactation (Fig. 3) from food-restricted rats, control rats and those fed a high fat diet. Furthermore, this effect of maternal nutritional status on lactation performance is probably not limited to nutrient flux during lactation (Rasmussen 1992). The studies cited here reveal effects of maternal nutritional status on mammary gland development, rates of conception, implantation and fetal survival. Metabolic and endocrinologic changes at and after parturition are also important. The results of these studies extend to lactation the principle that extremes of maternal nutritional status are associated with adverse outcomes.

    ACKNOWLEDGMENTS

The contributions of Miriam Alexander, Heather Brigham-Matthews, Karen Fischbeck, Michelle McGuire, Tami Myers, Rebecca Kliewer Olson, Helena Pachón, Tami Sakanashi, Maureen Shaw, Mary Wallace and Carolyn Young to the work reported here are gratefully acknowledged.

    FOOTNOTES
1   Presented as part of the symposium "Maternal Body Composition, Caloric Restriction and Exercise during Lactation" given at the Experimental Biology 97 meeting, April 8, 1997, New Orleans, LA. This symposium was sponsored by the International Society for Research on Human Milk and Lactation and the American Society for Nutritional Sciences and was supported in part by educational grants from Carnation Nutrition Products Division, the Gerber Foundatin, Ross Products Division, Abbot Laboratories and Wyeth-Ayerst International. Guest editors for the symposium publication were Kathryn G. Dewey, University of California, Davis, CA and Cheryl A. Lovelady, University of North Carolina, Greensboro, NC.
2   Supported by grants from the National Institutes of Health (HD14953) and the U.S. Department of Agriculture (92-34115-8073).

    LITERATURE CITED
Abstract
Introduction
References

0022-3166/98 $3.00 ©1998 American Society for Nutritional Sciences
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