Biology subjects

Korgan, A. C.

Publications and source records attributed to Korgan, A. C..

3 recordsLinked to original sources

bioRxiv2025

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

ObjectivesNeurons 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. MethodsFemale 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. ResultsWe 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. ConclusionsBoth sex and age significantly impact the function and modulation of AgRP/NPY neurons, emphasizing the need to include these biological variables in experimental design. HighlightsO_LIMale and female mice exhibit sex-dependent responses to a high-fat diet, with female mice requiring twice as long to develop an overt obese phenotype. C_LIO_LIAgRP/NPY neurons in young, lean female mice have significantly higher activity than those from male mice. C_LIO_LIAging female mice develop obesity and altered function and leptin sensitivity of AgRP/NPY neurons. C_LIO_LIThe hypothalamic glial response to high-fat diet is influenced by sex - age interactions. C_LI

neuroscience↗

bioRxiv2022

Hypothalamic gene network dysfunction is associated with cognitive decline and body weight loss in Alzheimer's disease mice

Recent studies, both clinical and experimental, indicate that many neurodegenerative disorders including Alzheimers disease (AD) often display coexisting metabolic dysfunctions, which may exacerbate neurological symptoms. The hypothalamus is a brain region highly involved in maintaining metabolic and other homeostatic processes and is known to be involved in the etiology of AD, although the role of hypothalamic dysfunction in the onset, progression, and severity of AD is poorly understood. In this study, we demonstrate that our new model of genetic diversity in AD, the AD-BXDs, exhibits non-cognitive symptoms consistent with hypothalamic dysfunction and examined hypothalamic bulk RNA sequencing data in the AD-BXD panel to investigate how the AD transgene impacts gene expression profiles in the hypothalamus. Mostly notably, we identified strong neuroinflammatory signatures from the hypothalamus in the AD-BXDs as early as six months of age. A functionally unknown WGCNA module showed correlation to female body weight and contextual fear acquisition. Eigengene expression of microglial/macrophagic modules and their hub gene expressions were correlated to cognitive phenotypes. From these analyses, we nominated Plek and Laptm5 as new targets to attenuate neuroinflammation in AD.

neuroscience↗

bioRxiv2021

High-fat diet induced loss of GABAergic inhibition decouples intrinsic and synaptic excitability in AgRP neurons

Obesity is a progressive, relapsing disease with few therapies. Diet and lifestyle interventions are effective but are often temporary and many individuals regain weight. High-fat diet increases the excitability of AgRP neurons, a critical neuronal population for the regulation of food intake and body weight. Here we investigate the plasticity of AgRP neurons and the impact of high-fat diet on modulation by synaptic input. We find that diet-induced hyperexcitability of AgRP neurons is not reversed by a lower-fat diet intervention. High-fat diet is associated with changes in the synaptic modulation of AgRP neurons, with a paradoxical increase in inhibitory input accompanied by a loss of GABA-mediated inhibition due to a depolarizing shift in the reversal potential of the GABA-evoked Cl- current. These findings reveal that high-fat diet leads to decoupling of intrinsic and synaptic excitability in AgRP neurons, such that hyperexcitability of AgRP neurons persists despite an increase in inhibitory input, revealing a mechanism for the difficulty in sustaining weight loss.

neuroscience↗