The interconnection between obesity and central nervous system (CNS) neurological dysfunction has been widely appreciated. Accumulating evidence demonstrates that obesity is a risk factor for CNS neuroinflammation and cognitive impairment. However, the extent to which CNS disruption influences peripheral metabolism remains to be elucidated. We previously reported that myelin-enriched sulfatide loss leads to CNS neuroinflammation and cognitive decline. In this study, we further investigated the impact of CNS sulfatide deficiency on peripheral metabolism while considering sex- and age-specific effects. We found that female sulfatide-deficient mice gained significantly more body weight, exhibited higher basal glucose levels, and were glucose-intolerant during glucose-tolerance test (GTT) compared to age-matched controls under a normal diet, whereas male sulfatide-deficient mice only displayed glucose intolerance at a much older age compared to female sulfatide-deficient mice. Mechanistically, we found that increased body weight was associated with increased food intake and elevated neuroinflammation, especially in the hypothalamus, in a sex-specific manner. Our results suggest that CNS sulfatide deficiency leads to sex-specific alterations in energy homeostasis via dysregulated hypothalamic control of food intake.

Innate immune activation plays a vital role in the development of Alzheimer's disease (AD) and related dementias (ADRD). Among which, the DNA sensing cyclic GMP-AMP synthase (cGAS)-STING pathway has been implicated in diverse aspects of AD progression. In the current study, we showed that the cGAS-STING signaling was up-regulated in AD and this elevation was mainly contributed by the microglial population other than non-microglial cell types in the brain. By establishing an inducible, microglia-specific cGAS knockout mouse model in 5xFAD background, we found that deleting microglial cGAS at the onset of amyloid-β (Aβ) pathology significantly limited plaque formation, and protected mice from Aβ-induced cognitive impairment. Mechanistically, we found cGAS was necessary for plaque-associated microglial enrichment potentially driven by IRF8, and was indispensable for the development of disease-associated microglia (DAM) phenotype. Meanwhile, the loss of microglial cGAS reduced the levels of dystrophic neurites which led to preserved synaptic integrity and neuronal function. Our study provides new insights in understanding the effects of innate immune in AD via a cell-type specific manner, and lays the foundation for potential targeted intervention of the microglial cGAS-STING pathway toward the improvement of AD.