Several lines of evidence support the hypothesis that feeding and body adiposity are regulated by circulating factors which reflect the size of adipose stores. One such candidate is the pancreatic hormone insulin which may regulate body adiposity and body weight in the CNS via several mechanisms, including food intake, thermogenesis, and metabolic rate (1- 5). Insulin may enter the CNS via receptor-mediated transcytosis across brain capillary endothelial cells (6), and interact there with several different CNS neurotransmitter systems. Proposed studies focus upon the mechanism(s) underlying my observation that insulin enhances endogenous noradrenergic activity within the CNS (7). CNS noradrenergic pathways play a critical role in the regulation of feeding (8) and thermogenesis (9). I now have evidence for a specific mechanism underlying this action of insulin: insulin downregulates the function, number, and steady state mRNA levels of the norepinephrine re-uptake transporter (NET). Inhibition of re-uptake should cause increased synaptic norepinephrine (NE) concentrations. Studies in this renewal proposal address the hypotheses that a) Insulin is a physiological regulator of CNS noradrenergic activity via its regulation of the NE transporter, and b) This action of insulin may contribute to its CNS function as a regulator of energy balance and body weight. The efficacy of insulin to regulate CNS noradrenergic activity may be impaired in models of genetic (Zucker fa/fa rats) and dietary obesity. This may contribute to the impaired behavioral efficacy of insulin in these models. NE transporter membrane concentrations will be assessed by 3H-desipramine binding to brain membranes from insulin- or vehicle-treated rats. NE transporter mRNA will be assessed by in situ hybridization. CNS uptake of 3H-NE will be measured after insulin treatment in vitro or in vivo. Postsynaptic consequences of insulin effects on NE neurons will be assessed by measuring CNS adrenergic receptors and major receptor-coupled cell signals after in vivo insulin treatment. Normal weight Wistar rats, dietary-obese Wistar rats, and genetically obese Zucker rats will serve as models. Together these studies should allow me to determine the in vitro and in vivo capacity of insulin to regulate the synaptic function of NE neurons, and to evaluate changes of their basal and insulin-regulated function with the pathophysiology of obesity and its associated CNS insulin resistance.
| Figlewicz, Dianne P; Jay, Jennifer; West, Constance H et al. (2018) Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat. Am J Physiol Regul Integr Comp Physiol 314:R191-R200 |
| Figlewicz, Dianne P (2016) Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat: Historical perspective. Brain Res 1645:68-70 |
| Figlewicz, Dianne P (2015) Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective. Psychosom Med 77:664-70 |
| Figlewicz, D P; Hill, S R; Jay, J L et al. (2014) Effect of recurrent yohimbine on immediate and post-hoc behaviors, stress hormones, and energy homeostatic parameters. Physiol Behav 129:186-93 |
| Stice, Eric; Figlewicz, Dianne P; Gosnell, Blake A et al. (2013) The contribution of brain reward circuits to the obesity epidemic. Neurosci Biobehav Rev 37:2047-58 |
| Figlewicz, Dianne P; Jay, Jennifer L; Acheson, Molly A et al. (2013) Moderate high fat diet increases sucrose self-administration in young rats. Appetite 61:19-29 |
| Overduin, Joost; Figlewicz, Dianne P; Bennett-Jay, Jennifer et al. (2012) Ghrelin increases the motivation to eat, but does not alter food palatability. Am J Physiol Regul Integr Comp Physiol 303:R259-69 |
| Seaquist, Elizabeth R; Lattemann, Dianne Figlewicz; Dixon, Roger A (2012) American Diabetes Association research symposium: diabetes and the brain. Diabetes 61:3056-62 |
| Davis, Jon F; Choi, Derrick L; Schurdak, Jennifer D et al. (2011) Leptin regulates energy balance and motivation through action at distinct neural circuits. Biol Psychiatry 69:668-74 |
| Figlewicz, Dianne P; Bennett-Jay, Jennifer L; Kittleson, Sepideh et al. (2011) Sucrose self-administration and CNS activation in the rat. Am J Physiol Regul Integr Comp Physiol 300:R876-84 |
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