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Dynamics and Heterogeneity of Hypothalamus and White Adipose Tissue under Internal and External Cues

Abstract

The hypothalamus and the white adipose tissue are both key regulator of energy homeostasis. The hypothalamus is the central hub in metabolic control and links the neuronal, endocrine, and metabolic systems. White adipose tissue (WAT) is highly metabolically dynamic and has emerged as a multifaceted endocrine organ with crucial roles in energy metabolism. Characterized by cell type heterogeneity, these key metabolic tissues exhibit complex cell-type-specific dynamics in response to numerous factors, including age, sex, nutritional state, and pharmacological interventions. Discerning the impacts of these factors broadens our understanding of how metabolic tissue dynamics are shaped and their implications for the development of metabolic disorders. This knowledge further holds promise for the advent of personalized therapeutic strategies. Our research commences by probing the influences of the sex chromosome effect (SCE) and gonadal sex effect (GSE) at a cellular level in the hypothalamus, employing the Four Core Genotypes (FCG) mouse model and single-cell RNA sequencing (scRNA-seq). Analyses of SCE, GSE, and SCE-GSE interactions show that they contribute over 70% of the genetically determined normative sex differences across all hypothalamic cell types and neuronal subtypes. Notably, enrichment analyses of Genome-Wide Association Study (GWAS) signals of these sex factor-specific differentially expressed genes (DEGs) highlight their relevance to neurological disorders, obesity, and Type 2 diabetes. Therefore, the comprehensive understanding of cell types and pathways underlying sex-specific risks paves the way for sex-based personalized therapies. Next, we turn our attention to aging and its effects on WAT. Our findings unveil a surprising age-induced surge in adipogenesis, particularly in visceral fat. Contrary to the conventional age-associated decline in stem cell activity, we reveal that adipocyte progenitor cells (APCs) enhance their adipogenic potential during aging. We identify and characterize a novel Committed Preadipocyte population uniquely enriched in aged mice (CP-A) through scRNA-seq, showcasing high proliferation and adipogenesis activity. Furthermore, we delineate Leukemia Inhibitory Factor Receptor (LIFR) as a functional marker of CP-A, thereby uncovering a novel mechanism pertinent to fat tissue aging with potential clinical implications for age-related metabolic disorders. Lastly, we elucidate the effects of the PPARγ activator rosiglitazone on WAT remodeling and cellular reprogramming in obesity. We demonstrate rosiglitazone's profound influences on adipogenesis, gene expression modulation in epididymal white adipose tissue (eWAT) and inguinal white adipose tissue (iWAT) progenitor cells and preadipocytes, inflammation mitigation, and the promotion of ATP synthesis and ribosome biogenesis. Interestingly, our data suggest a potential role of PPARγ in enhancing ribosome biogenesis efficiency, a facet that merits future exploration. In summary, our studies underscore the importance of understanding the varying metabolic processes and cellular dynamics across metabolic tissues under the influence of internal and external cues, including age, sex, nutritional state, and pharmacological intervention. The delineation of the precise cell types and molecular mechanisms underlying health modulating factors will bolster target identification and pave the way for personalized therapeutic interventions.

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