Despite importance of counter-regulatory mechanisms to combat starvation and hypoglycemia, a significant component of this adaptive network, adipose tissue, remains understudied. It is functionally and evolutionarily conceivable that signals must exist to integrate this major source of energy during fasting to rest of the counter- regulatory network. The major adipocyte fatty acid binding protein (FABP) member FABP4, is secreted from adipocytes circulating levels rise in fasting and in the context of obesity, and the hormone acts on the liver to promote hepatic glucose production. In this way, the high levels of circulating FABP4 that occur in obese animals appear to have an effect reminiscent of the hyperglucagonemia that characterizes the diabetic state. The objective of this proposal is to understand the contribution of circulating FABP4 in mediating aberrant hepatic gluconeogenesis in the diabetic condition. Our overarching hypothesis is that FABP4 potentiates the action of glucagon signaling and is a critical component of counter-regulatory machinery and mediator of the development of obesity-related diabetes. The studies described in the current proposal will test this hypothesis by determining whether FABP4 is required to mediate the effect of hyperglucagonemia in diabetes, by characterizing a potential FABP4-glucagon-glucagon receptor (GCGR) physical interaction, and by defining the mechanism by which the FABP4 signal is propagated in hepatocytes. These experiments will make use of genetic mouse models and biochemical and cell-based assays to dissect the function of circulating FABP4 and its interaction with the glucagon signaling pathway. This contribution is significant because it will illuminate the molecular signaling pathways that underlie the well-established connection between obesity and diabetes, and may lead to the development of novel therapeutic strategies. The innovation of this work lies in pinpointing a novel mechanism of endocrine regulation - the interaction between an adipokine and a glucoregulatory hormone that links the adipose tissue to counter-regulatory mechanisms- and carries important implications for metabolic disease pathogenesis.
The work proposed in these aims will determine the role for hormonal FABP4 in the development of insulin resistance and diabetes, illuminating the molecular signaling pathways that underlie the well-established connection between obesity and metabolic disease. Understanding the mechanism of FABP4 action and its interaction with other endocrine systems will provide unique insight into targetable pathways for therapy development. In the face of an epidemic of obesity, the development of novel therapeutic approaches to obesity-related diseases is highly relevant to public health and to the NIH mission.