Biology subjects

Sebag, S. C.

Publications and source records attributed to Sebag, S. C..

2 recordsLinked to original sources

bioRxiv2025

Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging elevates BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved age-related BAT senescence, metabolic decline, and cognitive dysfunction. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging. HighlightsO_LIAging elevates general protein S-nitrosylation while downregulating ADH5 expression in BAT. C_LIO_LILoss of thermogenic adipose tissue ADH5 accelerates BAT senescence and exacerbates aging-associated metabolic and cognitive dysfunctions. C_LIO_LIDisruption of HSF1-activated Adh5 in BAT contributes to aging-associated metabolic and cognitive impairments. C_LIO_LIPharmacological targeting of BAT HSF1 alleviates aging-related BAT senescent and systemic declines. C_LI

physiology↗

bioRxiv2020

ADH5-mediated NO Bioactivity Maintains Metabolic Homeostasis in Brown Adipose Tissue

Brown adipose tissue (BAT) thermogenic activity is tightly regulated by cellular redox status but the molecular mechanisms underlying this regulation are incompletely understood. Protein S-nitrosylation, the nitric oxide-mediated cysteine thiol modification of proteins, plays important roles in cellular redox regulation. Here we show that both diet-induced obesity (DIO) and acute cold exposure elevates protein S-nitrosylation of BAT proteins, including UCP1, to regulate thermogenesis. This effect in BAT is regulated largely by S-nitrosoglutathione reductase (GSNOR, ADH5), a denitrosylase that balances the intracellular nitroso-redox status. Loss of ADH5 specifically in BAT impairs UCP1-dependent thermogenesis during acute cold challenge and worsens metabolic dysfunction during diet-induced obesity. Mechanistically, we demonstrate that Adh5 expression in BAT is controlled by the transcription factor heat shock factor 1 (HSF1) and administration of an HSF1 activator to the BAT of mice with DIO increased Adh5 expression and significantly improved UCP1-mediated mitochondrial respiration. Together, these data demonstrate that ADH5 controls BAT nitroso-redox homeostasis to regulate adipose thermogenesis which may be therapeutically targeted to improve metabolic health. HighlightsO_LIThermogenesis induces protein S-nitrosylation modification in the BAT; C_LIO_LIADH5, a major cellular denitrosylase, is required for maintaining BAT metabolic homeostasis under both overnutrition and cold stress conditions; C_LIO_LIDiet-induced obesity suppresses HSF1-mediated activation of Adh5 in the BAT; C_LIO_LIADH5 overexpression in BAT improves whole-body glucose homeostasis in obesity. C_LI

molecular biology↗