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Most studies of selenium and thyroid hormone have used sodium selenite in rats. However, rats regulate thyroid hormone differently, and selenite, which has unique pharmacologic activities, does not occur in foods. We hypothesized that selenium in food would have different effects in humans. Healthy men were fed foods naturally high or low in selenium for 120 d while confined to a metabolic research unit. Selenium intake for all subjects was 47[micro]g/d (595 nmol/d) for the first 21 d, and then changed to either 14 (n = 6) or 297 (n = 5)[micro]g/d (177 nmol/d or 3.8 [micro]mol/d) for the remaining 99 d, causing significant changes in blood selenium and glutathione peroxidase. Serum 3,3',5-triiodothyronine [T.sub.3] decreased in the high selenium group, increased in the low selenium group, and was significantly different between groups from d 45 onward. A compensatory increase of thyrotropin occurred in the high selenium group as [T.sub.3] decreased. The changes in [T.sub.3] were opposite in direction to those reported in rats, but were consistent with other metabolic changes. By d 64, the high selenium group started to gain weight, whereas the low selenium group began to lose weight, and the weight changes were significantly different between groups from d 92 onward. Decreases of serum [T.sub.3] and compensatory increases in thyrotropin suggest that a subclinical hypothyroid response was induced in the high selenium group, leading to body weight increases. Increases of serum [T.sub.3] and serum triacylglycerol accompanied by losses of body fat suggest that a subclinical hyperthyroid response was induced in the low selenium group, leading to body weight decreases. KEY WORDS: * selenium * thyroid * thyrotropin * body weight * energy metabolism

Dietary calcium plays a pivotal role in the regulation of energy metabolism, in that we have found high calcium diets to attenuate adipocyte lipid accretion and weight gain during periods of overconsumption of an energy-dense diet and to increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Our studies of the agouti gene in obesity and insulin resistance demonstrate a key role for intracellular [Ca.sup.2+] in regulating adipocyte lipid metabolism and triglyceride storage, with increased intracellular [Ca.sup.2+], resulting in stimulation of lipogenic gene expression and lipogenesis, and suppression of lipolysis, resulting in adipocyte lipid filling and increased adiposity. Moreover, we have recently demonstrated that the increased calcitriol produced in response to low calcium diets stimulates [Ca.sup.2+] influx in human adipocytes and thereby promotes adiposity. Accordingly, suppressing calcitriol levels by increasing dietary calcium is an attractive target for the prevention and management of obesity. In support of this concept, transgenic mice expressing the agouti gene specifically in adipocytes (a humanlike pattern) respond to low calcium diets with accelerated weight gain and fat accretion, whereas high calcium diets markedly inhibit lipogenesis, accelerate lipolysis, increase thermogenesis and suppress fat accretion and weight gain in animals maintained at identical caloric intakes. Further, low calcium diets impede body fat loss, whereas high calcium diets markedly accelerate fat loss in transgenic mice subjected to caloric restriction. Notably, dairy sources of calcium exert markedly greater effects in attenuating weight and fat gain and accelerating fat loss. This augmented effect of dairy vs. supplemental calcium is likely attributable to additional bioactive compounds in dairy that act synergistically with calcium to attenuate adiposity; among these are angiotensin converting enzyme inhibitory peptides, which limit angiotensin II production and thereby limit angiotensin II stimulation of adipocyte lipogenesis. These concepts are confirmed by both epidemiological and clinical data, which similarly demonstrate that dairy products exert a substantially greater effect on both fat loss and fat distribution compared to an equivalent amount of supplemental calcium. KEY WORDS: * calcium * obesity * dairy * adipocyte * vitamin D

Medium chain fatty acids (MCFA) are readily oxidized in the liver. Animal and human studies have shown that the fast rate of oxidation of MCFA leads to greater energy expenditure (EE). Most animal studies have also demonstrated that the greater EE with MCFA relative to long-chain fatty acids (LCFA) results in less body weight gain and decreased size of fat depots after several months of consumption. Furthermore, both animal and human trials suggest a greater satiating effect of medium-chain triglycelides (MCT) compared with long-chain triglycerides (LCT). The aim of this review is to evaluate existing data describing the effects of MCT on EE and satiety and determine their potential efficacy as agents in the treatment of human obesity. Animal studies are summarized and human trials more systematically evaluated because the primary focus of this article is to examine the effects of MCT on human energy metabolism and satiety. Hormones including cholescytokinin, peptide YY, gastric inhibitory peptide, neurotensin and pancreatic polypeptide have been proposed to be involved in the mechanism by which MCT may induce satiety; however, the exact mechanisms have not been established. From the literature reviewed, we conclude that MCT increase energy expenditure, may result in faster satiety and facilitate weight control when included in the diet as a replacement for fats containing LCT. J. Nutr. 132: 329-332, 2002. KEY WORDS: * medium-chain triglycerides * satiety * energy expenditure * obesity

