Rosiglitazone attenuates the cognitive deficits induced by high fat diet feeding in rats

Abstract

The present study was designed to test the hypothesis that insulin resistance plays a role in high fat diet feeding induced cognitive deficits. Rats consuming the high fat diet exhibited characteristic features of insulin resistance viz. mild hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Further, these rats showed a severe deficit in learning and memory. In contrast, rosiglitazone at the dose of 5 mg/kg, p.o. for 7 days prior to biochemical and behavioral testing significantly lowered the plasma glucose, triglycerides, cholesterol, and insulin levels. These animals also performed better on Morris water maze task, suggesting improved spatial memory. Our data demonstrate that the insulin sensitizers can overcome the cognitive deficits arising from high fat diet feeding, which may be in part mediated through the development of peripheral insulin resistance.

Introduction

Obesity and related cardiometabolic syndromes are becoming the major health concern across the globe. Indeed, with population aging, the prevalence of glucose intolerance and non-insulin dependent diabetes mellitus is on the rise and consumption of high fat diet is a known risk factor for these physiological changes. Insulin resistance, which is usually associated with hypertrophic obesity, is believed to be the major underlying mechanism for these abnormalities (Nisoli and Carruba, 2004). In addition to this, insulin resistance is under scrutiny for its effect on cognitive function in recent years (Elias et al., 2003). Patients with Alzheimer's disease, a most common form of dementia have shown elevated plasma insulin levels and reduced insulin sensitivity (Watson and Craft, 2004). Conversely, abnormalities in insulin metabolism may influence the onset of Alzheimer's disease via their role in synthesis and degradation of β-amyloid, a peptide held central to Alzheimer's neuropathology. Additionally, recent studies have indicated that certain signal transduction pathways [e.g., glycogen synthase kinase (GSK)-3] downstream of the insulin receptor, may also promote the generation of Aβ peptides by modulating the cleavage of the parent APP at the γ-secretase site, a site determinant of Aβ amyloidogenicity (Ho et al., 2004).

Type 2 diabetic rats such as the Goto–Kakizaki showed impaired memory on lever-press task, a behavioral paradigm that allows response-reinforcement learning (Moreira et al., 2007). Similarly, the obese Zucker rat, a widely used model of type 2 diabetes showed impaired performance on a variable-interval delayed alternation test of learning and memory (Winocur et al., 2005). Further, Streptozotocin-diabetic rats also showed deficits in spatial learning on a water maze task (Biessels et al., 1998). These evidences suggest that hyperinsulinemia and type 2 diabetes, a condition associated with insulin resistance, increase the risk of memory impairment and Alzheimer's disease (Luchsinger et al., 2004, Watson and Craft, 2003).

Consistent with this notion, rats fed with higher amount of dietary fat showed widespread cognitive deficit on various tasks of learning and memory such as, Olton's radial arm maze, a non-spatial test of conditional associative learning, the Hebb–Williams complex maze series, and a variable-interval delayed alternation test that highlighted deficits in rule-learning and specific memory function (Greenwood and Young, 2001, Molteni et al., 2002, Winocur and Greenwood, 1999). The mechanisms of adverse effects of dietary fat on cognitive function are not completely understood. However, it is well established that high fat diet leads to glucose intolerance and insulin resistance in rats (Srinivasan et al., 2004), raising the possibility that abnormalities in glucose utilization might contribute to memory deficits. Neurotransmitter metabolism, cerebral blood flow, blood brain barrier and microvascular function may all be affected to varying degrees by chronic disruption of glucose metabolism (McCall, 2004). This contention is strengthened by the observation that acute intraperitoneal administration of glucose (100 mg/kg) improves the high fat diet induced cognitive deficits in rat (Greenwood and Winocur, 2001).

If the disruption of glucose metabolism is contributing to the hippocampal function impairment, a reasonable hypothesis is that insulin sensitizer's should restore the hippocampal function and a corresponding cognition in high fat diet fed rats. The anti-diabetic compounds such as rosiglitazone and pioglitazone are considered as an insulin sensitizer's and mediate their effect through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) (Vasudevan and Balasubramanyam, 2004). Activation of PPAR-responsive genes accounts for the maintains of an appropriate level of expression of key gluco- and liporegulatory molecules, as well as other proteins that are involved in the transduction of the insulin signal (Stumvoll, 2003). The present study was therefore designed to study the effect of rosiglitazone treatment on high fat diet induced spatial memory impairment in rat. Rosiglitazone was used in present study as it does not cross the intact blood brain barrier in rodents (Pedersen et al., 2006). Thus, the effects of rosiglitazone on the cognitive function may be indirectly mediated through its peripheral actions. To begin to test this hypothesis, we subjected high fat diet fed rats to the rosiglitazone treatment and determined if the peripheral insulin sensitization action of the drug is concomitant with improved learning and memory performance in rat.