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.
The leptin signaling pathway is considered to be the most critical pathway in the control of food intake and body weight. Defects in this pathway lead to obesity and type 2 diabetes. However, obese patients, as well as type 2 diabetic patients who are commonly obese, response poorly to exogenous leptin treatment, and are thus considered to be leptin resistant. Our studies address the underlying mechanism of leptin resistance, which will clearly be very useful for the development of new therapies.