Search Results (168)

Adipose tissue (AT) browning is an inducible cellular phenomenon that promotes lipid oxidation to increase energy expenditure, reducing adiposity. Various transcription regulators involved in the AT browning process have been reported, but their complex molecular mechanisms remain poorly understood. Here, we explore the effects of SIRT7, one of seven mammalian sirtuins, on AT browning and elucidate the underlying mechanisms. SIRT7 deficiency increased the expression of browning genes in beige adipocytes differentiated from subcutaneous white AT (scWAT) stromal vascular fraction (SVF) cells isolated from adipocyte-specific Sirt7 knockout (Sirt7 AdKO) mice. The effect of SIRT7 on beige adipocyte differentiation was confirmed in Sirt7 knockdown (KD) mouse scWAT and human supraclavicular brown AT (scBAT) SVF cell lines. Mechanistically, SIRT7 deacetylated PPARγ2 (peroxisome proliferator-activated receptor γ2) at lysine (K) 382, thereby attenuating interaction with the transcriptional coactivator PRDM16 (PR domain-containing 16). In differentiated beige adipocytes, the acetylation-mimicking mutant PPARγ2^K382Q had higher transcriptional activity compared with the deacetylation-mimicking mutant PPARγ2^K382R. Furthermore, the interaction between endogenous SIRT7 and PPARγ2 decreased at the onset of beige adipocyte differentiation. Our findings reveal that SIRT7 is an important thermogenic regulator that puts the brake on AT browning by deacetylating PPARγ2. Full article

Background/Objectives: Promoting white adipose tissue (WAT) browning into thermogenic beige adipocytes is a promising anti-obesity strategy. Yanggyeoksanhwa-tang (YST) has been used traditionally to alleviate obesity-related conditions. Catalpol and rhoifolin are major bioactive components of Rehmannia glutinosa (Gaertn.) and Lonicera japonica (Thunb.) with known metabolic or anti-inflammatory effects. However, their direct roles in adipocyte browning and the mechanisms via β3-adrenergic receptor (β3-AR) signaling are not well defined, and this study addresses this gap. Methods: To evaluate browning potential, 3T3-L1 adipocytes were treated with catalpol and rhoifolin during differentiation. The expression of browning markers and lipid metabolism or catabolism transcription factors was analyzed using Western blotting and quantitative real-time polymerase chain reaction. The involvement of the β3-AR and adenosine monophosphate–activated protein kinase (AMPK) signaling pathways was further validated using specific agonists and antagonists. Results: Both compound treatments significantly upregulated beige-specific (Cd137, Cited, Tbx1, Cidea, Fgf21, Tmem26) and mitochondrial biogenesis markers (Cox4, Nrf1, Tfam), accompanied by a marked increase in thermogenic markers (UCP1, PGC-1α, Prdm16). Concurrently, lipolysis-related genes such as Atgl, Hsl, and Plin1 were elevated, while lipogenesis targets (Fasn, Lpl, Srebf1, Acaca) were downregulated through activation of the β3-AR signaling pathway. Conclusions: These findings suggest that catalpol and rhoifolin, key phytochemicals of YST, promote WAT browning and lipolysis. Our findings indicate that these compounds induce browning and modulate metabolism via the β3-AR pathway. These results serve as a cornerstone for natural anti-obesity therapy, pending further validation in vivo and clinical studies. Full article

Obesity is a major health crisis that impacts social and economic burdens worldwide, and it is being studied intensively to understand the molecular mechanisms and regulators of this complex condition. Over the past decade, significant insights into adipocyte fate have been gained, demonstrating that adipocyte behavior is influenced by intracellular pathways, systemic mediators, and environmental signals. In this review, we discuss the current understanding of key molecular and functional changes in adipose tissue. We focused on ER–mitochondrial dynamics and their role in beige adipocytes. We examined the biological properties of beige fat cells, including their inflammatory status, redox balance, and regulation of adipocyte transdifferentiation via signaling molecules. Finally, we explored the effects of naturally derived compounds on adipocyte function and their potential to combat obesity using a comprehensive approach. The process of adipocyte beiging induced by coordinated intracellular signaling pathways highlights mechanisms that can reprogram metabolic homeostasis and reduce obesity-related phenotypes. Full article

