The Minnesota human starvation experiment is renowned for its comprehensive set of careful measurements over an extended duration of precisely controlled feeding. Such a study is unlikely to be repeated due to both its magnitude and the hardships endured by its subjects (36
). At that time, it was not possible to measure all of the important metabolic fluxes participating in macronutrient balance. To address this issue, the present study introduced a computational model that integrates in vivo
human data from a variety of published studies to predict the unmeasured daily rates of carbohydrate, fat, and protein turnover and oxidation, the total energy expenditure and its components, as well as the rates of gluconeogenesis and de novo
Several investigators have used mathematical modeling to study the regulation of body weight (6
) and composition (4
). Most previous models of body weight and composition regulation assumed that the macronutrient composition of the diet had no effect on the partitioning of energy between lean and fat tissue – an assumption that runs counter to the nutrient balance concept (27
). Rather, most models defined a parameter or a simple function of initial body composition that determined the fraction of energy imbalance partitioned towards deposition or mobilization of body protein versus fat (11
). The physiological basis for this partitioning is unclear and begs the question of how body composition is regulated. A more recent model incorporated carbohydrate and fat balances, but ignored protein (28
). A few previous models have also been applied to the data from the Minnesota experiment (4
), but the present study is the first to validate a human model by comparing model predictions with body composition and metabolic data from an independent human feeding study.
Previous mathematical models have represented RMR
as a linear function of lean body mass (4
), occasionally with coefficients significantly greater than those determined from cross-sectional analysis (16
). Such models fail to capture the loop traced by the RMR
versus lean body mass curve throughout semi-starvation followed by re-feeding. In a pair of elegant studies re-analyzing the Minnesota experiment, Dulloo et al
. argued for the existence of an adaptive thermogenic mechanism to explain the measured RMR
). In agreement with these authors, the mathematical model presented here suggested that adaptive thermogenesis at the onset of semi-starvation caused a rapid drop of RMR
which then decreased slowly as lean tissue was catabolized and protein turnover decreased. During re-feeding, the level of adaptive thermogenesis and the energy costs of DNL
and protein turnover were increased, resulting in a higher RMR
at the same lean mass during re-feeding versus semi-starvation.
The physiological mechanisms underlying adaptive thermogenesis are unknown. Several investigators have suggested that underfeeding causes metabolically active organs such as the liver, intestines, or kidneys to rapidly decrease their mass (47
). Alternatively, the concentrations of circulating catecholamines and thyroid hormones have been observed to rapidly decrease with underfeeding (53
) and may reflect a reduction of sympathetic outflow and concomitant decrease of RMR
. The present model was empirical and did not distinguish between these mechanisms.
While changes of RMR contributed significantly to energy balance, the decrease of PAE during semi-starvation was responsible for the majority of the slow decline of total energy expenditure. The physiological mechanisms underlying the changes of PAE are unclear. Since PAE for most common activities is proportional to body weight, the loss of body weight itself contributed to some decrease of PAE, but this was insufficient to account for the required decrease.
Adaptation of PAE
has been hypothesized to involve altered energy efficiency of muscular work (40
). However, no change of physical activity energy efficiency was observed during treadmill tests at various stages of the Minnesota experiment (36
). Nevertheless, it is possible that changes of muscular work efficiency during typical daily activities may not have been reflected by the more physically demanding treadmill tests. Keys et al
. noted that the subjects became apathetic and avoided voluntary physical activity towards the end of the semi-starvation phase, but no systematic monitoring of physical activity was performed (36
). Questionnaires completed by the subjects showed a progressive decrease of their physical “activity drive” over the course of semi-starvation which slowly improved with re-feeding (36
). Therefore, it is possible that PAE
changes with semi-starvation were the result of decreased voluntary as well as altered spontaneous physical activity expenditures such as fidgeting, posture control, and muscle tone (41
The remarkable regulation of long-term carbohydrate balance was due to the limited whole-body glycogen storage capacity. Therefore, relatively little energy could be accumulated or lost in the form of glycogen in comparison to protein or fat. However, large short-term changes of glycogen were permitted and led to potent modulation of both carbohydrate oxidation (24
) and DNL
). Thus, glycogen feedback ensured that carbohydrate imbalances were only transient. In comparison, the relatively less significant short-term change of the body protein pool had little effect on protein oxidation so that protein imbalances were more sustained and led to long-term changes of the lean body mass. Unlike carbohydrate and protein, fat intake did not directly stimulate its own oxidation and the relative change of the body fat pool only weakly affected fat oxidation (26
). Thus, large fat imbalances were observed during semi-starvation and re-feeding and these imbalances were sustained resulting in significant changes of body fat mass.
The model predicted that the fat mass overshoot was not permanent provided that the original pre-starvation diet and physical activity level were returned. However, recovery of the original body composition was predicted to take more than a year. The predicted mechanism of the fat mass overshoot was an enhanced rate of de novo
lipogenesis in the early re-feeding period, followed by a dramatic increase of fat intake during ad libitum
feeding. In contrast, Dulloo et al
. postulated that the improved energy economy resulting from adaptive thermogenesis was somehow specifically channeled to accelerate fat mass gain during re-feeding based on a “fat-stores memory” (17
). The present study demonstrates that such a novel mechanism was not necessary to explain the data.
The present version of the computational model does not explicitly include the effects of hormones, but several hormonally mediated effects are implicitly included. For example, insulin’s effect is implicit in the function of dietary carbohydrate to inhibit lipolysis, as well as stimulate carbohydrate oxidation, glycogen synthesis, and DNL. Future work will explicitly account for the effects of important hormones and will extend the model to study overfeeding and body composition regulation in altered metabolic states like obesity, anorexia nervosa, and cachexia.