Leptin deficiency leads to weight gain, obesity, and insulin resistance. Leptin replacement in the form of metreleptin has been approved by the FDA for congenital or acquired generalized lipodystrophy. The current analysis reveals that metreleptin also improves central insulin sensitivity primarily via hypothalamus and to a lesser extent prefrontal cortex.
Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism.
In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution.
After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group.
In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity.
Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.