Interestingly these cognitive impairments were not observed

Interestingly, these cognitive impairments were not observed in a model of T1D, as mice with STZ-induced diabetes performed these tasks at levels similar to age-matched controls. While several studies have demonstrated cognitive dysfunction in rodent models of T1D (Biessels et al., 1996; Ramanathan et al., 1998; Alvarez et al., 2009; Rajashree et al., 2011), our data is consistent with human studies where learning and memory are generally spared in T1D patients (Brands et al., 2005), while multiple memory deficits are noted even in the early stages of T2D (Ruis et al., 2009). It should be noted, however, that differential metabolic effects have been observed depending on the mouse strain and caloric source, i.e. high fat vs high-sucrose diets (Surwit et al., 1995; West et al., 1995). Thus, while similar cognitive impairments in rodents can be brought on by increased caloric intake in the form of either simple nos inhibitor or saturated fats (Kanoski and Davidson, 2011), it is important to point out that the metabolic and cognitive effects observed in this study may still be specific to a high fat diet. Additionally, as we employed only high-fat fed female mice of advanced age, the extent to which these data extend across sex, age and degree of metabolic dysfunction is unclear, and further studies are needed to elucidate these issues. In order to examine the effects of weight loss and improvements in metabolism on cognitive function, we subjected HFD mice to a brief, but intensive reduction in dietary fat and caloric intake. This one month low-fat diet intervention improved nearly every measure of peripheral metabolism and led to a complete restoration of the cognitive deficits associated with MetS. The intervention employed in this study would be considered extreme by human standards, and although translation is difficult given the differences in lifespan between mice and humans, perhaps the most appropriate comparison is the extensive weight loss observed in obese patients following bariatric surgery. There is evidence of rapid improvement in memory among bariatric surgery patients (Gunstad et al., 2011), and together with other weight loss studies reporting improvement in various cognitive domains (Siervo et al., 2011), the data presented here suggest that the cognitive dysfunction associated with MetS is at least partially reversible. Unfortunately, a very small percentage of patients with T2D makes the significant lifestyle changes necessary to send the disease into remission (Karter et al., 2014). However, recent work suggests that time restricted feeding (Chaix et al., 2014) and intermittent fasting (Brandhorst et al., 2015) may provide similar metabolic and/or cognitive benefits, and thus may represent more easily adoptable behavioral interventions for obese individuals and patients with MetS or T2D. Memory impairment as a result of neurodegeneration, as in cases of Alzheimer\'s disease (AD) and Vascular Dementia (VsD) is believed to be largely irreversible once it occurs. In general, the cognitive deficiencies associated with MetS and T2D appear to occur early, perhaps in concert with the obesity and IR which typically occur prior to overt diabetes (Kim and Feldman, 2015; Ruis et al., 2009; Sellbom and Gunstad, 2012). The model employed here reflects these early stages of T2D in humans, and it is probable that there becomes a point at which the cognitive dysfunction associated with T2D becomes irreversible. For example, there is evidence of decreased brain volume (Espeland et al., 2013) and exacerbation of cerebrovascular and Alzheimer\'s disease (AD) pathology in diabetic humans (Peila et al., 2002; Ahtiluoto et al., 2010; Sonnen et al., 2009) and rodents (Park, 2011). In these cases, it is less likely that a simple lifestyle intervention would significantly improve neurological function. Given the resistance of T2D to therapy in its late stages, it becomes critical for future studies to determine if and when this “point of no return” occurs, and intervene with medical and public health initiatives focused on early stages of the disease.