Misconceptions in body weight regulation: implications for the obesity pandemic.

Energy is a concept of universal importance. In applying it to body weight regulation, the focus has been on energy balance and how this balance is affected by intakes and expenditures. However, energy is an abstract concept without biological equivalent and applying it to explain body weight regulation has led to various misconceptions and created intellectual obstacles in understanding the obesity problem. When nutrient and substrate interactions are considered, instead, a number of important issues pertaining to body weight regulation and to the obesity epidemic can be much more pertinently addressed.

Macronutrient composition and food selection.

Humans can maintain health on diets differing widely in their macronutrient content, and numerous diet recommendations have been made to maintain health and to help weight control. Net adenosine triphosphate yields during the oxidation of carbohydrate, fat, and protein come to 75%, 90%, and 55%, respectively. However, macronutrient proportions can only be varied within limits, and differences in energy dissipation achievable by macronutrient exchanges are minor. In the National Health and Nutrition Examination Survey III data, stature explains 10% to 16% of the variance in fat-free mass in adults (the most significant predictor of resting energy expenditure), but <1% of the variance in the percentage of body fat. Thus, differences in resting energy expenditure cannot be expected to have much effect on adiposity. Recommendations designed to facilitate weight control, therefore, should be based on their potential impact on food consumption and energy intake. They should also reflect the fact that the logic for nutrient selection is not the same during weight maintenance and weight reduction. Glycogen levels, along with inherited traits and exercise habits, influence fat oxidation, and, hence, the size that the adipose tissue mass has to reach for fat oxidation to become commensurate with fat intake. Recent increases in the prevalence of obesity could have been brought about by the effect of changes in the food supply and by further declines in physical activity on habitual glycogen levels. Given that biological evolution led to food intake regulating mechanisms that are more powerful in promoting search for food than in seeking to restrain energy intake, it is not surprising that constant availability of desirable foods would lead to a high prevalence of obesity.

Malonyl-CoA content and fatty acid oxidation in rat muscle and liver in vivo.

Malonyl-CoA acutely regulates fatty acid oxidation in liver in vivo by inhibiting carnitine palmitoyltransferase. Thus rapid increases in the concentration of malonyl-CoA, accompanied by decreases in long-chain fatty acyl carnitine (LCFA-carnitine) and fatty acid oxidation have been observed in liver of fasted-refed rats. It is less clear that it plays a similar role in skeletal muscle. To examine this question, whole body respiratory quotients (RQ) and the concentrations of malonyl-CoA and LCFA-carnitine in muscle were determined in 48-h-starved rats before and at various times after refeeding. RQ values were 0.82 at baseline and increased to 0.93, 1. 0, 1.05, and 1.09 after 1, 3, 12, and 18 h of refeeding, respectively, suggesting inhibition of fat oxidation in all tissues. The increases in RQ at each time point correlated closely (r = 0.98) with increases (50-250%) in the concentration of malonyl-CoA in soleus and gastrocnemius muscles and decreases in plasma FFA and muscle LCFA-carnitine levels. Similar changes in malonyl-CoA and LCFA-carnitine were observed in liver. The increases in malonyl-CoA in muscle during refeeding were not associated with increases in the assayable activity of acetyl-CoA carboxylase (ACC) or decreases in the activity of malonyl-CoA decarboxylase (MCD). The results suggest that, during refeeding after a fast, decreases in fatty acid oxidation occur rapidly in muscle and are attributable both to decreases in plasma FFA and increases in the concentration of malonyl-CoA. They also suggest that the increase in malonyl-CoA in this situation is not due to changes in the assayable activity of either ACC or MCD or an increase in the cytosolic concentration of citrate.

What do we most need to learn about food intake regulation?

Many mechanisms are known to contribute to the regulation of food intake. This notwithstanding, variations in food intake from day to day and deviations from daily energy balance are substantial and very readily tolerated. Yet, despite this very loose short-term adjustment of food intake to energy expenditure, most adults maintain stable body compositions during long periods of their lives. This is particularly puzzling when it occurs in the face of an ubiquitous supply of appealing foods and under circumstances that, in many ways, promote food consumption. Thus, the question arises as to why people in affluent societies eat substantially less on most days, than the amounts that they can so readily consume on high-intake days? In addition to conscious decisions, physiological phenomena restraining food consumption must be presumed to play an important role in limiting weight. But what are the phenomena that cause spontaneous reduction in food intake after a few days of overeating? Our ignorance about the nature and impact of these effects stands in the way of a better understanding of body weight regulation and of the factors responsible for the induction and maintenance of obesity.

How NOT to approach the obesity problem.

The emphasis given to the energy balance equation has fostered the widespread belief that obesity is a problem of energy balance. This mistaken view has led to many unjustified and unfortunate interpretations, because obesity is, rather, a problem of the interaction between body composition and food intake regulation.

Effects of glucocorticoids on energy metabolism and food intake in humans.

