Obesity is the foremost yet preventable biomedical problem of the 21st century.Understanding brain mechanisms governing the way we eat,gain and lose weight is essential for developing new strategies to treat and prevent obesity and co-morbid illnesses.Using a preclinical rodent model of diet-induced obesity,we demonstrated that the "thin hormone" leptin acts importantly in two brain regions in the midbrain reward circuitry,the ventral tegrental area (VTA) and SubstantiaNigra (SN) to regulate high-fat diet consumption,food choice and dietary weight gain.We collected evidence for differential leptin sensitivity in the VTA in obesity-prone versus obesity-resistant animals that may in part underscore a dichotomy in obesity susceptibility.In particular,leptin sensitivity in the VTA appears to be inherently compromised and further compounded by-HF feeding in the obesity-prone rats.This impairment precedes obesity and is associated with the inability of the animals to curb-HF consumption and consequential weight gain.In contrast,the obesity-resistant rats retain the VTA leptin sensitivity throughout the HF feeding period.Our findings imply that leptin function in the VTA is an important modulator of-HF feeding and susceptibility to dietary obesity.This research involves novel experimental paradigms and provides important mechanistic insights into ingestive behavior and obesity control.