Biology subjects

Giorgi, M.

Publications and source records attributed to Giorgi, M..

4 recordsLinked to original sources

bioRxiv2025

Pde5a Deficiency Prevents Diet-Induced Obesity via Adipose cAMP-PKA Activation Enhancing Fat Browning

Cyclic nucleotides are critical regulators of adaptive thermogenesis and adipogenesis, with their intracellular levels finely tuned by phosphodiesterases. Phosphodiesterase type 5 (PDE5A) modulates cyclic guanosine monophosphate levels in adipocytes. While PDE5A inhibition has shown promise in patients with diabetes, its role in metabolism remains unclear. Using Pde5a knockout mouse models, we demonstrated that mice lacking Pde5a exhibit enhanced browning of white adipose tissue and reduced hepatic fat content. Following high-fat diet, Pde5a-/- mice are resistant to obesity, displaying improved glucose metabolism and enhanced thermogenesis. These protective effects stem from an early developmental knockdown of Pde5a, leading to a metabolic reprogramming driven by cAMP-PKA pathway activation. The convergence of cGMP and cAMP signaling orchestrates thermogenic and systemic metabolic adaptations. Our findings establish PDE5A as a novel regulator of energy homeostasis, suggesting its inhibition as a valuable adjuvant therapy for metabolic disorders.

cell biology↗

bioRxiv2023

Defects in AMPAR trafficking and microglia activation underlie socio-cognitive deficits associated to decreased expression of Phosphodiesterase 2A

Phosphodiesterase 2A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/- mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/- females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of GluR1 in CA1, producing reduced mGluR-dependent LTD. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer Disease, schizophrenia, FXS as well as other forms of ASD.

animal behavior and cognition↗

bioRxiv2022

Cellular redox metabolism is modulated by the distinct localization of cyclic nucleotide phosphodiesterase 5A isoforms

3-5 cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionary conserved cAMP and/or cGMP hydrolysing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5, being a regulator of vascular smooth muscle contraction, is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension. Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of MmPDE5A2 for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)+/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors.

cell biology↗

bioRxiv2018

Prenatal growth map of the mouse knee joint by mean of deformable registration technique

Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63[1/4]m) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions were found for both epiphyses (between 0.7 and 1.4 m, along all directions and anatomical sites) for nodal spacing of 1 voxel. The protocol was found to be reproducible with maximum Modified Housdorff Distance differences equal to 1.9 m and 1.5 m for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps by 21.7 m and 21.9 m for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors.

bioengineering↗