Direct measurement of thermogenic heat production remains a major challenge in adipose biology. Isothermal microcalorimetry offers a label-free approach to quantify metabolic heat output, yet key parameters governing its application to adipose tissue remain poorly defined. Here, we systematically evaluate the use of the CalScreener isothermal microcalorimetry platform to quantify thermogenic heat production across multiple adipose models, including adipocyte spheroids, freshly isolated adipocytes, and intact adipose tissue explants. Heat production scaled with spheroid size within a defined range and increased linearly with spheroid number per well, demonstrating the quantitative sensitivity of the calorimetric measurements. Pharmacological modulation of mitochondrial respiration in cultured primary beige adipocytes demonstrated that oxidative phosphorylation is a major driver of the calorimetric heat signal, including heat generation associated with mitochondrial proton leak. Freshly isolated adipocytes and intact adipose tissue exhibited depot-specific thermogenic activity and retained responsiveness to β-adrenergic stimulation ex vivo. Across adipose depots, intact tissue explants revealed unexpected differences in thermogenic heat production that were not fully reflected by thermogenic gene expression, highlighting divergence between molecular and functional readouts. Intact adipose tissue maintained measurable thermogenic heat production following extended ex vivo handling in nutrient-containing medium, such that tissues collected across a prolonged harvest window exhibited comparable calorimetric activity, enabling batch analysis of large experimental cohorts. Microcalorimetry further resolved regional differences in thermogenic heat production within the inguinal adipose depot following cold exposure. Together, these findings define key experimental considerations for applying isothermal microcalorimetry to adipose biology and demonstrate its utility for directly quantifying thermogenic metabolism in cells and intact tissues. Full article

Adipose tissues (ATs) are dynamic and heterogeneous organs divided into three distinct categories, including white, beige, and brown ATs. Collectively, they contribute to systemic energy homeostasis in various ways. White adipocytes primarily store excess energy, whereas brown and beige adipocytes dissipate energy as heat through non-shivering thermogenesis. Recent advances in multi-omics technologies have transformed our understanding of adipocyte biology, enabling comprehensive interrogation of transcriptional, epigenetic, proteomic, and metabolomic networks that define adipocyte identity and function. Transcriptomic studies reveal distinct gene signatures underlying thermogenic activation and lineage commitment, while epigenomic profiling highlights regulatory elements that orchestrate adipocyte plasticity, particularly the inducible browning of white fat. Proteomic and metabolomic analyses further uncover mitochondrial remodeling, lipid turnover pathways, and metabolite, hormone interactions that regulate thermogenic capacity and metabolic health. Integrating these multi-layered datasets provides systems-level insights into the roles of environmental cues, such as diet and temperature, and endogenous factors, including hormonal signaling, circadian rhythms, and genetic background, in reshaping adipocyte phenotypes and influencing whole-body metabolism. Multi-omics approaches are increasingly identifying potential novel biomarkers and therapeutic targets aiming to enhance the activity of brown and beige adipocyte to combat obesity and metabolic disorders. Overall, these technologies provide a powerful framework for elucidating the complexity of ATs and advancing precision strategies for metabolic disease management and prevention. Full article

Obesity, driven by chronic energy imbalance, has become a major global health burden and is strongly associated with metabolic disorders, including diabetes, hypertension, and cardiovascular disease. Conventional pharmacotherapies often exhibit limited long-term efficacy and are accompanied by undesirable side effects, highlighting the urgent need for safer and more sustainable strategies. Browning of White adipose tissue (WAT)—a process in which white adipocytes acquire brown fat-like thermogenic characteristics—has emerged as a promising approach to enhance energy expenditure and counteract obesity. Increasing evidence demonstrates that various diets and naturally occurring dietary bioactive compounds can effectively induce WAT browning through diverse molecular pathways. Among these, AMPK-, PPAR-, SIRT-, TRP channel-, β3-adrenergic-, and FGF21-related signaling cascades represent the major regulatory hubs linked to mitochondrial biogenesis, lipid metabolism, and thermogenesis. This review summarizes recent advances in diet-induced WAT browning, with particular emphasis on key dietary ingredients, their molecular targets, mechanistic pathways, and metabolic benefits. By integrating findings from in vitro studies, animal models, and emerging translational research, we provide updated insights that may guide the development of novel nutritional interventions, functional foods, and therapeutic strategies for obesity prevention and management. Full article

Adipocyte browning refers to the inducible transdifferentiation or de novo recruitment of thermogenically active beige adipocytes within white adipose tissue depots. Beige adipocytes, characterized by multilocular lipid droplets and high mitochondrial density, express uncoupling protein 1 and possess a metabolic phenotype similar to that of classical brown adipocytes. This plasticity of adipose tissue is regulated by a complex network of transcriptional coactivators (e.g., PRDM16, PGC-1α), epigenetic modulators, non-coding RNAs, and hormonal signals. Environmental cues, such as chronic cold exposure, exercise, and caloric restriction, further potentiate browning via sympathetic nervous system activation and endocrine crosstalk. At the systemic level, adipocyte browning enhances energy expenditure, improves insulin sensitivity, and mitigates lipid accumulation, making it a promising target for the treatment of obesity, type 2 diabetes mellitus, and other metabolic syndromes. Several browning agents (natural products and repositioned drugs) and novel chemicals that induce browning have been reported. However, the translational application of these agents in humans faces challenges related to interspecies differences, depot-specific responses, and long-term safety. This review critically examines molecular regulators, existing browning agents, and the discovery of novel browning agents, with the aim of harnessing them for metabolic disease intervention. Full article