The widespread occurrence of excess weight and related diseases demands that efforts be made to understand energy expenditure from the gene to the whole animal. For some time, it has been understood that mitochondrial oxidation of fuels generates an electrochemical gradient via outward pumping of protons by the electron transport chain. ATP production via [F.sub.1][F.sub.0] ATP synthase is then facilitated by the inward flux of protons down the gradient. There is a growing appreciation that a significant portion of the metabolic rate of endotherms is attributable to counteracting 'proton leak' (uncoupling), wherein a flux of protons down the electrochemical gradient generates heat independently of ATP production. Proton leak is especially apparent in thermogenic brown adipose tissue, which expresses a tissue-specific uncoupling protein (UCP1). The recent discovery of widely expressed putative UCP1 homologs [UCP2, UCP3, UCP4, UCP5/brain mitochondrial carrier protein-1 (BMCP1)] raised the possibility that innate proton leak and metabolic rate are regulated by UCP1-like proteins. On the basis of current published data, one may not exclude the possibility that UCP homologs influence metabolic rate. J. Nutr. 130: 711-714, 2000. KEY WORDS: * metabolic rate * proton leak * oxidative phosphorylation

In this review, the emerging evidence that excessive energy intake relative to energy expenditure increases the risk of prostate cancer is discussed. The adverse effects of energy imbalance can be inferred from an experimental study demonstrating reduced prostate tumor growth, lower circulating concentrations of insulin-like growth factor-I and decreased expression of vascular endothelial growth factor with energy restriction in transplantable tumor models. The effects of energy restriction on factors mediating greater proliferation relative to apoptosis and angiogenesis suggest that energy imbalance may act late in the carcinogenic pathway. Energy intake also has been evaluated in relation to prostate cancer risk in 23 analytic epidemiologic studies. Among studies reporting effect estimates, 8 of 14 case-control studies support a direct association [top versus bottom quantile, O[R.sub.summary] = 1.3; 95% confidence interval (CI), 1.1-1.4], but none of four cohort studies do (R[R.sub.summary] = 1.0; 95% CI, 0.8-1.2). The four case-control studies that evaluated advanced disease suggest a higher risk with higher energy intake (O[R.sub.summary] = 1.6; 95% CI, 1.2-2.0). However, none of these studies considered the balance of energy intake with body size and physical activity, the major determinants of variability in energy demand. Numerous research questions remain to be addressed, including, Which biological pathways are adversely affected by energy imbalance? Does energy imbalance act early or late in prostate carcinogenesis? What is the optimal energy balance for minimizing risk of clinically important prostate cancer? Evidence is beginning to show that energy intake in excess of expenditure may affect prostate carcinogenesis and, in particular, risk of advanced disease. KEY WORDS: * prostate cancer * energy intake * risk

A framework representing the major biochemical pathways of nutrient metabolism is developed allowing quantification of the energy efficiency of different nutritional scenarios. The model is based on a number of carbon chain pivots (glucose, pyruvate, acetyl coenzyme A, [alpha]-ketoglutarate, oxaloacetate and serine) and cofactors involved in metabolism. Excess pivots yield acetyl coenzyme A, which may be used for ATP or lipid synthesis. In contrast to previous work of this kind, the framework was constructed so that new insights in nutrient metabolism can be easily incorporated. Traditionally, integral values have been used to quantify mitochondrial ATP synthesis from cofactors (i.e., 3 ATP/NADH and 2 ATP/FAD[H.sub.2]), but current estimates are approximately 0.20 lower than previously assumed. Based on the latter, the energy expenditure for ATP synthesis from glucose was 91.0 kJ/ATP. For lipid (tripalmitin), 96.3 kJ/ATP was required whereas for amino acids energy expenditures varied between 99.2 (glutamate) and 153.2 kJ/ATP (cysteine). Energy derived from amino acid catabolism is stored and transferred either via carbon chain pivots or cofactors. It is hypothesized that this may affect the ultimate utilization of this energy (e.g., for ATP or lipid synthesis). The energy cost of nitrogen transport appeared relatively modest for most nonessential amino acids. Likewise, the net cost of using dietary glutamate and glutamine for ATP synthesis (e.g., in the viscera) and de novo synthesis of these amino acids in muscle is relatively minor and of similar magnitude as the cost of storing glucose energy as glycogen. KEY WORDS: * energy efficiency * nutritional models * nutrient utilization * biochemistry

