Age and duration of obesity modulate the inflammatory response and expression of neuroprotective factors in mammalian female brain

Obesity has become a global epidemic and is associated with comorbidities, including diabetes, cardiovascular, and neurodegenerative diseases, among others. While appreciable insight has been gained into the mechanisms of obesity-associated comorbidities, effects of age, and duration of obesity on the female brain remain obscure. To address this gap, adolescent and mature adult female mice were subjected to a high-fat diet (HFD) for 13 or 26 weeks, whereas age-matched controls were fed a standard diet. Subsequently, the expression of inflammatory cytokines, neurotrophic/neuroprotective factors, and markers of microgliosis and astrogliosis were analyzed in the hypothalamus, hippocampus, and cerebral cortex, along with inflammation in visceral adipose tissue. HFD led to a typical obese phenotype in all groups independent of age and duration of HFD. However, the intermediate duration of obesity induced a limited inflammatory response in adolescent females' hypothalamus while the hippocampus, cerebral cortex, and visceral adipose tissue remained unaffected. In contrast, the prolonged duration of obesity resulted in inflammation in all three brain regions and visceral adipose tissue along with upregulation of microgliosis/astrogliosis and suppression of neurotrophic/neuroprotective factors in all brain regions, denoting the duration of obesity as a critical risk factor for neurodegenerative diseases. Importantly, when female mice were older (i.e., mature adult), even the intermediate duration of obesity induced similar adverse effects in all brain regions. Taken together, our findings suggest that (1) both age and duration of obesity have a significant impact on obesity-associated comorbidities and (2) early interventions to end obesity are critical to preserving brain health.