The effect of glucocorticoid administration on energy metabolism and food intake was studied in 20 healthy, nondiabetic Caucasian male volunteers [27 +/- 5 (SD) yr, 72 +/- 9 kg, 20 +/- 7% body fat] randomly and blindly assigned to glucocorticoid (methylprednisolone, METH; n = 10) or placebo (PLAC; n = 10) treatment. Each subject was studied twice: during a weight maintenance diet and during ad libitum food intake. Energy metabolism was measured by indirect calorimetry and food intake by an automated food-selection system. Twenty-four-hour urinary norepinephrine excretion (24-h NE) was used as an estimate of sympathetic nervous system activity. During weight maintenance, METH intravenous infusion (125 mg/30 min) increased energy expenditure compared with PLAC, and after 4 days of oral therapy, METH (40 mg/day) decreased 24-h NE and increased energy expenditure compared with PLAC. During ad libitum food intake, after 4 days of METH (40 mg/day) or PLAC oral therapy, both groups increased their energy intake over weight maintenance, but the increase was significantly larger in the METH group compared with the PLAC group (4,554 +/- 1,857 vs. 2,867 +/- 846 kcal/day; P = 0.04). Our data suggest that therapeutic doses of glucocorticoids induce obesity mostly by increasing energy intake, an effect which may be related to the ability of glucocorticoids to act directly or indirectly on the central regulation of appetite.

Glycogen levels and obesity.

The degree of replenishment of the body's glycogen stores influences the contribution made by glucose and free fatty acids to the fuel mixed oxidized. The expansion of the adipose tissue mass required to promote fat oxidation to rates commensurate on average with fat intake is therefore influenced not only by the diet's fat content, but by glycogen levels as well. It seems possible that recent changes in the food supply and a further decline in physical activity could have led to some increase in the range within which glycogen levels are habitually maintained, and that this could be a cause for the recent increase in the incidence of obesity noted in many countries.

Body composition, respiratory quotient, and weight maintenance.

For weight maintenance, the fuel mix oxidized must match the nutrient distribution in the diet. The composition of the fuel mix oxidized and the respiratory quotient are influenced by circulating substrate and hormone concentrations, which, among other things, reflect the degree of replenishment of the body's fuel reserves. Carbohydrate and protein balances are maintained without obvious changes in the body's glycogen stores and protein pools. One of the most readily quantifiable measures by which to judge the effect of various inherited and circumstantial factors on energy metabolism and body composition is the percentage body fat for which weight maintenance occurs. The amount of body fat for which the steady state of weight maintenance tends to become established is therefore a key fact on which an understanding of body weight regulation should be based, rather than rates of energy turnover or past circumstances that may have led to fat accumulation, as often believed.

Integration of the overall response to exercise.

Physical activity ellicits major perturbations in metabolism during the period of exertion and continues to influence metabolism afterwards as well. The overall effect of these intermittent and extended effects on the balance between energy expenditure and food intake regulation can best be judged by the impact of exercise on the fat mass. Expansion of the adipose tissue mass promotes fat oxidation more than glucose oxidation, but excessive fat accumulation is often necessary to reach the state where fat oxidation becomes commensurate with fat intake. Since the steady-state of weight maintenance is achieved with less body fat in physically active individuals, exercise is a substitute for an enlarged fat mass in bringing about rates of fat oxidation commensurate with fat intake. The increases in energy expenditure induced by expansion of the adipose tissue mass or by physical activity are quantitatively very different. The fact that they are substitutes for each other in relation to body weight maintenance indicates that the critical issue, under conditions where food availability is not a limiting factor, is not overall energy turnover. It appears therefore that it is the effect of exercise on the 24-h RQ that allows the organism to operate with an average RQ as low as the diet's FQ in the presence of less body fat. This also explains why the diet's carbohydrate-to-fat ratio can be an important parameter in shaping the interactions between physical activity and body weight maintenance.

Use and storage of carbohydrate and fat.

Starch, sugars, and triglycerides provide the bulk of dietary energy. To preserve homeostasis, most of the glucose and fat absorbed must be stored to be mobilized later at rates appropriate to bring about the oxidation of a fuel mix matching on average the macronutrient distribution in the diet. The body's glycogen stores are so small that regulatory mechanisms capable of efficiently adjusting carbohydrate oxidation to carbohydrate intake have developed through evolution. Fat oxidation is regulated primarily by events pertaining to the body's carbohydrate economy, rather than by fat intake. Adjustment of fat oxidation to intake occurs because cumulative errors in the fat balance lead over time to changes in adipose tissue mass, which can substantially alter free fatty acid concentration, insulin sensitivity, and fat oxidation. Fat intake and habitual glycogen concentrations are important in determining how fat one has to be to oxidize as much fat as one eats.

Body weight, fat storage, and alcohol metabolism.

Ethanol account for a significant fraction of the energy intake of persons consuming even moderate amounts of alcohol. A recent study has shown that although alcohol does not reveal itself as a layer floating at the top of a drink, metabolically it behaves more like oil than sugar.