The epidemics of obesity and diabetes represent a public health emergency. We must understand the mechanisms that link energy balance and glucose homeostasis, as these may represent potential therapeutic targets. In this proposal, entitled, "A leptin-regulated neural pathway that modulates the counter-regulatory response," we will analyze novel leptin receptor (LepRb)-expressing neural pathways in the brainstem lateral parabrachial (lPBN) and periaqueductal grey (PAG) nuclei. Together, these regions contain the majority of brainstem LepRb neurons;each contains numbers of LepRb neurons similar to those found in major hypothalamic nuclei. The projections from lPBN and PAG LepRb cells (along with their activation by physiologic stressors such as hypoglycemia and discomfort) suggest the importance of these neurons in modulating the counter-regulatory response. Indeed, ablation of LepRb in a subpopulation of lPBN and PAG LepRb neurons enhances the counter-regulatory response to glucoprivic and noxious stimuli, suggesting that leptin acts on these brainstem LepRb cells to restrain the counter-regulatory response. In this application, we will employ a variety of cre-dependent viral and genetic systems to understand the function, importance, and mechanisms of action of these brainstem LepRb neurons. These studies reveal the mechanisms by which leptin acts in the brainstem to contribute to overall leptin action and aspects of neural function that are crucial for glucose homeostasis. This information will in turn lay the groundwork for understanding mechanisms that modulate glycemic control, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the twin epidemics of obesity and diabetes.
The ongoing twin epidemics of obesity and diabetes in the United States represent a public health emergency that remains unchecked and without adequate therapy. To design specific treatments to prevent and treat these disorders, we must first understand the mechanisms that regulate energy balance and glucose homeostasis. In this proposal, we will determine the function and mechanisms of action for novel leptin- regulated neural pathways that contribute to the counter-regulatory response and glycemic control, and which represent potential therapeutic targets.
|Rosario, Wilfredo; Singh, Inderroop; Wautlet, Arnaud et al. (2016) The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions. Diabetes 65:2711-23|
|Flak, Jonathan N; Myers Jr, Martin G (2016) Minireview: CNS Mechanisms of Leptin Action. Mol Endocrinol 30:3-12|
|Meek, Thomas H; Nelson, Jarrell T; Matsen, Miles E et al. (2016) Functional identification of a neurocircuit regulating blood glucose. Proc Natl Acad Sci U S A 113:E2073-82|
|Flak, Jonathan N; Patterson, Christa M; Garfield, Alastair S et al. (2014) Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat Neurosci 17:1744-50|
|Allison, Margaret B; Myers Jr, Martin G (2014) 20 years of leptin: connecting leptin signaling to biological function. J Endocrinol 223:T25-35|
|Garfield, Alastair S; Shah, Bhavik P; Madara, Joseph C et al. (2014) A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab 20:1030-7|