Deletion of Lipoprotein Receptor LRP1 in GABAergic Neurons Promotes Obesity and Insulin Resistance

초록

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. Recent studies have implicated hypothalamic LRP1 in the regulation of feeding and leptin signaling, yet the underlying neurocircuitry involved in LRP1 action is unclear. Because GABAergic neurons are a major mediator of leptin’s anorexigenic action, we addressed the question of whether deleting LRP1 from GABAergic neurons can affect adiposity and energy balance. Here we show that LPR1 deficiency in GABAergic neurons results in increased body weight in mice fed a normal chow diet both in males and females (Male, control 30.7±2.2g vs. GABA-LRP1 deficient mice 45.1±3g; Female, control 27.9±0.8g vs. GABA-LRP1 deficient mice 41.1±3.6g, p<0.01, respectively). This is most likely due to increased daily food intake in GABA-LRP1 deficient mice (control mice 4.6g±0.2g vs. GABA-LRP1 deficient mice 5.7±0.3g, p<0.05). Concurrently, MRI analysis indicated that fat mass in GABA-LRP1 deficient mice was significantly increased by ~120% without changes in lean mass, compared with control mice. Adiposity in GABA-LRP1 deficient mice is accompanied by increased blood glucose and insulin levels. In addition, GABA-LRP1 deficient mice exhibited insulin resistance, as evidenced by the fact that blood glucose levels blunted to decreased after insulin injection (0.5U/kg body weight), whereas in control mice, glucose decreased about 40%. Furthermore, LPR1 deficiency in GABAergic neurons leads to glucose intolerance. In conclusion, our data demonstrate that hypothalamic LRP1 regulates systemic energy balance through GABAergic neurons, by modulating food intake and insulin sensitivity. These effects could be due to LRP1 action on GABAergic leptin signaling and neuronal activity.