Currently, nearly 10% of Americans have Type 2 Diabetes (T2D) and a further 34% have prediabetes - placing it among the most common chronic diseases in the United States. The capacity of the brain to elicit sustained remission of diabetic hyperglycemia in rodent models of T2D following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is now well established. Previously, we reported that prolonged (>24 hr) hypothalamic signaling by extracellular signal-related kinases 1 and 2, members of the mitogen-activated protein kinase (MAPK) family, is required for the sustained antidiabetic action of FGF1. Recent studies have now revealed that in addition to FGF1, FGF17 also stimulates the MAPK/ERK signaling pathway, which promotes oligodendrocyte proliferation and overall neurocircuit remodeling. Based on this observation, we hypothesize that FGF17 would have potent antidiabetic actions by activating hypothalamic MAPK/ERK signaling and remodeling hypothalamic neurocircuits. To test this hypothesis, cohorts of adult male C57BL/6J wild-type mice recieved a single icv injection of either FGF17 or saline vehicle. Analysis revealed that FGF17 induced sustained hypothalamic MAPK/ERK signaling, though the magnitude of this induction was less than that obtained with FGF1. We then injected FGF17 or a saline vehicle icv in a cohort of adult, male, diabetic ob/ob mice (diabetic and obese due to mutation in the leptin gene) and took daily measurements of blood glucose, food intake, and body weight. We found that FGF17 induced a transient reduction in food intake and body weight, but was able to normalize diabetic hyperglycemia for 30 days. This data shows that FGF17 is able to induce sustained activation of hypothalamic MAPK/ERK signaling and has antidiabetic actions. This is significant because sustained remission of hyperglycemia can reduce the risk of developing associated chronic diseases such as cardiovascular disease, diabetic nephropathy, and diabetic retinopathy.v Currently, I am performing immunohistochemical studies to identify the specific hypothalamic neurocircuits that FGF17 acts upon to produce these effects.

 Cystic fibrosis (CF) is a progressive, life-threatening disease, that results from the formation of thick mucus that builds up in the lungs, digestive tract, and other parts of the body. It leads to severe respiratory and digestive problems as well as other complications including opportunistic infections and diabetes. CF is caused by a mutation of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Recently, the initiation of highly effective CFTR modulators including Trikafta (a combination of the medications elexacaftor, tezacaftor, and ivacaftor) has significantly improved the quality of life and life expectancy of patients with CF. However, recent clinical studies have shown that CF patients taking Trikafta have an increased risk of developing obesity and diabetes, though the underlying mechanisms remain unknown. In addition to being expressed in peripheral tissues, the Cftr gene is also expressed in the brain in the arcuate nucleus (ARC), a key brain area involved in metabolic regulation. To begin testing the hypothesis that Trikafta predisposes to metabolic syndrome by altering the activity of signaling of neurocircuits that regulate metabolism in the ARC, I investigated the ability of Trikafta to activate neurons in the ARC of mice (based on histochemical detection of c-Fos, a marker of neuronal activation). Following a single intracerebroventricular injection of Trikafra, compared to vehicle-treated mice, I found that mice treated with Trikafta had significantly increased activation of neurons in the ARC. I am now conducting studies to identify the phenotype of the neurons in the ARC that are activated by Trikafta and predict that successful completion of these studies will advance our understanding of the pathogenesis of obesity and metabolic impairment induced by Trikafta and inform the development of strategies that can avert these deleterious side effects.