Leptin and Body Weight Regulation

Energy homeostasis is the balance between energy intake (the kilocalories in fat, carbohydrate and protein from our diet) and energy expenditure (the kilocalories required for cellular maintenance and muscle contraction). There will be no weight gain or loss as long as energy intake matches energy expenditure.

The hormone leptin is an important component in the regulation of energy homeostasis. Leptin participates in a negative feedback loop that regulates the amount of energy stored in adipose tissue (adiposity), which is a major determinant of body weight. Leptin is secreted by adipocytes. Leptin secretion increases when the amount of adipose tissue increases, signaling that there is increased energy stored in the body.

Leptin is transported into the brain, primarily acting on neurons in the hypothalamus. Increased leptin causes decreased energy intake (feeding).  Leptin is not thought to be a satiety signal, which would be a factor that would cause a person to end a meal because he feels “full”. Instead, leptin is thought to act over a longer time course to enhance the response to satiety signals. Leptin also affects energy expenditure through various mechanisms. Increased leptin causes an increase in metabolic rate.

Leptin was discovered through studies of the obese mutant mouse. The obese mutation is caused by a deletion of the gene encoding leptin, so homozygous mutant mice completely lack leptin. These mutant mice eat constantly, are incredibly obese, and develop diabetes mellitus due to insulin resistance. They are also infertile, indicating that leptin is a signal that is required for activation of the reproductive axis. Injections of leptin very effectively cause weight loss and improved insulin sensitivity in obese mutant mice.

There was much excitement after the discovery of leptin because it was hoped that it might be an effective weight loss therapy. Unfortunately, human obesity is not caused by leptin deficiency. In fact, obese people have higher levels of circulating leptin, reflecting their higher amount of adipose tissue. In clinical trials, leptin was not able to cause weight loss except at very high doses. Obese individuals may have leptin resistance, in which there is decreased responsiveness to leptin.

Another way of understanding the disappointing results for leptin as a weight loss therapy is to consider that this negative feedback loop may be more important for preventing starvation rather than overfeeding. Scarcity of food was a significant factor during human evolution, whereas food overabundance is only a recent phenomenon.  Thus, our physiology may be more sensitive to decreases in leptin signaling.

The above figure shows this feedback loop in response to weight loss, as might occur in someone who is dieting. This shows why it is so difficult for dieters to keep weight off: decreased leptin secretion leads to increased hunger and decreased energy expenditure. Leptin might be effective therapeutically if it was administered after weight loss, where it could counteract the decrease in leptin secretion and prevent the changes that make it so hard to maintain weight loss.  At present, leptin is not an approved weight-loss therapy.

Leptin has been used to treat lipodystrophy, a rare disorder in which there is degeneration of adipose tissue and insulin resistance. Because there is decreased adipose tissue, lipodystrophy results in decreased leptin secretion. Leptin treatment improves insulin sensitivity in patients with lipodystrophy.  In 2014, the FDA approved metreleptin (a leptin agonist) for the treatment of generalized lipodystrophy.

Fill-in Answer Correct False Correct Answer
1. In what part of the brain would you find neurons that respond to leptin?
2. Which of the following occurs after weight gain:  increased or decreased leptin secretion?
3. Which of the following occurs as a consequence of decreased leptin signaling:  decreased feeding or decreased metabolic rate?
4. In human obesity, there is _______ leptin secretion. [increased or decreased]
5. Name a disorder for which leptin has been shown to be a useful treatment.

(Spelling must be correct)