Biology subjects

Panic, V.

Publications and source records attributed to Panic, V..

3 recordsLinked to original sources

bioRxiv2025

Mapping the Glycogen Synthase 1 Interactome in Brown Adipocytes

Brown adipose tissue (BAT) is distinguished by its ability to dissipate energy through thermogenesis, a process with considerable therapeutic potential for obesity, type 2 diabetes, and related metabolic disorders. Although glycogen represents a relatively minor energy reserve in adipocytes compared with liver and muscle, emerging evidence shows that glycogen turnover increases sharply during metabolic transitions and is required for full thermogenic activation in brown adipocytes. The rate-limiting enzyme glycogen synthase 1 (GYS1) catalyzes glycogen chain elongation, and adipose-specific Gys1 deletion impairs adaptive thermogenesis, highlighting the importance of GYS1 in coordinating glucose and lipid metabolism; however, the mechanisms regulating GYS1 in BAT remain poorly defined. To address this gap, we used an unbiased proximity-labeling strategy in brown adipocytes by fusing GYS1 to the biotin ligase TurboID and identifying biotinylated proteins through mass spectrometry, revealing 425 putative interactors. These included canonical glycogen-handling proteins such as glycogenin and glycogen phosphorylase, validating the approach, while gene ontology analysis uncovered broader enrichment in cytoskeletal remodeling, vesicle trafficking, and transcriptional regulation, suggesting previously unrecognized roles for GYS1 beyond glycogen synthesis. Notably, we identified several novel candidate interactors, including CAST, PDAP1, and CCDC102A. Together, these findings define the most comprehensive GYS1 interactome reported to date and provide new insights into the molecular mechanisms linking glycogen metabolism to thermogenic function in BAT.

biochemistry↗

bioRxiv2022

Mitochondrial Phosphatidylethanolamine Directly Regulates UCP1 to Promote Brown Adipose Thermogenesis

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of ATP synthase. Here we provide evidence that mitochondrial phosphatidylethanolamine (PE) directly regulates UCP1-dependent proton conductance across IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to {beta}3 adrenergic receptor agonist-induced increase in whole-body oxygen consumption. High-resolution respirometry and fluorometry of BAT mitochondria showed that loss of mitochondrial PE specifically lowers UCP1-dependent respiration without compromising electron transfer efficiency or ATP synthesis. These findings were confirmed by a reduction in UCP1 proton current in PSD-deficient mitoplasts. Thus, PE performs a previously unknown role as a temperature-responsive rheostat that regulates UCP1-dependent thermogenesis.

biochemistry↗

bioRxiv2019

Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis

Brown adipose tissue (BAT) is composed of thermogenic cells that convert chemical energy into heat to help maintain a constant body temperature and counteract metabolic disease in mammals. The metabolic adaptations required for thermogenesis are not fully understood. Here we explore how steady state levels of metabolic intermediates are altered in brown adipose tissue in response to cold exposure. Transcriptome and metabolome analysis revealed changes in pathways involved in amino acid, glucose, and TCA cycle metabolism. Using isotopic labeling experiments, we found that activated brown adipocytes increased labeling of pyruvate and TCA cycle intermediates from U13C-glucose. Although glucose oxidation has been implicated as being essential for thermogenesis, its requirement for efficient thermogenesis has not been directly tested. Here we show that mitochondrial pyruvate uptake is essential for optimal thermogenesis, as conditional deletion of Mpc1 in brown adipocytes leads to impaired cold adaptation. Isotopic labeling experiments using U13C-glucose showed that loss of MPC1 led to impaired labeling of TCA cycle intermediates, while labeling of glycolytic intermediates was unchanged. Loss of MPC1 in BAT increased 3-hydroxybutyrate levels in blood and BAT in response to the cold, suggesting that ketogenesis provides an alternative fuel source that partially compensates for impaired mitochondrial oxidation of cytosolic pyruvate. Collectively, these studies highlight that complete glucose oxidation is essential for optimal brown fat thermogenesis.

biochemistry↗