Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.

中文翻译：

---

下丘脑外侧GLP-1受体对于控制食物强化，摄食行为和体重至关重要。

奖励高奖励食物的动机增加是肥胖的主要因素。大多数文献集中在中脑边缘核作为奖励行为调节的核心。但是，下丘脑外侧（LH）也是大脑中关键的奖励控制位点。在这里，我们假设在LH中选择性操纵胰高血糖素样肽1受体（GLP-1R）活性可以深刻影响食物奖励行为，最终导致肥胖。在LH中激活GLP-1R并对其进行药理或遗传GLP-1R阻滞后，在雄性和雌性大鼠中检查了对蔗糖的递进比例操作员反应。还评估了LH GLP-1R激活的摄食行为和代谢参数以及分子和传出靶标。LH GLP-1R的激活降低了饮食动机。反过来，LH GLP-1R的急性药理阻断作用增加了食物动力，但仅在雄性大鼠中。GLP-1R的活化还引起食物摄入量和体重的显着降低。实质内腺相关病毒短发夹RNA构建体的实质内递送诱导的LH GLP-1R的长期敲低足以显着并持续提高摄食行为和体重，并最终导致男性和女性的脂肪量增加一倍。有趣的是，仅在男性中再次发现增强的食物强化作用。我们的数据表明LH GLP-1R是正常食物强化，食物摄入和体重调节必不可少的元素。这些发现还表明，对于我们来说，这是第一次，大脑GLP-1R的操纵可以导致健壮而长期的体重增加。