Chris J. Hukshorn

Leptin and energy expenditure.

Purpose of reviewA fundamental advance in our understanding of endocrine control of energy balance and body weight came with the discovery of the adipocyte-derived hormone leptin. The leptin pathway appeared to be the long-sought peripheral signal pathway from the adipose tissue to the brain involved in the regulation of feeding and energy balance. Recent findingsInitially, leptin was considered to function as the long-sought antiobesity hormone. According to this hypothesis, rising concentrations of leptin with increasing adiposity would generate a signal to reduce food intake and increase energy expenditure in order to limit further weight gain. However, widespread resistance to the proposed antiobesity action of leptin is observed in humans, which might reflect the fact that the inability to store energy efficiently at times of abundance is evolutionarily disadvantageous. According to this alternative view, falling leptin concentrations observed during fasting act as a peripheral signal of starvation, which serves to conserve energy in the face of limited reserves. However, leptin administration failed to blunt the changes in energy expenditure during severe energy restrictions in several clinical studies. In addition, leptin therapy in several different human low-leptin states failed to affect energy expenditure in recent studies. SummaryIncreasing evidence from human studies suggests that leptin predominantly influences the human energy balance through appetite but appears not to be involved in regulating energy expenditure. None of the expected factors such as resting metabolic rate, total diurnal energy expenditure or dietary induced thermogenesis was related to blood leptin concentrations.

Effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB) treatment of overweight men

OBJECTIVE: To examine the effect of dietary restraint during and following pegylated recombinant leptin (PEG-OB protein) treatment in overweight men.DESIGN: A randomized double-blind placebo-controlled trial in 24 overweight men (BMI: 28.8±0.3 kg/m2; age: 34.8±0.9 y). PEG-OB protein (80 mg) or placebo was administered subcutaneously weekly for 6 weeks, combined with a 2.1 MJ/day energy restriction program. Dietary restraint was determined by the Three-Factor Eating Questionnaire before and after treatment, and after 8 weeks follow-up.RESULTS: During treatment dietary restraint increased, and general hunger, resting energy expenditure and respiratory quotient decreased similarly in the PEG-OB and the placebo group. With PEG-OB treatment, additional weight loss (P<0.03) was observed. During 8 weeks follow-up, body weight increase was larger in the PEG-OB group compared to placebo (P<0.05), and body weight regain was faster. Body weight regain was inversely correlated with the increase in cognitive dietary restraint during treatment (PEG-OB group: r2=0.49, P<0.02; placebo group: r2=0.60, P=0.01).CONCLUSION: Although treatment with PEG-OB protein led to a greater body weight loss relative to placebo, weight maintenance thereafter was mainly supported by dietary restraint, which was more effective in the placebo-treated group, resulting in a slower regain of body weight.

Effects of very low calorie diet induced body weight loss with or without human pegylated recombinant leptin treatment on changes in ghrelin and adiponectin concentrations.

The aim of the study was to investigate the effects of energy restriction with or without pegylated recombinant leptin (PEG-leptin) treatment on ghrelin, adiponectin, insulin and glucose concentrations. A randomized double-blind placebo-controlled trial was performed in 24 moderately overweight/obese men. PEG-leptin or placebo was administered weekly for 6 weeks, combined with a restricted energy intake of 2.1 MJ/d. At days 1, 25, and 46 a blood sample was taken and body-weight (BW) was measured. Days 1-25 was named phase 1, and days 25-46 phase 2. During phase 1 the rate of BW loss was significantly higher in the PEG-leptin compared to the placebo group (0.38+/-0.07 vs 0.32+/-0.06 kg/d, p<0.05). The rate of BW loss during phase 2 was 0.24+/-0.08 and 0.18+/-0.09 kg/d, respectively (p=0.07). In both groups the rate of BW loss during phase 1 was significantly higher than during phase 2 (p<0.001). Energy balance (EB) was significantly more negative during phase 1 than during phase 2 in both groups (p<0.0005). During phase 1 insulin, glucose and adiponectin decreased significantly in both groups. Adiponectin and ghrelin concentrations changed in the opposite direction between phase 1 and phase 2 (p<0.05). Initial BW loss due to a considerable negative EB induced decreased ghrelin, adiponectin, insulin and glucose levels. However, when EB became less negative and the rate of BW loss decreased, these changes were reversed for adiponectin and ghrelin. The PEG-leptin injections did not have an effect on the changes in insulin, glucose and adiponectin, but had an effect on the changes in ghrelin concentrations.