Type 2 diabetes mellitus (T2DM) is characterized not only by chronic hyperglycemia but also by profound adipose tissue dysfunction, including impaired lipid handling, low-grade inflammation, mitochondrial dysfunction, and extracellular matrix (ECM) remodeling. These adipose tissue alterations play a central role in the development of systemic insulin resistance, ectopic lipid accumulation, and cardiometabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), particularly semaglutide, have emerged as highly effective therapies for T2DM and obesity. While their glucose-lowering and appetite-suppressive effects are well established, accumulating evidence indicates that semaglutide exerts pleiotropic metabolic actions that extend beyond glycemic control, with adipose tissue representing a key target organ. This review synthesizes current preclinical and clinical evidence on the molecular and cellular mechanisms through which semaglutide modulates adipose tissue biology in T2DM. We discuss depot-specific effects on visceral and subcutaneous adipose tissue, regulation of adipocyte lipid metabolism and lipolysis, enhancement of mitochondrial biogenesis and oxidative capacity, induction of beige adipocyte programming, modulation of adipokine and cytokine secretion, immunometabolic remodeling, and attenuation of adipose tissue fibrosis and ECM stiffness. Collectively, available data indicate that semaglutide promotes a functional shift in adipose tissue from a pro-inflammatory, lipid-storing phenotype toward a more oxidative, insulin-sensitive, and metabolically flexible state. These adipose-centered adaptations likely contribute to improvements in systemic insulin sensitivity, reduction in ectopic fat deposition, and attenuation of cardiometabolic risk observed in patients with T2DM. Despite compelling mechanistic insights, much of the current evidence derives from animal models or in vitro systems. Human adipose tissue-focused studies integrating molecular profiling, advanced imaging, and longitudinal clinical data are therefore needed to fully elucidate the extra-glycemic actions of semaglutide and to translate these findings into adipose-targeted therapeutic strategies. Full article

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states. Full article

Brown adipose tissue (BAT) and beige adipocytes play a crucial role in adaptive thermogenesis, primarily via uncoupling protein 1 (UCP1)-driven heat production. Once considered physiologically irrelevant in adults, BAT is now recognized as an active tissue that contributes to energy expenditure and metabolic homeostasis and represents a potential therapeutic target for obesity and metabolic disorders. This review provides an integrated overview of the molecular regulation of thermogenic adipocytes, emphasizing both canonical UCP1-dependent as well as non-canonical UCP1-independent mechanisms of heat generation. Key transcriptional and epigenetic regulators are discussed in the context of mitochondrial biogenesis, substrate utilization, and thermogenic gene programs. Major upstream signaling routes are further summarized, encompassing classical β-adrenergic pathways, as well as alternative regulatory nodes including AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) together with diverse nutrient- and hormone-responsive cues that converge to activate brown and beige adipocytes. Finally, the cross-talk among neuronal, endocrine, immune, and gut microbiota-derived signals is highlighted as a key determinant of thermogenic adipocyte function. Together, these multilayered regulatory inputs provide a comprehensive framework for understanding how thermogenic adipose tissue integrates environmental, metabolic, and microbial cues to regulate systemic energy balance—knowledge that is essential for developing targeted therapies to combat obesity and metabolic diseases. Full article

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

Metabolic reprogramming allows cancer cells to proliferate rapidly, survive nutrient limitation, and resist stress, making tumor metabolism an important therapeutic target. However, pharmacological inhibition of metabolic enzymes often causes systemic toxicity and compensatory pathway activation. To overcome these limitations, recent studies have highlighted an alternative host-centered strategy based on increasing systemic energy expenditure. Recent studies highlight an alternative strategy in which the host increases energy expenditure through uncoupling protein 1 (UCP1) dependent thermogenesis, thereby lowering systemic glucose, fatty acid, and nucleotide availability for tumors. Engineered beige adipocytes overexpressing UCP1, PR domain-containing protein 16 (PRDM16), or peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A/PGC1A) suppress tumor growth through nutrient competition, suggesting that activating endogenous UCP1 may provide a non-genetic and physiologically aligned anticancer approach. Building on this concept, natural products such as polyphenols, terpenoids, alkaloids, and carotenoids have emerged as promising UCP1 activators that stimulate beige and brown adipocyte thermogenesis through pathways involving AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC1A, PRDM16, and mitochondrial biogenesis. In parallel, computational studies further indicate that several plant-derived compounds bind directly to the central cavity of UCP1 with high affinity, offering structural support for their thermogenic action. Importantly, many of these compounds also inhibit cancer cell intrinsic metabolism by reducing glycolysis, oxidative phosphorylation, lipid synthesis, and amino acid dependent anaplerosis. This review integrates UCP1 biology, natural product mediated thermogenesis, molecular docking evidence, and tumor metabolic suppression, proposing a unified framework in which natural compounds impose coordinated metabolic pressure on cancer through both adipocyte-driven nutrient competition and direct inhibition of tumor metabolism. Full article

