Revisiting leptin's role in obesity and weight loss

Abstract

Maintenance of weight loss is often unsuccessful because of metabolic adaptations that conserve energy. Studies in rodents suggest that a reduction in leptin level during weight loss signals to the brain to increase feeding and decrease energy expenditure. In this issue of the JCI, Rosenbaum et al. examined this concept in obese patients who lost weight and were maintained at 10% below their initial weight (see the related article beginning on page 2583). Brain activity responses to visual food stimuli were visualized using functional MRI. Leptin levels fell during weight loss and increased brain activity in areas involved in emotional, cognitive, and sensory control of food intake. Restoration of leptin levels maintained weight loss and reversed the changes in brain activity. Thus, leptin is a critical factor linking reduced energy stores to eating behavior. Potentially, leptin therapy could sustain weight loss by overriding the tendency toward energy conservation.

Figure 1. Schematic illustration of peptides secreted by the gut and adipose tissue (fat) that control energy balance.

Ghrelin is produced in the stomach and is a potent stimulator of appetite in the brain. In addition to increasing the uptake of nutrients by muscle, liver, and fat, insulin acts in the brain to suppress food intake. Gut-derived peptides such as GLP-1 augment insulin release from the pancreas. Leptin levels decline during weight loss and signal to the hypothalamus to stimulate feeding, reduce energy expenditure, and promote weight regain. As Rosenbaum et al. demonstrate in this issue of the JCI (4), low leptin levels during weight loss also increase the activity of brain areas involved in the decision-making and reward aspects of eating behavior. Thus, preventing the decline of leptin levels during weight loss by hormone replacement may be a means of overriding the homeostatic and behavioral tendencies toward energy conservation and weight regain during dieting. Image modified with permission from Gastroenterology (23). CCK, cholecystokinin; GLP-1, glucagon-like peptide–1; GRP, gastrin-releasing peptide; NMB, neuromedin B; OXY, oxyntomodulin; PAI-1, plasminogen activator inhibitor 1; PP, pancreatic polypeptide; PYY, peptide YY; RBP4, retinol-binding protein–4.