Ongoing epidemiological studies by the Centers for Disease Control estimate that greater than 60% of the adult US population may be categorized as either overweight or obese [1]. The incidence of obesity is even greater in the VA population, with current estimates suggesting that over 72% of veterans may be classified as obese or overweight [2]. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). One of the neurological complications of obesity is an increased risk of developing co-morbidities like depressive illness. In obesity phenotypes, plasma leptin is increased but leptin transport across the blood-brain barrier (BBB) is impaired, suggesting that brain leptin resistance may be a mechanistic link between obesity and major depressive illness. This leptin resistance may be related to a combination of decreased leptin BBB transport and reduced leptin receptor (LepR) signaling. The overarching hypothesis of this proposal is that brain leptin resistance represents a mechanistic link in the etiology and progression of co-morbid depression in obesity. This hypothesis will be tested in two innovative experimental models of obesity: a novel antagonist that selectively blocks BBB transport of leptin and using a lentivirus vector that selectively downregulates hypothalamic insulin receptor expression (hypo-IRAS).
In Aim 1 we will examine the ability of a leptin receptor antagonist (LRA) that impairs BBB leptin transport and creates a CNS leptin deficient state to elicit depressive-like and anxiety-like behaviors. We will also examine whether these behavioral changes are reversible. Using our hypo-IRAS model of obesity, we will assess whether decreases in brain leptin levels and LepR signaling are responsible for the development of depression-like behaviors in hypo-IRAS rats (Aim 2).
In Aim 3, we will test the hypothesis that food restriction restores BBB transport of leptin and LepR-mediated signaling, thereby reversing the depressive-like phenotype observed in hypo-IRAS rats.
In Aim 4, we will examine the ability of a drug that has been extensively studied in VA patients, namely gemfibrozil, to reverse behavioral despair and anhedonia in obese rodents. Successful completion of these studies will directly test our hypothesis that CNS leptin resistance elicits the development of depressive-like behaviors, which would enhance our understanding of the mechanisms through which reductions in body weight and normalization of metabolic parameters have positive effects on mood and anxiety measures in obese individuals. Most importantly, our studies will examine the ability of lifestyle and pharmacological interventions to reverse the depression-like phenotypes in obese rodents. Such findings would be directly translatable to VA patient populations.

Public Health Relevance

The spiraling cost of the obesity epidemic has enormous socio-economic and health-care implications. This is especially relevant for the Veterans Health Administration as overweight/obesity rates are significantly higher in Veterans compared to the general US population. One somewhat overlooked complication of obesity is the development of neurological co-morbidities, including increased risk for depressive illness. Indeed, similar to investigations related to obesity prevalence, clinical and epidemiology studies clearly indicate that the incidence of depression is increased in the VA population when compared to the general population. In view of these observations, the goals of the current studies are: 1) to identify the mechanistic links between obesity and depression; and 2) to identity treatment strategies to effectively treatment co-morbid depression and obesity that may be directly translatable to Veterans Administration patient populations.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001804-03
Application #
8803333
Study Section
Neurobiology A (NURA)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
086371846
City
Columbia
State
SC
Country
United States
Zip Code
29209
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Macht, Victoria A; Reagan, Lawrence P (2018) Chronic stress from adolescence to aging in the prefrontal cortex: A neuroimmune perspective. Front Neuroendocrinol 49:31-42
Finnell, Julie E; Muniz, Brandon L; Padi, Akhila R et al. (2018) Essential Role of Ovarian Hormones in Susceptibility to the Consequences of Witnessing Social Defeat in Female Rats. Biol Psychiatry 84:372-382
Ferrario, Carrie R; Reagan, Lawrence P (2018) Insulin-mediated synaptic plasticity in the CNS: Anatomical, functional and temporal contexts. Neuropharmacology 136:182-191
Van Doorn, Catherine; Macht, Victoria A; Grillo, Claudia A et al. (2017) Leptin resistance and hippocampal behavioral deficits. Physiol Behav 176:207-213
Macht, V A; Vazquez, M; Petyak, C E et al. (2017) Leptin resistance elicits depressive-like behaviors in rats. Brain Behav Immun 60:151-160
Fadel, Jim R; Reagan, Lawrence P (2016) Stop signs in hippocampal insulin signaling: the role of insulin resistance in structural, functional and behavioral deficits. Curr Opin Behav Sci 9:47-54
Biessels, Geert Jan; Reagan, Lawrence P (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16:660-71
Wilson, Marlene A; Grillo, Claudia A; Fadel, Jim R et al. (2015) Stress as a one-armed bandit: Differential effects of stress paradigms on the morphology, neurochemistry and behavior in the rodent amygdala. Neurobiol Stress 1:195-208
Grillo, Claudia A; Piroli, Gerardo G; Lawrence, Robert C et al. (2015) Hippocampal Insulin Resistance Impairs Spatial Learning and Synaptic Plasticity. Diabetes 64:3927-36

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