Jules Hirsch

Changes in Energy Expenditure Resulting from Altered Body Weight

BACKGROUND No current treatment for obesity reliably sustains weight loss, perhaps because compensatory metabolic processes resist the maintenance of the altered body weight. We examined the effects of experimental perturbations of body weight on energy expenditure to determine whether they lead to metabolic changes and whether obese subjects and those who have never been obese respond similarly. METHODS We repeatedly measured 24-hour total energy expenditure, resting and nonresting energy expenditure, and the thermic effect of feeding in 18 obese subjects and 23 subjects who had never been obese. The subjects were studied at their usual body weight and after losing 10 to 20 percent of their body weight by underfeeding or gaining 10 percent by overfeeding. RESULTS Maintenance of a body weight at a level 10 percent or more below the initial weight was associated with a mean (+/- SD) reduction in total energy expenditure of 6 +/- 3 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 5 kcal per kilogram per day in the obese subjects (P < 0.001). Resting energy expenditure and nonresting energy expenditure each decreased 3 to 4 kcal per kilogram of fat-free mass per day in both groups of subjects. Maintenance of body weight at a level 10 percent above the usual weight was associated with an increase in total energy expenditure of 9 +/- 7 kcal per kilogram of fat-free mass per day in the subjects who had never been obese (P < 0.001) and 8 +/- 4 kcal per kilogram per day in the obese subjects (P < 0.001). The thermic effect of feeding and nonresting energy expenditure increased by approximately 1 to 2 and 8 to 9 kcal per kilogram of fat-free mass per day, respectively, after weight gain. These changes in energy expenditure were not related to the degree of adiposity or the sex of the subjects. CONCLUSIONS Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of a body weight that is different from the usual weight. These compensatory changes may account for the poor long-term efficacy of treatments for obesity.

The role of adipose cell size and adipose tissue insulin sensitivity in the carbohydrate intolerance of human obesity

Glucose metabolism and insulin sensitivity of isolated human adipose tissue was studied as a function of adipose cell size and number. Glucose metabolism by these tissues was closely related to the number of cells in the fragment, irrespective of cell size. Adipose cells of obese individuals metabolized glucose to carbon dioxide and triglyceride at rates similar to adipose cells of nonobese subjects. In contrast, insulin responsiveness of adipose tissue was dependent upon adipose cell size. The larger its adipose cells the less insulin sensitive was the tissue. Thus, adipose tissue of obese subjects, with enlarged cells, showed a diminished response to insulin. After weight loss and reduction in adipose cell size, insulin sensitivity of the adipose tissue of obese patients was restored to normal. When adipose tissue of obese individuals showed impaired responsiveness to insulin, their plasma insulin levels, after oral glucose, were elevated. Weight loss and reduction in adipose cell size restored plasma insulin concentration to normal, concomitant with the return of normal tissue insulin sensitivity.

Effect of early nutrition on the development of rat epididymal fat pads: cellularity and metabolism

The effect of infantile nutritional levels on adipose tissue cellularity and metabolism was studied in two groups of Sprague-Dawley rats. Caloric intake was varied during the suckling period by manipulating litter size immediately after birth; however, all animals had free access to food after weaning. The epididymal fat pads of animals raised in small litters were heavier than those of their paired siblings raised in large litters. Initially, the differences in pad weight were accounted for primarily by differences in total cell number; however, at 20 wk both cell number and cell size contributed equally. The rate of glucose incorporation into CO(2) and triglyceride during in vitro incubations was the same for both groups if expressed on a per cell basis; therefore total tissue incorporation was greater in animals with more cells. The results support the hypothesis that early nutritional experiences can effect permanent changes in the cell number and size of the epididymal fat depot and that total cell number is important in the total metabolism of this organ. These findings and the fact that extreme human obesity is accompanied by similar alterations in cellularity and metabolism indicate that early nutritional experiences should be studied further as a guide to the etiology of obesity in man.

The fatty acids of human milk. II. Alterations produced by manipulation of caloric balance and exchange of dietary fats.

This report describes specific alteration of the fatty acid pattern of human milk produced by rigidly controlled variations in the maternal diet. The subject was a 23-year old white para 3 who had a normal pregnancy and delivered spontaneously at term. The baby girl was breastfed exclusively 6 feedings/day at 4-hour intervals. An orally administered liquid formula supplemented by vitamins and minerals was the sole nourishment of the mother. Maternal milk output was determined by weighing the baby immediately before and after each nursing. Milk samples were collected at the end of each dietary period for chemical analysis. 2 independent but complementary methods the gas liquid chromatography and ultraviolet spectrophotometry after isomerization with alkali were used to analyze fatty acid patterns. The experimental design consisted of: promoting of synthesis of milk fat from carbohydrates by feeding excess calories and no fat (period 3); promotion of transfer of depot fat by feeding deficient calories (period 4); and promotion of transfer of dietary fat by feeding excess calories as corn oil (period 5). The effects of substituting 1 fat for another were compared in periods 2 (lard) and 7 (corn oil). The results show that the fatty acid composition of human milk can be radically altered without affecting milk volume or milk fat output. During energy equilibrium milk fat appears like dietary fat. During caloric deficiency milk fat resembles human depot fat. These findings show that fatty acid pattern of human breast milk is influenced by transfer of dietary or depot fat. During excess nonfat calories the milk exhibited a striking increase in lauric and myristic acids and a marked decline of all polyenoic acid. None of the serum ester groups (cholesterol esters triglycerides and phospholipids) showed a parallel rise in these acids. The study also shows that human mammary acid synthesis differs in many ways from that in extramammary depots.

