The battle of the bulge: defense versus offense

Obesity is caused by ingesting more calories than expended over a long period of time. The initial positive energy balance expands body mass and endogenous fat stores, which must then be maintained by continued adequate energy intake. Calorie restriction induces a negative energy balance, which results in consumption of endogenous fat stores as fuel to supplement the inadequate energy intake and to meet the metabolic demands of the body. The decrease in body mass (both fat mass and fat-free mass) results in a decrease in daily energy expenditure. At some point, the reduced-energy diet will match the amount of energy expended, which will lead to a cessation of weight loss and a plateau in body weight at a new lower level. Although many obese people are able to lose weight, successful long-term weight loss maintenance is much more difficult to achieve with lifestyle interventions (diet, physical activity, and behavioral therapy) (1), and most patients who have had bariatric surgery also experience some recidivism over time, even when they maintain a substantial weight loss (2). Why is weight loss so hard to maintain? A prominent theory is that a complex neuroendocrine system regulates food intake and energy expenditure to defend a certain individualized set point in body weight (3, 4). When weight loss occurs, these regulatory signals spring into action to move body weight back to its original predetermined value. In this issue of the Journal, Ferrannini et al (5) expand the details of this theory by examining longitudinal data from 1) normal-weight, overweight, and obese participants in the Relation between Insulin Sensitivity and Cardiovascular Disease (RISC) Study (n 1⁄4 223), who lost weight spontaneously (presumably from intentional reductions in energy intake) during the 3-y study period, and 2) extremely obese patients before and 1 y after Roux-en-Y gastric bypass surgery (n 1⁄4 71) or biliopancreatic diversion (n 1⁄4 111). Their results show that despite a nearly 10-fold difference in the amounts of weight loss between groups (5 6 3 kg or w7% of initial body weight in the diet group and 46 6 17 kg or w35% of initial body weight in the surgery group), there was a very strong association between initial BMI and final BMI in the diet group (r 1⁄4 0.96) and a weaker, albeit still impressive, association between initial BMI and final BMI in the surgery group (r 1⁄4 0.67). Furthermore, in a subgroup of 110 bariatric surgery patients, serum leptin concentrations were measured and were found to correlate with BMI both before and after weight loss, but the slope of the regression line was significantly flatter after weight loss than before weight loss, so that the same BMI was associated with much lower serum leptin after weight loss than at baseline. However, lower leptin concentrations were not evident across the whole BMI range after weight loss but were limited to BMI values (in kg/m) above w40 (ie, for people who remained morbidly obese even after surgically induced weight loss). The authors suggest that, despite the differences in magnitude of weight loss and the mechanisms responsible for weight loss among diet and different surgical therapies, the reduced body weight is still governed by a predetermined set point, and they propose a ‘‘threshold shift paradigm’’ for the relation between adiposity signals (particularly leptin) and body weight control. This model posits that the decline in body fatness that occurs with weight loss results in a reduction in neuroendocrine signals that inhibit food intake and increase energy expenditure. When the intensity of these signals falls below a threshold, a sharp and concerted anabolic response is triggered to increase energy intake and to reduce energy expenditure, and thereby halt the loss of body weight and favor weight regain toward baseline. This defensive response is maximal once the threshold is reached, so that greater weight loss does not produce proportionate increases in the anabolic response (4). The authors further propose that chronic increases in adiposity cause a progressive upward shift in the body fat threshold that is defended. The data from the study by Ferrannini et al (5) are consistent with those observed in previous diet and surgery weight-loss studies, which also found that greater initial body weight and BMI predict greater absolute (kg) and relative (% of initial body weight) weight loss and greater final body weight and BMI (6–9). However, a simpler mechanism than the ‘‘threshold theory’’ could explain this relation. In general, daily energy expenditure is directly correlated with BMI, and ‘‘large’’ people require greater energy intake to maintain body mass than do ‘‘small’’ people. Accordingly, the negative energy balance induced by a specific reduced energy intake is greater for large than for small people. It is possible that the range of actual (not prescribed) energy intake (or absorption) of obese people prescribed a hypocaloric diet or who have had bariatric surgery is limited, so that the relatively larger persons will invariably be at a greater negative energy balance and will therefore lose more weight than the relatively smaller