Astrocytes regulate neuroendocrine functions in a sex-dependent manner through Cdk4 signalization.
Astrocytes are key regulators of hypothalamic neuronal circuits controlling neuroendocrine functions. They also display sexually dimorphic features across several hypothalamic regions. However, the astrocytic factors contributing to the sex-specific regulation of these functions remain poorly understood. We recently identified the kinase Cdk4 as a potential regulator of neuroendocrine functions related to reproduction, stress, and metabolism, in a sex-dependent manner, using Cdk4 Neo-RIP mice (a full body KO). While Cdk4 is classically known for its role in cell cycle control, it has also been implicated in regulating cellular plasticity and metabolism in cancer and peripheral tissues. In the brain, Cdk4 is predominantly expressed in glial cells, particularly hypothalamic astrocytes, where its expression is modulated by both diet and sex. Based on these findings, we hypothesize that astrocytic Cdk4 modulates adult neuroendocrine functions through sex-specific effects on astrocyte metabolism and/or plasticity. To test this, we generated an inducible astrocyte-specific Cdk4 knockout model using the Cre-LoxP system (Cdk4flox/flox hGFAP-Cre ERT2 mice). Mice (Cre ERT2 +/+ or Tg/+) received intraperitoneal injections of tamoxifen (100 mg/kg/day) for four consecutive days.
Female KO mice exhibited disrupted estrous cycles, though fertility remained intact in both sexes. Under chow diet, increased weight gain and adiposity were observed only in male KO mice, with no differences in females. In contrast, under a 60% high-fat-diet, these differences disappeared in males but emerged in females.
Under chow diet and mildly stressful novel condition (e.g., calorimetric cages), both sexes displayed reduced food intake and body weight, with males also exhibiting elevated circulating corticosterone. Behavioral assessments of novelty responses revealed sex-specific differences: male KO mice entered novel zones more rapidly, reflecting increased exploratory behavior, while female KO mice showed decreased entries into the light zone and central food area, indicative of heightened anxiety or stress-related avoidance.
Altogether, our findings indicate that astrocytic Cdk4 regulates energy homeostasis in a sex and diet-specific manner and contributes to behavioral adaptation to novel or mildly stressful environments. Ongoing studies aim to identify hypothalamic regions exhibiting altered astrocyte number or morphology (immunofluorescence) and characterizing molecular pathways affected by Cdk4 loss (single-cell RNA sequencing). Future studies will selectively delete Cdk4 in astrocytes of specific hypothalamic nuclei using viral vectors and investigate the underlying mechanisms in vitro through primary hypothalamic astrocyte cultures.