Aging reveals divergent responses of AgRP/NPY neurons to diet in male and female mice.

Objectives: Neurons coexpressing Agouti-related peptide (AgRP) and Neuropeptide Y (NPY) are an essential component of an interoceptive circuit regulating hunger and metabolism. Their activity is closely linked to metabolic state and their output is sensitive to diet-induced plasticity, which may influence the development of obesity and associated metabolic diseases. However, most studies use young male mice, even though obesity and its comorbidities are sensitive to both biological sex and aging, leaving a significant gap in our understanding of the role of these neurons in females and in older animals. Our goal was to begin to address this gap by investigating the effects of diet and age on AgRP/NPY neuronal activity in female mice in both early adulthood and midlife. Methods: Female transgenic NPY-GFP mice aged 8-32 weeks were fed either a standard control chow diet or a high-fat, high-sugar diet (HFD) for 8-24 weeks and brain slice patch clamp electrophysiology was used to measure the response of AgRP/NPY neurons. Results: We found that in young, lean female mice, the baseline firing rate of AgRP/NPY neurons is significantly elevated compared to age-matched males, thus the impact of HFD on the output of these neurons is blunted relative to control. However, in the baseline firing rate of neurons from lean middle-aged female mice is significantly lower, resulting in a greater relative impact of HFD on AgRP/NPY neuronal output, the development of neuronal leptin resistance, and significant weight gain. Conclusions: Both sex and age significantly impact the function and modulation of AgRP/NPY neurons, emphasizing the need to include these biological variables in experimental design.