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Cristianne Frazier
B.S., University of Wisconsin, Madison
email: frazierc at uchicago dot edu

Advisor: Xiaoxi Zhuang

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Two-thirds of Americans are overweight or obese and around the world 
obesity rates are rising. A hallmark of obesity is elevated plasma 
leptin concentrations but a resistance to leptin signaling in the brain. 
Leptin circulates in the blood in proportion to the amount of white 
adipose tissue in the body. Under non-resistant conditions leptin 
signaling inhibits feeding and promotes energy expenditure when food is 
readily available. The resistance to leptin that occurs in diet-induced 
obesity is thought to be evolutionarily adaptive because it enables the 
accumulation of energy stores when food is readily-available, which 
presumably promotes survival during periods scarcity. The consequences 
of leptin resistance once food becomes scarce are unclear. Evidence 
suggests that leptin promotes energy expenditure without inhibiting 
feeding when animals have access to a limited amount of food. The 
behavioral consequence of leptin signaling as scarcity increase has not 
been studied. Using homecage operant boxes, we found that mice that do 
not secrete leptin (ob/ob mice) overeat when food is relatively easy to 
obtain, but are less likely to seek food when it is relatively scarce. 
This suggests that leptin signaling promotes food-seeking when resources 
are scarce. We hypothesize that leptin may achieve this end through 
signaling in brain regions important for promoting food-seeking when the 
cost of acquiring it is relatively high. The dopamine system plays a 
critical role in feeding when work is required to obtain food. It has 
been shown that the absence of leptin signaling in the brain reduces 
intracellular dopamine production. We will test: 1) whether chronic 
leptin replacement in ob/ob mice restores food-seeking as scarcity 
increases; and 2) whether restoring dopamine production in the brain 
using systemic l-dopa injections restores food-seeking as scarcity 
increases in ob/ob mice. To establish whether the ability of leptin to 
promote food-seeking is dependent on its direct effects on dopamine 
neurons, we will test whether leptin signaling in dopamine neurons is 
required for food-seeking as scarcity increases. We will induce 
leptin-resistance in dopamine neurons by employing a tissue-specific 
functional knockout of leptin receptors in dopamine neurons only. Public 
Statement: The development of obesity in environments where energy-dense 
foods are readily-available is thought to be an evolutionary adaptation 
that promotes survival when food becomes scarce. A resistance to leptin 
signaling in the brain is a hallmark of this predisposition, however the 
behavioral the consequences leptin resistance as food becomes scarce has 
not been studied. Using mice, this project aims to investigate the 
effects of leptin signaling on food-seeking when resources become scarce 
and the brain systems that are involved in generating these behaviors.

Publications:

Frazier, C.R., Trainor, B.C., Cravens, C.J., Whitney, T.K., & Marler, C.A. (2006) Paternal behavior influences the

development of aggression and vasopressin expression in male California mouse offspring. Horm. Behav. 50(5):699-707

Frazier CRM, Mason P, Zhuang X, Beeler JA (2008) Sucrose Exposure in Early Life Alters Adult Motivation and 
Weight Gain. PLoS ONE 3(9): e3221. doi:10.1371/journal.pone.0003221   

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Committee on Neurobiology  |  University of Chicago

10/20/2008