The alarming epidemic of obesity and type 2 diabetes mellitus (T2DM) in the US and worldwide represents one of the most costly and pressing healthcare burdens confronting modern society today, heightening the need for new strategies for improving glycemic control and prevention of associated co-morbidities including cardiovascular disease, neuropathy, nephropathy and retinopathy. However, much about the pathogenesis of these disorders remains unknown, hampering this effort. Since insulin-independent glucose disposal, referred to as glucose effectiveness (GE) is also markedly impaired in obesity and T2DM, and since it contributes as much to glucose homeostasis as insulin itself, strategies based on increasing GE have important therapeutic potential. Recent work from the applicant's laboratory indicates that the anti-diabetic effect of the intestinal hormone Fibroblast growth factor-19 (FGF19) involves an action in the brain to potently, rapidly, and selectively increase GE which has important translational implications for T2DM therapy. Moreover, the glucose lowering effect of systemic FGF19 appears to involve an action in the brain. An overarching goal of this proposal is to delineate the physiological relevance and neuronal mechanisms that govern how the brain increases GE in response to increased FGF19 signaling. Based on available literature and our preliminary data, we hypothesize that hypothalamic neuronal FGFR1 and its co-receptor -Klotho are required for this effect. We therefore propose to determine if -Klotho-FGFR1 signaling in hypothalamic neurons is required for 1) normal glucose homeostasis and 2) the effect of FGF19 to increase GE. This will be accomplished by using a viral strategy and mouse genetics to create mice with hypothalamic neuron-specific deletion of either FGFR1 or -Klotho expression in combination with complementary stereotaxic surgical and pharmacological approaches, sophisticated FSIGT/Minimal Modeling, and clamp techniques. Together, these studies are expected to establish a physiological role for the brain in the maintenance of normal GE and glucose tolerance via a mechanism involving FGF19 signaling. This information will inform of the development of novel drugs that increase GE which may one day offer an effective complement to insulin-based therapies.
Insulin-independent glucose disposal, referred to as glucose effectiveness (GE) is crucial for glucose homeostasis and is impaired in obesity and type 2 diabetes mellitus. Thus, strategies based on increasing GE have important therapeutic potential. The gut-derived hormone Fibroblast growth factor-19 (FGF19) exerts potent anti-diabetic effects in obese rodent models and recent work from the applicant's laboratory indicates that this effect involves an action in the brain. The goal of this proposal is to delineae the physiological relevance and neuronal mechanisms that govern how the brain increases GE in response to increased FGF19 signaling with the ultimate goal of translating these discoveries into new strategies for diabetes treatment.
|Scarlett, Jarrad M; Rojas, Jennifer M; Matsen, Miles E et al. (2016) Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents. Nat Med 22:800-6|