Obesity/hyperleptinemic phenotype impairs structural and functional plasticity in the rat hippocampus
2011
Grillo, Claudia A. | Piroli, Gerardo G. | Junor, Lorain | Wilson, Steven P. | Mott, David D. | Wilson, Marlene A. | Reagan, Lawrence P.
Epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese, and there is a growing appreciation that the complications of obesity extend to the central nervous system (CNS). While the vast majority of these studies have focused on the hypothalamus, more recent studies suggest that the complications of obesity may also affect the structural and functional integrity of the hippocampus. A potential contributor to obesity-related CNS abnormalities is the adipocyte-derived hormone leptin. In this regard, decreases in CNS leptin activity may contribute to deficits in hippocampal synaptic plasticity and suggest that leptin resistance, a well-described phenomenon in the hypothalamus, may also be observed in the hippocampus. Unfortunately, the myriad of metabolic and endocrine abnormalities in diabetes/obesity phenotypes makes it challenging to assess the role of leptin in hippocampal neuroplasticity deficits associated with obesity models. To address this question, we examined hippocampal morphological and behavioral plasticity following lentivirus-mediated downregulation of hypothalamic insulin receptors (hypo-IRAS). Hypo-IRAS rats exhibit increases in body weight, adiposity, plasma leptin and triglyceride levels. As such, hypo-IRAS rats develop a phenotype that is consistent with features of the metabolic syndrome. In addition, hippocampal morphological plasticity and performance of hippocampal-dependent tasks are adversely affected in hypo-IRAS rats. Leptin-mediated signaling is also decreased in hypo-IRAS rats. We will discuss these findings in the context of how hyperleptinemia and hypertriglyceridemia may represent mechanistic mediators of the neurological consequences of impaired hippocampal synaptic plasticity in obesity.
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