A sexually dimorphic hypothalamic response to chronic high-fat diet consumption

Area of Science:

• Neuroendocrinology
• Metabolic disease research
• Lipidomics

Background:

• High-fat diet (HFD) consumption is linked to obesity and metabolic dysfunction.
• Sex differences in metabolic responses to HFD are increasingly recognized.
• The central nervous system (CNS) role in regulating systemic metabolism is critical.

Purpose of the Study:

• To investigate sex-specific alterations in CNS lipid profiles and hypothalamic inflammation following chronic HFD exposure.
• To elucidate the role of estrogen receptor alpha (ERα) in mediating HFD-induced hypothalamic inflammation and metabolic disturbances.
• To examine the impact of HFD-induced ERα depletion on glucose tolerance and cardiac function.

Main Methods:

• Comparative analysis of CNS lipid composition (fatty acids, sphingolipids) in male and female mice on HFD.
• Quantification of hypothalamic inflammatory markers in response to HFD.
• Assessment of proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and ERα levels in the hypothalamus.
• Evaluation of HFD effects on ERα total-body knockout mice.
• Measurement of glucose tolerance and myocardial function.

Main Results:

• Male mice exhibited higher saturated fatty acids and sphingolipids, with lower polyunsaturated fatty acids in the CNS compared to females after HFD.
• Males showed increased hypothalamic inflammation markers, linked to reduced PGC-1α and ERα, unlike females.
• Hypothalamic inflammation was induced in HFD-exposed ERα knockout mice of both sexes.
• HFD-induced hypothalamic ERα depletion correlated with impaired glucose tolerance and myocardial function.

Conclusions:

• Chronic HFD exposure induces sex-specific changes in CNS lipids and hypothalamic inflammation.
• Estrogen receptor alpha is crucial for preventing HFD-induced hypothalamic inflammation and maintaining metabolic homeostasis.
• ERα deficiency exacerbates HFD-related metabolic and cardiac dysfunctions.