Functional redundancy between glucocorticoid and mineralocorticoid receptors in mature corticotropin-releasing hormone neurons protects from obesity.

OBJECTIVE: Here, we aimed to investigate the role of glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) in the regulation of energy homeostasis. METHODS: We used three mouse models with simultaneous deletion of GRs and MRs in either forebrain neurons, the paraventricular nucleus, or corticotropin-releasing hormone (CRH) neurons and compared them with wild-type controls or isolated knockout groups. In addition to body weight, food intake, energy expenditure, insulin sensitivity, fat/lean mass distribution, and plasma corticosterone levels, we also performed transcriptomic analysis of CRH neurons and assessed their response to melanocortinergic stimulation. RESULTS: Similar to global double-knockout models, deletion of GRs and MRs specifically in mature CRH neurons resulted in obesity. Importantly, the latter was accompanied by insulin resistance, but not increased plasma corticosterone levels. Transcriptomic analysis of these neurons revealed upregulation of several genes involved in postsynaptic signal transduction, including the Ptk2b gene, which encodes proline-rich tyrosine kinase 2. Knockout of both nuclear receptors leads to upregulation of Ptk2b in CRH neurons, which results in their diminished responsiveness to melanocortinergic stimulation. CONCLUSIONS: Our data demonstrate the functional redundancy of GRs and MRs in CRH neurons to maintain energy homeostasis and prevent obesity. Simultaneous targeting of both receptors might represent an unprecedented approach to counteract obesity.

SKN-1/NRF2 upregulation by vitamin A is conserved from nematodes to mammals and is critical for lifespan extension in Caenorhabditis elegans.

Vitamin A (VA) is a micronutrient essential for the physiology of many organisms, but its role in longevity and age-related diseases remains unclear. In this work, we used Caenorhabditis elegans to study the impact of various bioactive compounds on lifespan. We demonstrate that VA extends lifespan and reduces lipofuscin and fat accumulation while increasing resistance to heat and oxidative stress. This resistance can be attributed to high levels of detoxifying enzymes called glutathione S-transferases, induced by the transcription factor skinhead-1 (SKN-1). Notably, VA upregulated the transcript levels of skn-1 or its mammalian ortholog NRF2 in both C. elegans, human cells, and liver tissues of mice. Moreover, the loss-of-function genetic models demonstrated a critical involvement of the SKN-1 pathway in longevity extension by VA. Our study thus provides novel insights into the molecular mechanism of anti-aging and anti-oxidative effects of VA, suggesting that this micronutrient could be used for the prevention and/or treatment of age-related disorders.

Neuronal miR-29a protects from obesity in adult mice.

OBJECTIVE: Obesity, a growing threat to the modern society, represents an imbalance of metabolic queues that normally signal to the arcuate hypothalamic nucleus, a critical brain region sensing and regulating energy homeostasis. This is achieved by various neurons many of which developmentally originate from the proopiomelanocortin (POMC)-expressing lineage. Within the mature neurons originating from this lineage, we aimed to identify non-coding genes in control of metabolic function in the adulthood. METHODS: In this work, we used microRNA mimic delivery and POMCCre-dependent CRISPR-Cas9 knock-out strategies in young or aged mice. Importantly, we also used CRISPR guides directing suicide cleavage of Cas9 to limit the off-target effects. RESULTS: Here we found that mature neurons originating from the POMC lineage employ miR-29a to protect against insulin resistance obesity, hyperphagia, decreased energy expenditure and obesity. Moreover, we validated the miR-29 family as a prominent regulator of the PI3K-Akt-mTOR pathway. Within the latter, we identified a direct target of miR-29a-3p, Nras, which was up-regulated in those and only those mature POMCCreCas9 neurons that were effectively transduced by anti-miR-29 CRISPR-equipped construct. Moreover, POMCCre-dependent co-deletion of Nras in mature neurons attenuated miR-29 depletion-induced obesity. CONCLUSIONS: Thus, the first to our knowledge case of in situ Cre-dependent CRISPR-Cas9-mediated knock-out of microRNAs in a specific hypothalamic neuronal population helped us to decipher a critical metabolic circuit in adult mice. This work significantly extends our understanding about the involvement of neuronal microRNAs in homeostatic regulation.