Sex-Specific Links Between Low Choline, Metabolic Dysfunction, andNeuropathology in Obesity: Insights from Humans and the 3xTg-AD MouseModel of Alzheimer's disease.

Abstract

The growing prevalence of obesity, a risk factor for disorders such as Alzheimers Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (A{beta}) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, [~]90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5-24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. HighlightsO_LIObesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimers disease (AD). C_LIO_LIWomen exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. C_LIO_LILower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. C_LIO_LI3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants. C_LI