Combatting Cognitive Decline in Obesity and Diabetes: The Use of Lifestyle and Drug Interventions That Target Neuroplasticity

Obesity and Type 2 Diabetes (T2D), driven by sedentary lifestyles and poor diets, are associated with a 30% increased risk of dementia and are major public health challenges. These conditions impair hippocampal function, disrupt neurogenesis, and compromise cognitive processes essential for learning and memory. While aerobic exercise is a well-established intervention for mitigating cognitive decline, resistance exercise and metformin may offer added or unique benefits through mechanisms of neuroplasticity in those with obesity and T2D. In this thesis, I employed a bench-to-bedside strategy—integrating preclinical mouse models of diet-induced obesity with a clinical trial in older adults at risk for diabetes (overweight/obese or prediabetes) —to explore the efficacy of resistance exercise and metformin in preventing obesity- and T2D- related cognitive decline. First, we examined whether resistance exercise and metformin treatment can prevent diet-induced deficits in pattern separation, an aspect of memory that is often reduced in older adults. Both interventions were similarly effective to aerobic exercise in mitigating such impairments. These benefits occurred independently of changes in neurogenesis, suggesting alternative mechanisms are likely to be at play. Second, we conducted a six-month randomized controlled trial of resistance exercise in older adults at risk for diabetes. Resistance exercise, compared to balance-and-tone training, improved working memory and cognitive flexibility. Additionally, three touchscreen tests, mirroring their rodent version, were implemented to assess cognition in this clinical trial. While no differences were observed between training groups, this work has provided a strong foundation for the development of future translational cognitive tests. Third, to advance the translational assessment of cognition in diet-induced obesity, we determined if water manipulation using 2% citric acid as an alternative to food restriction can motivate touchscreen task performance in obese mice. Water manipulation successfully elicited task engagement on touchscreen tests in mice with diet-induced obesity. Moreover, although we found reductions in motivation, this did not impact learning in obese mice. Collectively, these findings highlight resistance exercise and metformin as effective strategies for mitigating obesity-related cognitive decline. Moreover, this research advances cross-species cognitive assessments, enabling rigorous investigations into diet and interventions.