Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

Maintenance of reduced or elevated body weight results in respective decreases or increases in energy expended in physical activity, defined as 24-h energy expenditure excluding resting energy expenditure and the thermic effect of feeding, beyond those attributable to weight change. We examined skeletal muscle work efficiency by graded cycle ergometry and, in some subjects, rates of gastrocnemius muscle ATP flux during exercise by magnetic resonance spectroscopy (MRS), in 30 subjects (15 males, 15 females) at initial weight and 10% below initial weight and in 8 subjects (7 males, 1 female) at initial weight and 10% above initial weight to determine whether changes in skeletal muscle work efficiency at altered body weight were correlated with changes in the energy expended in physical activity. At reduced weight, muscle work efficiency was increased in both cycle ergometry [mean (SD) change = +26.5 (26.7)%, P < 0.001] and MRS [ATP flux change = -15.2 (23.2)%, P = 0.044] studies. Weight gain resulted in decreased muscle work efficiency by ergometry [mean (SD) change = -17.8 (20.5)%, P = 0.043]. Changes in muscle efficiency at altered body weight accounted for 35% of the change in daily energy expended in physical activity.

BACKGROUNDWeight gain and loss increases and decreases energy expenditure, respectively, out of proportion to changes in metabolic mass.OBJECTIVEWe hypothesized that changes in energy expenditure associated with weight gain or loss were due in part to changes in catecholamine release, thyroid hormones, carbohydrate utilization, or a combination thereof.METHODSUrinary catecholamine excretion, serum thyroid hormone concentrations, and results of 3-h oral-glucose-tolerance tests were examined in obese and never-obese subjects at their usual weights, during weight loss or gain, and at stable weights 10-20% below or 10% above usual.RESULTSUrinary norepinephrine excretion decreased significantly during and after weight loss and increased during and after weight gain. Serum concentrations of reverse triiodothyronine increased significantly during and after weight loss, whereas serum concentrations of triiodothyronine increased significantly (by approximately 0%) during and after weight gain. Serum insulin and glucose concentrations during the oral-glucose-tolerance test increased significantly after weight gain in obese subjects. The percentage change in urinary norepinephrine excretion and in serum concentrations of triiodothyronine were significantly correlated with percentage changes in energy expenditure and with each other.CONCLUSIONSChanges in body weight were associated with changes in catecholamine excretion and thyroid hormones, which might-by virtue of the effects on energy expenditure-have favored a return to usual body weight. Weight gain induced more apparent insulin resistance in the obese than the never-obese subjects, suggesting a threshold effect of total body fat on this phenomenon.

By virtue of its potential effects on rates of energy expenditure, uncoupling protein 3 (UCP3) is an obesity candidate gene. We identified nine sequence variants in UCP3, including Val9Met, Val102Ile, Arg282Cys, and a splice site mutation in the intron between exons 6 and 7. The splice mutation results in an inability to synthesize mRNA for the long isoform (UCP3L) of UCP3. Linkage (sib pair), association, and transmission disequilibrium testing studies on 942 African-Americans did not suggest a significant effect of UCP3 on body composition in this group. In vastus lateralis skeletal muscle of individuals homozygous for the splice mutation, no UCP3L mRNA was detectable; the short isoform (UCP3S) was present in an increased amount. In this muscle, we detected no alterations of in vitro mitochondrial coupling activity, mitochondrial respiratory enzyme activity, or systemic oxygen consumption or respiratory quotient at rest or during exercise. These genetic and physiologic data suggest the following possibilities: UCP3S has uncoupling capabilities equivalent to UCP3L; other UCPs may compensate for a deficiency of bioactive UCP3L; UCP3L does not function primarily as a mitochondrial uncoupling protein.

Circulating concentrations of leptin are closely correlated with body fat mass, and may thus constitute an afferent limb of a system regulating body fatness, with efferent limbs that affect energy expenditure and food intake. We studied 50 subjects (27 males, 23 premenopausal females; 31 never-obese, 19 obese) at usual body weight during active weight loss or weight gain and during the maintenance of body weights 10% above usual (WT + 10%) and 10% and/or 20% below usual body weight (Wt -10% and Wt -20%) to test the hypotheses that the dynamic process of weight change and the maintenance of an altered body weight are associated with significant changes in circulating concentrations of leptin and/or the relationship between fat mass and leptin, and such changes in the plasma concentration of leptin are related to changes in energy expenditure at altered body weight. Subjects were admitted to the Rockefeller University Hospital, and energy metabolism (24-h energy expenditure, resting energy expenditure, thermic effect of feeding, and nonresting energy expenditure) and circulating concentrations of leptin and insulin were examined at various weight plateaus (usual body weight, 10% above usual body weight, 10% below usual body weight, and 20% below usual body weight). Plasma leptin was also measured in some subjects during dynamic periods of weight gain or loss. Though both plasma leptin concentrations and fat mass were significantly correlated with resting energy expenditure, only the correlation of fat mass and energy expenditure remained significant in a multiple stepwise linear regression analysis. Neither absolute nor relative changes in plasma leptin between weight plateaus were significantly correlated with any of the observed changes in energy expenditure. Plasma leptin concentrations were significantly lower during weight loss than during weight maintenance at the same body composition. Plasma leptin concentrations, normalized to fat mass, were significantly lower during the maintenance of a reduced body weight in females and higher during the maintenance of an elevated body weight in males than in the same subjects at usual body weight. At all weight plateaus, plasma leptin concentrations normalized to fat mass were significantly higher in females than in males, but gender was not a significant covariate of the relationship between leptin and energy expenditure. Postabsorptive serum concentrations of insulin was a significant covariate of plasma leptin concentration in males, but not females, at Wt initial and Wt + 10%. Although plasma leptin is significantly reduced during dynamic weight loss compared with static weight maintenance at the same body weight, the lack of correlation between changes in plasma leptin and changes in energy expenditure between weight plateaus suggests that leptin is not the primary signal that mediates the changes of energy expenditure that accompany the maintenance of an altered body weight in humans.