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Reema Patel Vazirani
Interdisciplinary Biomedical Sciences Program
B.Sc. 2005, Carnegie Mellon University
Thesis Advisor: Vanessa H. Routh, Ph.D.
Department of Pharmacology and Physiology
Wednesday, August 1, 2012
10:30 A.M., MSB-H609, Pharmacology Conference Room
The brain contains specialized neurons which integrate energy balance signals and regulate mechanisms to maintain or restore homeostasis. These include glucose sensing neurons which are sensitive to various metabolites and hormones. Ventromedial hypothalamus (VMH) glucose-inhibited (GI) neurons depolarize in response to decreased glucose. VMH GI neurons are important in the detection of energy deficit and are proposed to inhibit energy expenditure, mobilize energy stores, and promote food intake. In obesity, there is hyperleptinemia and chronic inflammation. Both leptin and proinflammatory cytokines are proposed to have anorectic and catabolic effects, however obesity persists despite the elevation of both. We hypothesize that leptin and proinflammatory cytokines inhibit activation of VMH GI neurons by glucose decreases, thereby contributing to their anorectic and catabolic effects upon energy homeostasis. Further, we hypothesize that there is both leptin and cytokine resistance in obesity, explaining why obesity persists despite their elevations.
Using primary dissociated VMH neurons and membrane potential dye imaging, we have demonstrated that leptin inhibits activation of VMH GI neurons by decreased glucose in ~50% of VMH GI neurons. This inhibition by leptin is due to PI3K inhibition of AMPK. Further, we have shown that the proinflammatory cytokines interleukin-1â (IL1â) and tumor necrosis factor-á also inhibit activation of VMH GI neurons by decreased glucose. For IL1â, the mechanism is dependent upon IL1â inhibition of AMPK. Using immunoblotting of VMH tissue, we found that while AMPK is a point of convergence for glucose, leptin and IL1â signaling, the pathways upstream of AMPK are distinct.
Studies in our laboratory have demonstrated that there is enhanced sensitivity to decreased glucose both in GI neurons from fasted mice as well as glucose-excited (GE) neurons from db/db mice. db/db mice have a leptin receptor mutation and are used as a diabetes/obesity model. We hypothesized that VMH GI neurons from mice which developed diet-induced obesity (DIO) on a high fat diet would also have enhanced sensitivity to decreased glucose due to the resulting leptin resistance. We also hypothesized that GI neurons from these mice would be cytokine resistant since these animals clearly do not exhibit normal cytokine induced anorexia and wasting. This work established the study of GI neurons in adult VMH neurons, allowing for the use of disease models at adult ages and allowing for the study of DIO, a physiological model of obesity. We found that VMH GI neurons from DIO mice are more sensitive to moderate glucose decreases. This indicates that small decreases in glucose would be more likely to activate VMH GI neurons and shift toward positive energy balance. The inhibitory effect of leptin upon the VMH GI neuronal response to decreased glucose was lost in DIO, representing leptin resistance at the level of VMH GI neurons. Interestingly, we also found resistance to the inhibitory effect of IL1â. This supports the novel concept of cytokine resistance and introduces a new mechanism to target in obesity.