Diminished Energy Requirements in Reduced-Obese Patients

In assessing the reasons for the frequent regaining of weight by reduced-obese patients, we examined retrospectively the seven-day energy intake requirements for weight maintenance of 26 obese patients (12 males, 14 females) at maximum weight (152.5 +/- 8.4 kg) and after weight loss (100.2 +/- 5.7 kg). These results were compared with those obtained in 26 age- and sex-matched control patients who had never been obese (62.6 +/- 2.3 kg). The obese and control subjects required comparable caloric intakes: 1432 +/- 32 kcal/m2/d vs 1341 +/- 33 kcal/m2/d, respectively. Following weight loss, the reduced-obese subjects required only 1021 +/- 32 kcal/m2/d, a 28% decrease (P less than 0.001) in requirements relative to their obese state and a 24% decrease relative to the control patients (P less than 0.001). The mean individual energy requirement of the reduced-obese subjects (2171 kcal/d) was less than that for the control subjects (2280 kcal/d) despite the fact that they still weighed 60% more than the controls. In order to maintain a reduced weight, some reduced-obese or even partially reduced patients must restrict their food intake to approximately 25% less than that anticipated on the basis of metabolic body size. The reasons why this finding is unlikely to be an artifactual consequence of changes in lean body mass or body water content are discussed. This finding has implications with regard to the pathophysiology and treatment of obesity in humans.

Human eating : evidence for a physiological basis using a modified paradigm

The aim of these studies was to determine if meal requests and changes in hunger ratings in humans were related to spontaneous changes in blood glucose concentration. In our first study, 18 healthy subjects were acutely isolated from food ant time cues. Blood glucose was continuously monitored online and visual analog ratings of hunger were obtained following an overnight fast. Spoken meal requests, if they occurred, were also recorded. In 83% of the subjects, both the perception and behavioral expression of hunger, as assessed by changes in hunger ratings and meal requests, were preceded by, and correlated with, brief, transient declines in blood glucose (nadir: -10% at 27 min). The pattern, magnitude and time course of these declines was similar to those observed in rats. This significant association, between increased expression of hunger and declines in blood glucose, is being tested in a second, ongoing study using acute insulin infusions to mimic spontaneous transient declines in blood glucose. Each subject was studied twice: either insulin or saline was infused while hunger ratings were obtained. Preliminary results in five subjects indicate that hunger ratings increased after insulin-induced transient declines in blood glucose. No change in hunger ratings occurred when blood glucose concentration was stable. These results suggest that this temporal pattern of blood glucose reflects an antecedent physiological event or provides a signal related to the expression of hunger in humans. Further understanding of human eating may result from investigation of the complex interaction of physiological and other factors in an experimental setting that allows the expression the behavior under study.

Brain cholecystokinin and nutritional status in rats and mice.

Under certain conditions, exogenously administered cholecystokinin (CCK) or its COOH-terminal octapeptide can terminate feeding and cause behavioral satiety in animals. Furthermore, high concentrations of CCK are normally found in the brains of vertebrate species. It has thus been hypothesized that brain CCK plays a role in the control of appetite. To explore this possibility, a COOH-terminal radioimmunoassay was used to measure concentrations of CCK in the cerebral cortex, hypothalamus, and brain stem of rats and mice after a variety of nutritional manipulations. CCK, mainly in the form of its COOH-terminal octapeptide, was found to appear in rat brain shortly before birth and to increase rapidly in cortex and brain stem throughout the first 5 wk of life. Severe early undernutrition had no effect on the normal pattern of CCK development in rat brain. Adult rats deprived of food for up to 72 h and rats made hyperphagic with highly palatable diets showed no alterations in brain CCK concentrations or distribution of molecular forms of CCK as determined by Sephadex gel filtration of brain extracts. Normal CCK concentrations were also found in the brains of four strains of genetically obese rodents and in the brains of six animals made hyperphagic and obese by surgical or chemical lesioning of the ventromedial hypothalamus. It is concluded that despite extreme variations in the nutritional status of rats and mice, CCK concentrations in major structures of the brain are maintained with remarkable constancy.

The fat cell.

Investigations of how fat cells develop, store, and release energy, and what role they play in energy metabolism are presented. The importance of adipose tissue in the pathogenesis of obesity is considered.

ADIPOSE-CELL SIZE AND IMMUNOREACTIVE INSULIN LEVELS IN OBESE AND NORMAL-WEIGHT ADULTS

Abstract The relationship between adipose-cell size and plasma levels of immunoreactive insulin (I.R.I.) was studied in 73 normal and obese individuals and in 12 obese patients before and after weight reduction. A strong positive correlation was found between adipose-cell size and fasting I. R . I . in both groups. This relation exists despite the widely differing degrees of obesity (and, therefore, their probable different total carbohydrate intakes). It is suggested that the increased adipose-cell size seen in obesity could sensitise the pancreas to produce more insulin.

Food deprivation and hypothalamic neuropeptide gene expression: effects of strain background and the diabetes mutation

We have used a novel method to identify genes expressed in the hypothalamus which may be potentially involved in controlling food intake and energy metabolism. We assumed that food deprivation, a powerful stimulus of food intake, would stimulate the activity of neural pathways involved in feeding behavior which should be reflected in an increase in the synthesis of any relevant neuropeptide and its messenger RNA. A study of 5 neuropeptides in 5 strains of mice has identified neuropeptide Y (NPY) as a gene whose expression in the hypothalamus is controlled by nutritional status, suggesting that hypothalamic NPY neurons are a link in the neural network regulating feeding behavior and energy metabolism. In addition, we have studied the effect of the diabetes mutation on neuropeptide gene expression during fasting and refeeding. Our findings suggest that abnormal NPY and enkephalin gene expression in the hypothalamus may be two important determinants of the expression of the diabetes mutation.