Biology subjects

Belaidouni, Y.

Publications and source records attributed to Belaidouni, Y..

3 recordsLinked to original sources

bioRxiv2025

Single-Nucleus Analysis of Human White Adipose Tissue Reveals Adipocyte Subsets with Distinct Metabolic Profiles

Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis revealed 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAThi vs. ADIPOMATlo). ADIPOMATlo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMATlo were more abundant in higher BMI donors, while SAT-resident ADIPOMATlo associated with impaired glycemia. TSHZ3 was identified as a candidate regulator of ADIPOMATlo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibited differentiation, with downregulation of early adipogenic regulators (e.g. CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduced SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.

cell biology↗

bioRxiv2023

Leptin antagonism improves Rett syndrome phenotype in symptomatic male Mecp2-null mice.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by mutations in MECP2. Elevated circulating levels of the adipocyte hormone leptin are consistently observed in patients and in mouse models, yet their contribution to disease progression has remained unclear. Here, we show that reducing leptin signaling--either pharmacologically or genetically-- significantly alleviates RTT-like phenotypes in Mecp2-deficient mice. In males, these interventions preserved general health, prevented weight loss, and improved breathing and locomotor functions. At the neuronal level, they restored excitatory/inhibitory balance in the hippocampus and somatosensory cortex and rescued hippocampal synaptic plasticity. In females, delaying the pathological rise of leptin levels postponed symptom progression. These findings uncover leptin as a key contributor to RTT pathophysiology and position leptin-targeted interventions as a promising therapeutic strategy for this currently untreatable disorder.

neuroscience↗

bioRxiv2021

Targeted Tshz3 deletion in corticostriatal circuit components segregates core autistic behaviors

We previously linked TSHZ3 haploinsufficiency to autism spectrum disorder (ASD) and showed that embryonic or postnatal Tshz3 deletion in mice results in behavioral traits relevant to the two core domains of ASD, namely social interaction deficits and repetitive behaviors. Here, we provide evidence that cortical projection neurons (CPNs) and striatal cholinergic interneurons (SCINs) are two main and complementary players in the TSHZ3-linked ASD syndrome. We show that in the cerebral cortex, TSHZ3 is expressed in CPNs and in a proportion of GABA interneurons, while not in cholinergic interneurons or glial cells. TSHZ3-expressing cells, which are predominantly SCINs in the striatum, represent a low proportion of neurons in the ascending cholinergic projection system. We then characterized two new conditional knockout (cKO) models generated by crossing Tshz3flox/flox with Emx1-Cre (Emx1-cKO) or Chat-Cre (Chat-cKO) mice to decipher the respective role of CPNs and SCINs. Emx1-cKO mice show altered excitatory synaptic transmission onto CPNs and plasticity at corticostriatal synapses, with neither cortical neuron loss nor impaired layer distribution. These animals present social interaction deficits but no repetitive patterns of behavior. Chat-cKO mice exhibit no loss of SCINs but changes in the electrophysiological properties of these interneurons, associated with repetitive patterns of behavior without social interaction deficits. Therefore, dysfunction in either CPNs or SCINs segregates with a distinct ASD behavioral trait. These findings provide novel insights onto the implication of the corticostriatal circuitry in ASD by revealing an unexpected neuronal dichotomy in the biological background of the two core behavioral domains of this disorder.

neuroscience↗