Leptin Regulates Energy Balance and Motivation Through Action at Distinct Neural Circuits

• Published in: Biological psychiatry (1969) Vol. 69; no. 7; pp. 668 - 674
• Main Authors: Davis, Jon F, Choi, Derrick L, Schurdak, Jennifer D, Fitzgerald, Maureen F, Clegg, Deborah J, Lipton, Jack W, Figlewicz, Dianne P, Benoit, Stephen C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2011
• Subjects: Animals; Body Weight - drug effects; Brain - anatomy & histology; Brain - drug effects; Brain - metabolism; Conditioning, Operant - drug effects; Dietary Fats - administration & dosage; Dopamine - metabolism; Energy Metabolism - drug effects; Energy Metabolism - physiology; Green Fluorescent Proteins - drug effects; Green Fluorescent Proteins - genetics; Lateral hypothalamus; leptin; Leptin - pharmacology; Male; mesolimbic dopamine; midbrain; Motivation - drug effects; Neural Pathways - physiology; operant responding; Psychiatry; Rats; Rats, Long-Evans; Receptors, Leptin - genetics; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; STAT3 Transcription Factor - metabolism; mesolimbic dopamine; Lateral hypothalamus; midbrain; leptin; operant responding
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2010.08.028

Background Overconsumption of calorically dense foods contributes substantially to the current obesity epidemic. The adiposity hormone leptin has been identified as a potential modulator of reward-induced feeding. The current study asked whether leptin signaling within the lateral hypothalamus (LH) and midbrain is involved in effort-based responding for food rewards and/or the modulation of mesolimbic dopamine. Methods The contribution of endogenous leptin signaling for food motivation and mesolimbic dopamine tone was examined after viral-mediated reduction of the leptin receptor within LH and midbrain neurons in male rats. Results Knockdown of leptin receptors selectively in the LH caused increased body weight, caloric consumption, and body fat in rats maintained on a calorically dense diet. Knockdown of leptin receptors selectively in midbrain augmented progressive ratio responding for sucrose and restored high-fat, diet-induced suppression of dopamine content in the nucleus accumbens. Conclusions In summary, endogenous leptin signaling in the hypothalamus restrains the overconsumption of calorically dense foods and the consequent increase in body mass, whereas leptin action in the midbrain regulates effort-based responding for food rewards and mesolimbic dopamine tone. These data highlight the ability of leptin to regulate overconsumption of palatable foods and food motivation through pathways that mediate energy homeostasis and reward, respectively.