Underreporting of habitual food intake can be explained by underrecording and/or undereating. This study was designed to discriminate between the two errors mentioned, by measuring energy and water balance. Twenty-four lean female dieticians were recruited as subjects. Energy intake and water intake were measured for 1 wk with a weighed dietary record. Energy expenditure was estimated from measurements of resting metabolic rate, and measured physical activity with a triaxial accelerometer for movement registration. Water loss was estimated with deuterium-labeled water. Energy balance was determined by measuring the change in body mass over a nonrecording week (preceding the recording week) and over the recording week. Mean energy and water intake were 8.5 [+ or -] 1.0 MJ/d and 2.3 [+ or -] 0.5 L/d. The change in body mass in the nonrecording week was 0.1 [+ or -] 0.6 kg and in the recording week -0.6 [+ or -] 0.8 kg (paired t test; P = 0.02), indicating 16% undereating. Recorded water intake plus calculated metabolic water closely matched measured water loss (r = 0.93; P = 0.0001), which indicated a high recording precision. In conclusion, in the studied group of highly motivated lean women, there was 16% underreporting of habitual food intake, which could be explained by undereating. KEY WORDS: energy-intake; water-intake; energy-balance; water-balance; women

Experiments were conducted to investigate the combined effects of removal of the adrenal gland and chemically-induced castration on energy balance in rats. Results indicate that the development of obesity following castration in rats involves the hypothalamic-pituitary-adrenal axis. Adrenalectomy weakened the increased gain in body weight, fat and energy in chemically castrated female rats. This data suggests a possible interaction between adrenal glands and ovaries in regulating energy balance.

Studies examining the effects of low-protein diets on food intake and body weight have shown varied results. Many researchers have found low dietary protein to increase food intake, while others have found no effect or even a decrease. In 63 male Sprague-Dawley rats, we examined several low levels of dietary protein (2%, 5%, 8%, 10%, 15% vs. 20% casein) to determine the dose-response relationships between low dietary protein and food intake, body composition, energy balance and serum leptin concentrations. Food intake, over the range of low dietary protein, showed a quasi bell-shaped response curve with peak intake occurring in rats fed 8-10% casein. Peak feeding occurred at or just below the estimated protein requirement of the rats (10-12.5% casein). Compared to the 20% casein controls, food intake was severely reduced in rats fed 2% casein, while it was greater in the other low-protein groups. The amount of body fat steadily increased between the 15% casein group and the 8% casein group, and sharply declined between the 5% casein group and 2% casein group. The change in body fat reflected both the change in food intake and altered energy partitioning. Serum leptin concentrations were greater in rats fed the 5 and 8% casein diets than in control rats fed 20% casein. Serum leptin concentrations were positively associated with body fat content ([r.sup.2] = 0.763, P [is less than] 0.001). Increased serum leptin concentrations in the presence of increased food intake is suggestive of a state of leptin resistance. This animal model may provide important insights into diet-induced obesity. J. Nutr. 130: 514-521, 2000. KEY WORDS: * protein restriction * food intake * body composition * leptin * rats

Obesity represents a major threat to health and quality of life. Although obesity has strong genetic determinants, the increasing prevalence of obesity in populations around the world suggests that environmental factors are promoting or exacerbating the problem. Experts are calling for public health efforts to deal with the global epidemic of obesity. Such a campaign would require that we identify and modify environmental factors that promote obesity. Our current food supply is high in fat, and high fat diets have been suggested to promote obesity by increasing energy intake, thus increasing the probability of positive energy balance and weight gain. However, others argue that high fat diets are not promoting obesity. In this paper, we review evidence from animal studies, carefully controlled laboratory studies, cross-sectional studies, clinical trials and studies in individuals at high risk to develop obesity. Although there are many environmental factors promoting excess energy intake and discouraging energy expenditure, it is clear that consumption of a high fat diet increases the likelihood of obesity and that the risk of obesity is low in individuals consuming low fat diets. On the basis of the available data, the current public health recommendations to lower dietary fat intake appear to be appropriate. J. Nutr. 130: 284S-288S, 2000. KEY WORDS: * body weight regulation * energy balance

