{"doi":"10.20381/ruor-24489","title":"New Advances in Our Understanding of the Control and Functions of Brown Adipose Tissue Thermogenesis","abstract":"Brown adipose tissue (BAT) generates heat in a process referred to as non-shivering thermogenesis (NST). The process is dependent on the proton leak activity of uncoupling protein1 (UCP1), a protein found in the mitochondrial inner membrane. Physiologically, NST is activated by environmental cold, and to a lesser extent, diet. NST is an energetically costly process, and thus activated BAT consumes remarkable amounts of fatty acids and glucose, which positively influences systemic metabolism. Studies in mice have shown that defective BAT activity can contribute to the development of obesity, and increased BAT activity can protect against obesity. In humans, amounts of BAT are highest in newborns, and atrophy with age. BAT is also a secretory organ that releases ‘batokines’ and other signaling molecules, some of which are in small extracellular vesicels (sEV). The latter may act on BAT itself in a autocrine fashion, or on other tissues in an endocrine fashion, which may also contribute to the systemic effect of BAT activity. The overall aim of my Ph.D. thesis was to elucidate molecular mechanisms controlling BAT activity and its regulatory effects on other tissues/cells. In my first project, the deacetylation control of BAT activity was studied in mice. Mitochondrial deacetylation is mainly mediated by Sirtuin 3 (SIRT3). Previous studies showed that cold increases the transcript level of SIRT3 in BAT, and that fasted Sirt3 knockout (Sirt3KO) mice are cold intolerant, suggesting a potential thermoregulatory role of SIRT3. However, the molecular mechanisms by which SIRT3 regulates BAT thermogenesis are not fully understood. Here, we examined functional links between SIRT3 and UCP1. To study this, wild-type (WT) and Sirt3KO mice were used to perform physiological, molecular, and proteomic analyses of BAT when it is activated by cold or by the β3-adrenergic agonist, CL316,243. Our findings indicated that the absence of SIRT3 in ad libitum fed mice led to impaired use of BAT lipid droplets, defective thermoregulation and decreased BAT mitochondrial respiration, without affecting the expression of UCP1. Label-free mass spectrometry revealed that the absence of SIRT3 increased the acetylation status of several BAT mitochondrial proteins including UCP1 and proteins involved in crucial pathways upstream of UCP1, such as the complexes of the electron transport chain (ETC) and acylcarnitine/fatty acid oxidation (FAO) metabolism. Therefore, we next examined the effect of hyperacetylated sites found in those BAT mitochondrial proteins on their functions. Mutagenesis work conducted in a cellular model revealed that SIRT3-regulated acetylation sites on UCP1 did not impact proton leak respiration when UCP1 was activated. However, analysis of acylcarnitines in the blood showed that the absence of SIRT3 resulted in a decrease in the levels of selected medium-chain and long-chain acylcarnitines. Additionally, functional analysis of ETC complexes in BAT mitochondria demonstrated that the absence of SIRT3 decreased the activities of complex I and complex II (CI and CII), which could impair the production of proton motive force, required for the activity of UCP1. Altogether our results indicate that SIRT3 regulates BAT thermogenesis indirectly by targeting proteins involved in crucial pathways upstream of UCP1. In my second project, we studied the metabolic response of BAT to hypoxia in naked mole rats (NMRs). NMRs are exceptionally tolerant to hypoxic environments; during acute hypoxia their body temperature is decreased nearly to the ambient temperature. The underlying mechanisms of these observations are not well understood. We hypothesized that BAT activity in NMRs is decreased during hypoxia. To study this, NMRs were exposed to normoxia (21% O2/1hr), hypoxia (7% O2/1hr), or hypoxia followed by recovery (21% O2/1hr). Thermal imaging, body temperature measurements, thermogenic protein and overall protein ubiquitination levels, and mitochondrial mo","journal":"uO Research (University of Ottawa)","year":2020,"id":126526,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":573999,"name":"Rajaa Sebaa","orcid":"0000-0003-3638-8716","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:15:23.509897Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}