Recent studies have demonstrated that the abundance of brown adipose tissue is inversely associated with obesity in humans. Promoting the browning of white adipocytes therefore represents a promising therapeutic strategy for obesity treatment. LncRNAs are known regulators of adipocyte differentiation and metabolic processes. However, their specific roles in adipocyte browning remain poorly characterized. In this study, we performed transcriptomic analyses using publicly available RNA-seq datasets of mouse white, brown and beige adipose tissues from the EMBL-EBI database. Our analytical workflow included raw data quality control, alignment to the reference genome, transcript assembly, coding potential assessment and differential expression analysis. Functional annotation was conducted through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Key lncRNAs were further validated via Reverse Transcription Quantitative PCR (RT-qPCR). We identified 794 novel lncRNAs and 1499 DEGs, among which 95 were common across all three adipocyte types. Two lncRNAs, MSTRG.12661 and MSTRG.17758, were found to be closely related to critical biological processes, including extracellular matrix organization and fatty acid oxidation. Functional prediction suggests their potential involvement in adipocyte type-specific differentiation. In conclusion, our study reveals novel lncRNAs that may regulate adipocyte differentiation, offering new candidate targets for obesity treatment via induction of white adipose tissue browning. Full article

Brown adipose tissue (BAT) has emerged as a promising therapeutic target for metabolic disorders such as type 2 diabetes and obesity. To advance research on BAT activation and elucidate the mechanisms underlying adipogenesis, it is crucial to develop a reliable in vitro model. This study aimed to optimize the differentiation of adipose-derived stem cells (ADSCs) into beige adipocytes and to validate the protocol using primary human ADSCs obtained from eight donors. Protocol optimization was first performed with commercial ADSCs, testing more than 30 combinations of adipogenic conditions. Differentiation was assessed by microscopy, Oil Red O staining, and uncoupling protein 1 (UCP1) expression via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot. Among the key adipogenic factors, rosiglitazone proved more effective than indomethacin. Extending the induction phase from 4 to 8 days and maintaining dexamethasone throughout the culture markedly enhanced differentiation efficiency. Serum concentration above 5% was inhibitory, while optimal conditions were identified as 5 μM rosiglitazone and 20 μg/mL insulin. The optimized protocol successfully induced beige adipogenesis in ADSCs from eight independent donors, though efficiency varied considerably which could be attributed to individual donor variability. These findings provide a robust in vitro model for studying beige fat biology and highlight the relevance of personalized approaches in metabolic research. Full article

Background: The browning of white adipose tissue for thermogenesis is an effective strategy for combating obesity. The formation of beige adipocytes is reversible, making their maintenance a key therapeutic target. Rutin has been shown to promote the transition from white to beige adipocytes. It remains unclear whether rutin can prevent the reversion of beige adipocytes to white adipocytes and what mechanisms underlie this process. Objectives: This study aims to determine whether rutin can sustain the thermogenic phenotype of beige adipocytes and to elucidate its mechanism. Methods: We established a beige adipocyte model with CL-316, 243(CL) in vitro. A white adipocyte model was created by CL withdrawal after 3 days. Then, we conducted a co-intervention with CL and rutin, as well as sustained rutin intervention on beige adipocytes following CL withdrawal. In vivo, we utilized a C57BL/6 mouse model, including ND, high-fat diet (HFD), and HFD + Rutin groups. The mice were further divided into Cold and −Cold groups, with the former undergoing 7 days of exposure to 4 °C and the latter experiencing 10 days of 22–24 °C. Rutin was administered continuously until the conclusion of the experiment. Results: Rutin consistently ameliorates metabolic disorders and prevents the expansion of adipose tissue. It concomitantly suppresses mitochondrial autophagy during beige induction, upregulates thermogenic markers in brown adipocytes, and safeguards the mitochondrial-related functional indicators. Conclusions: In summary, rutin obstructs the transformation of beige adipocytes into white adipocytes and concomitantly suppresses mitochondrial autophagy, thereby continuously improving obesity induced by a high-fat diet. Full article