Dietary or energy restriction is the most potent and reproducible known means of reducing cancer risk in mammals. In the specific case of breast cancer, restriction is dominant with relation to genetic susceptibility, carcinogen exposure and specific components of the diet. Similarly, increased body mass index is associated with a twofold increase in postmenopausal breast cancer risk in humans. To further explore the relationship between energy intake and cancer risk, we have identified a biochemical profile that reflects the dietary restriction metabolome. Exploratory studies previously identified subsets of 20-63 redox-active small molecules from sera (measured by HPLC coupled with coulometric detector arrays) that distinguished dietary groups in both male and female rats. Expert system and pattern recognition-based approaches have 85-100% accuracy in distinguishing diet groups by using these profiles, indicating that the metabolites previously determined using principal component analysis and hierarchical cluster analysis contain sufficient information to construct classification models. We have now combined these disparate datasets into a single metabolic profile consisting of 104 chromatographically distinguishable peaks. These analyses bring to light fundamental differences between the metabolic response of females and males to energy restriction (e.g., more metabolites are significantly altered in females). Further analysis with projection methods shows that most samples fall within expected variation, but even most outliers are correctly classified. Significant components identified with projection methods (discriminant analysis) are sufficient to yield >95% accuracy in distinguishing metabolic type. These approaches have further highlighted a limited subset of metabolites that are important for this classification. [Supported by NIA-AG15354.]

Anorexia, hypermetabolism and weight loss are common in advanced cancer. The progressive wasting may be due to diminished dietary intake as well as to increased energy expenditure mediated by metabolic alterations caused by the tumor. We studied dietary intake, resting energy expenditure and weight loss in 297 patients with generalized malignant disease and their relation to survival. Patients were examined cross-sectionally at entry into an outpatient palliative care program that included anti-inflammatory treatment and nutritional counseling. Survivors were studied longitudinally after 4 mo during palliative care. We found at entry that the patients' mean dietary intake was low. Weight loss of >10% was present in 43% of the patients, and hypermetabolism was present in 48%. Dietary intake did not differ between normometabolic and hypermetabolic patients, nor was tumor type or gender related to energy and protein intake. Weight loss could not be accounted for by diminished dietary intake alone. Increased resting energy expenditure was not compensated for by an increase in spontaneous food intake. These findings indicate that feedback regulation of dietary intake in relation to energy expenditure is frequently lost in patients with cancer. Hypermetabolism and weight loss were significant predictors of decreased survival. Mean survival time was about 8 mo; 189 patients survived 4 mo or more, and 153 could be reexamined. At the 4-mo follow-up during palliative care, group mean weight was nearly maintained, with large individual variations. Weight loss during follow-up predicted decreased survival. Energy intake increased slightly, also with great variation, and an increased energy intake predicted longer survival. J. Nutr. 132: 3465S-3466S, 2002. KEY WORDS: * cancer cachexia * dietary intake * energy expenditure * weight loss * survival

Energy restriction repeatedly and strongly increases maximum life span in rodent models while retarding the appearance of age-associated pathologic and biological changes. Three main questions concerning energy restriction and aging will be addressed: 1) By what mechanisms does energy restriction retard aging and disease processes in rodents? Mechanistic insight was gained by using oligonucleotide microarrays by which we described the gene expression profile of aging skeletal muscle (1) and brain (2) in mice and its alteration by energy restriction. 2) Will energy restriction exert similar actions in primates? Two ongoing studies in rhesus monkeys subjected to energy restriction as well as limited human epidemiologic data support the notion of human translatability. 3) Can substances be identified that mimic the beneficial actions of energy restriction? The search for such substances is rapidly becoming an active area of inquiry and may benefit from genomic- and proteomic-based approaches.

The role of energy balance in the pathogenesis of postmenopausal breast cancer is of considerable medical and public health interest. This talk will summarize what has been learned on this topic from the Iowa Women's Health Study. The cohort was established in 1986 through the recruitment of 41,836 women aged 55-69 y with a valid Iowa driver's license. Data on physical activity, energy intake, anthropometrics and other risk factors at baseline were assessed through a mailed survey. Follow-up for cancer incidence was achieved through annual record linkage to the Iowa Cancer Registry and regular follow-ups by mail. Estimated energy intake at baseline is weakly associated with greater incidence. Regular physical activity appears to be weakly protective. The strongest evidence that energy imbalance is a risk factor comes from examination of the consequence, i.e., obesity. Adult body mass index, especially abdominal adiposity, is a consistent risk factor, primarily for tumors that express receptors for estrogen. Conversely, being overweight in adolescence is weakly protective, and the women at great risk are those who are thin early in life and gain the most weight as adults. Taken together, these results provide encouraging evidence that at least some fraction of postmenopausal breast cancer may be avoidable through maintenance of energy balance.

