Numerous clinical studies link obesity to neurologic impairment and elevated dementia risk. While these studies are generally retrospective or epidemiologic, experimental studies also provide compelling evidence that diet-induced obesity in rodents causes significant brain injury and cognitive impairment. There are several critically important reasons why the damaging effects of obesity on brain homeostasis must be experimentally resolved. First, despite the availability of various weight-loss interventions, obesity remains stubbornly prevalent and highly refractory to clinical remediation. Secondly, notwithstanding emotional devastation and family disruption, the monetary costs of caring just for Alzheimer's patients in the US could reach a staggering 1.2 trillion by 2050. If, however, the mechanisms of diet-induced brain injury are identified, it is possible that therapeutic regimens can be developed to preserve and optimize neurologic function in the context of obesity. To address this need, this proposal describes proof-of-concept studies designed to both: 1) determine if inflammatory signaling in visceral macrophages links visceral obesity to central neurologic impairment;and 2) to test the clinical utility of a new therapeutic target - the NOX2 subunit of the macrophage NADPH oxidase complex - to promote neurologically healthy obesity. Specifically, we will test the hypothesis that the selective knock-down of macrophage NOX2 prevents the progression of peripheral obesity to neurologic impairment in mice. This hypothesis is based on our recently published data showing that when compared to wild-type mice, NOX2 knockout mice are completely protected from the adverse neurologic effects of diet-induced obesity (see Appendix 1). These experiments show that the loss of NOX2 signaling in visceral macrophages confers dramatic decreases in visceral adiposopathy and inflammation, while additional recent data reveal a significant linear relationship between NADPH oxidase activity in visceral adipose and cognitive impairment in wild-type mice. These data collectively suggest that NOX2-based signaling in visceral macrophages links visceral adiposity to sustained and progressive cascades of inflammation that trigger brain injury and dysfunction. However, NOX2 is only a single component of the NADPH oxidase system, which is a pleiotropic enzyme complex mediating variety of physiologic processes. Indeed, intact NADPH oxidase function is necessary for cognitive function, ruling out broad-based inhibition of NADPH oxidase as a therapeutic approach for obesity. Therefore, to advance this important field and optimize therapeutic potential of NADPH oxidase in obesity, we have designed proof-of-concept studies using novel mouse models and cell type-specific pharmacologic targeting strategies in which the NOX2 subunit of NADPH oxidase will be individually manipulated only in macrophages.
Specific Aim 1 will determine if the selective deletion of macrophageNOX2 is sufficient to prevent high fat diet-induced neurologic injury in mice, while Specific Aim 2 will thoroughly map the clinical potential of a pharmacologic macrophage-targeted NOX2 regimen in diet-induced neurologic injury.

Public Health Relevance

Obesity caused by an unhealthy, high-fat diet can cause brain injury and dramatically increase the risk of dementia. This is a significant public health concern, as both the prevalence of obesity and the costs required to treat dementia continue to increase. However, clinical data show that some obese patients, maybe as many as 30%, do not develop disease, and are considered healthy obese. This suggests that it may not be necessary to cure obesity to dramatically improve public health. This proposal will determine if decreasing the function of specific protein involved in the inflammatory response to obesity - NOX2 - can prevent obesity from damaging the brain, and will test new, highly targeted strategies that modulate this protein to promote brain-healthy obesity.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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He, Janet
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Lsu Pennington Biomedical Research Center
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Baton Rouge
United States
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