Leptin Therapy Alters Appetite and Neural Responses to Food Stimuli in Brain Areas of Leptin-Sensitive Subjects Without Altering Brain Structure

Context: Leptin is a key regulator of energy intake and expenditure. Individuals with congenital leptin deficiency demonstrate structural and functional brain changes when given leptin. However, whether acquired leptin deficiency may operate similarly is unclear. Objective: We set out to determine whether the brains of individuals with acquired leptin deficiency may react to leptin in a similar manner. Design: We used functional magnetic resonance imaging before and after short-and long-term metreleptin treatment in three leptin-sensitive patients with acquired hypoleptinemia. Nine healthy women were scanned as normoleptinemic controls. Setting: The setting was an academic medical center. Patients or Other Participants: The participants were 3 hypoleptinemic women and nine normoleptinemic, matched women. Interventions: We used metreleptin, recombinant leptin, therapy for 24 weeks in hypoleptinemic women only. Main Outcome Measure: We measured neural changes in response to viewing food as compared to nonfood images. We hypothesized that metreleptin treatment would increase brain activity in areas related to cognitive control and inhibition and would decrease brain activity in areas related to reward processing, as compared to the normoleptinemic counterparts. Results: Unlike patients with congenital leptin deficiency, hypoleptinemic patients demonstrated no structural brain differences from healthy controls and/or structural changes in response to treatment. Short-term metreleptin treatment in leptin-sensitive hypoleptinemic subjects enhances areas involved in detecting the salience and rewarding value of food during fasting, whereas long-term treatment decreases attention to food and the rewarding value of food after feeding. Furthermore, hypothalamic activity is modulated by metreleptin treatment, and leptin decreases functional connectivity of the hypothalamus to key feeding-related areas in these hypoleptinemic subjects. Conclusions: Leptin replacement in acutely hypoleptinemic women did not alter brain structure but did alter functional cortical activity to food cues in key feeding and reward-related areas.