A novel adipokine suppresses leptin signaling and promotes obesity

我们的长期目标是了解能量稳态的信号转导途径，以及它们的改变如何导致肥胖和代谢疾病。瘦素信号通路被认为是控制食物摄入和体重的最关键的促瘦素途径。此外，该途径已被证明可改善葡萄糖稳态，而与其对体重和食物摄入的影响无关。然而，肥胖患者和通常肥胖的2型糖尿病患者对外源性瘦素治疗反应差，因此被认为是瘦素抵抗的。因此，阐明瘦素抵抗的潜在机制具有重要的医学意义。到目前为止，外周组织是否产生内分泌因子来减弱瘦素信号传导仍有待探索。我们发现了一个以前未表征的，脂肪组织选择性表达的8 kD脂肪因子，我们称之为Batotin。我们发现这种脂肪因子与瘦素受体结合并抑制瘦素信号传导。值得注意的是，在脂肪组织中表达巴托汀的转基因小鼠是暴食和病态肥胖的，并且具有与肥胖无关的升高的血糖水平。这些结果导致从外周组织分泌的Batotin以内分泌方式作为食欲肽以抑制瘦素信号传导的模型。在目标1中，我们将详细研究Batotin如何抑制瘦素信号传导。目的二：利用功能获得性小鼠模型研究巴托汀的作用机制。在目标3中，我们将研究功能丧失小鼠模型。

Our long-range goal is to understand signal transduction pathways underlying energy homeostasis and how their alterations contribute to obesity and metabolic diseases. The leptin signaling pathway is considered to be the most critical anorexigenic pathway in the control of food intake and body weight. Moreover, this pathway has been demonstrated to improve glucose homeostasis independently of its effects on body weight and food intake. However, obese patients, and type 2 diabetic patients who are commonly obese, response poorly to exogenous leptin treatment, and are thus considered to be leptin resistant. Therefore, elucidating the underlying mechanisms of leptin resistance is of great medical importance. To date, whether peripheral tissues produce endocrine factors to attenuate leptin signaling remains to be explored. We identified a previously uncharacterized, adipose tissue-selectively expressed 8 kD adipokine we called Batotin. We found that this adipokine binds to leptin receptor and suppresses leptin signaling. Remarkably, transgenic mice expressing Batotin in adipose tissue are hyperphagia and morbidly obese, and have elevated blood glucose level independent of obesity. These results lead to a model that secreted Batotin from peripheral tissue acts as an orexigenic peptide in an endocrine manner to suppress leptin signaling. In Aim 1, we will investigate in detail how Batotin suppresses leptin signaling. In Aim 2, we will use gain-of-function mouse models to investigate the function and mechanism of Batotin. In Aim 3, we will study loss-of-function mouse models.