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Zagmutt, S.

Publications and source records attributed to Zagmutt, S..

2 recordsLinked to original sources
bioRxiv2025

Sex-dependent hypothalamic microinflammation and microglial polarization: The role of JNK in high-fat diet-induced insulin resistance

Obesity and its associated metabolic disorders, including insulin resistance and type 2 diabetes, are major global health challenges. Early hypothalamic microinflammation is emerging as a key contributor to the onset of metabolic dysfunction, but its temporal dynamics, underlying mechanisms, and sex-specific differences remain unclear. Here, we examined the effects of short-term high-fat diet (HFD) exposure on hypothalamic microinflammation, glial activation, and insulin signaling in male and female mice. Males rapidly developed hypothalamic microinflammation, characterized by increased pro-inflammatory cytokines, reactive gliosis, and impaired insulin signaling, whereas females did not show these alterations. Interestingly, we also observed a sex-specific pattern in microglial M2 polarization: females maintained a sustained M2 response throughout the experimental period, while males exhibited only a transient peak that declined in the following days. These sex-specific differences in microglial dynamics and polarization may be linked to the c-Jun N-terminal kinase pathway, a classical mediator of inflammatory signaling. To further explore this, we analyzed mice lacking JNK3, the CNS-enriched isoform of JNK. Loss of JNK3 disrupted early microglial polarization, abolished the transient M2 response, and predisposed males to enhanced gliosis and partial hypothalamic insulin resistance, while females retained partial resilience. These findings indicate that JNK3 contributes to the regulation of microglial dynamics and polarization in response to metabolic stress. Overall, our study highlights a sex-dependent role of microglia and JNK in shaping early hypothalamic microinflammation and central insulin sensitivity, providing potential targets for intervention in obesity-associated metabolic disease.

neuroscience↗
bioRxiv2024

DEFICIENCY OF THE NUTRIENT SENSOR CPT1c IN SF1 NEURONS DISRUPTS THE ENDOCANNABINOID SYSTEM RESULTING IN COMPROMISED SATIETY AND FUEL SELECTION UPON FAT INTAKE

The SF1 neurons of the ventromedial hypothalamus (VMH) are pivotal in governing body weight and adiposity, particularly in response to a high-fat diet (HFD). Previous studies have shown that the activation of SF1 neurons induces satiety, increases energy expenditure, and promotes the preferential use of fats as energy substrate. Furthermore, SF1 neurons are necessary for recovering from insulin-induced hypoglycemia. Here we demonstrate the essential role of the nutritional sensor CPT1c in the activation of SF1 neurons by dietary fats. Mice deficient in CPT1C in SF1 neurons (SF1-CPT1c-KO) are unable to adjust their caloric intake during the initial exposure to a HFD. This is associated with an impaired metabolic transition in the liver, muscle, and adipose tissue, despite a normal response to a glucose or insulin challenge. During chronic HFD exposure, SF1-CPT1c-KO mice are more prone to obesity and glucose intolerance than controls. CPT1c deficiency in SF1 neurons also leads to alterations in hypothalamic endocannabinoid levels and their metabolism. Our findings posit CPT1C in SF1 neurons as a sensor for dietary fats, regulating satiety responses and nutrient partitioning likely through the modulation of the endocannabinoid system.

neuroscience↗