Cancer has long been recognized as one of the principal causes of adult deaths in both the developed and developing world. Excess weight gain, however, was seen as only one of several contributors to the risk of a range of adult chronic diseases including diabetes, hypertension and other cardiovascular diseases. Now, however, the pattern of cancer incidence is changing and a clearer picture of the risk factors and pathophysiologic processes underlying carcinogenesis is emerging. Traditionally, cancers of the breast and endometrium were recognized to be more common in obese women, but only recently has the issue of excess weight gain per se been considered as an etiological factor. A recent systematic review concluded that overweight and obesity contributed to 8.6% of postmenopausal breast cancers, ~11% of colon cancers, 39% of endometrial cancers, 4.5% of prostate cancers and ~25% to each of the much less common kidney and gallbladder cancers in the European Union. Thus overweight and obesity were associated with ~72,000 new EU cases per year as a conservative estimate. Most of these analyses depend on studies in only a small proportion of the world's population (i.e., the United States and European Union), but the problem of excess weight is now a global epidemic--the largest unrecognized public health problem in the world, with >1 billion adults affected when a conservative cut-off point for body mass index (BMI) of 25 kg/[m.sup.2] is used. In Asia, optimum health is seen in populations with an average BMI of 21 kg/[m.sup.2] and the degree of fatness per unit body weight is greater with selective abdominal fat accumulation and probably a different sex steroid, adrenal and hypothalamic hormonal profile and responsiveness. All of these differences may contribute to enhancing the risk of cancer in Asia. Rapid childhood growth with early puberty and overweight comprise an additional major problem. Distinguishing the different factors contributing to carcinogenesis in an overweight and obese population is challenging. Poor diets that are low in nonstarch polysaccharide-rich cereals, vegetables and fruit and physical inactivity likely contribute to both excessive weight gain and carcinogenesis. Distinguishing the differential roles of these potential confounders when analyzing the role of weight gain is a major clinical and epidemiologic issue that already involves functional genomic analyses and trials. Although these etiological studies present a novel and exciting prospect, an even greater challenge is now presenting itself in public health terms. How do we counteract the currently overwhelming societal and probably primeval biological pressures to overeat and do as little as possible? Inadvertently, we have allowed the creativity of government, commerce and socially responsible sectors of society to design a convenient and supposedly egalitarian environment geared to individual responsibility and opportunity. In practice, this has led to our producing a harmful environment geared to persuading young children and families to eat inappropriately and do little. The affluent, confident, intelligent and self-motivated sectors of society flourish in this environment. Our scientific approach to decision-making in medicine based on the needs for double-blind trials for new drugs has also now developed to the point at which it overwhelms the public health sector, which has become a rudimentary feature of policymaking in both the United States and the European Union. The World Cancer Research Fund produced a widely acclaimed new approach to the assessment of the role of diet in the development of cancer in its first report. Now we must consider how best to identify coherently and systematically the societal pressures that currently demand unusual behavior if overweight and the risk of cancer are to be limited. This is the next major intellectual and societal challenge for us all.

Over 20 years ago, we began reexploring the relationship between total energy intake and development of cancer in animal models. Previous work dated back to 1909, but nutritional requirements of rodents were not known then, and older diets lacked several essential nutrients. We showed that rats given carcinogens to induce mammary or colon cancer and fed high fat diets that were restricted in total energy were significantly less likely to develop tumors. The tumors that developed were much smaller, indicating growth inhibition of transformed cells. We went on to show that insulin and insulin-like growth factor-I levels were reduced by feeding low energy diets. Both of these hormones are growth factors for a variety of cancers, are elevated in overweight people and are associated with increased risk of cancer. Our work with rodents may explain the epidemiologic observations that dietary fat is associated with increased risk of breast or colon cancer but not after adjustment for total energy intake. In addition, an animal fed an unlimited amount of food should not be regarded as normal but as the equivalent of a morbidly obese human. Therefore, we are probably seeing the effects of obesity-associated sensitivity to carcinogenesis in control rats and a more normal response in those subjected to energy restriction. Recent results with DNA microarrays show that many previously unsuspected genes are affected by energy restriction. This technique may lead to genetic or pharmacologic interventions to inhibit or treat cancer.