Gut microbiota, brown adipose tissue whitening, and obesity: nutritional modulators and metabolic crosstalk

Abstract

Obesity reflects a chronic imbalance between energy intake and expenditure, accompanied by metabolic inflammation and ectopic lipid deposition. Accumulating evidence indicates that gut microbiota dysbiosis reshapes host nutrient handling and endocrine-immune signaling, with downstream consequences for thermogenic adipose tissues. Brown adipose tissue (BAT) supports energy dissipation via UCP1-dependent adaptive thermogenesis; however, in obesity, BAT often undergoes “whitening,” a maladaptive transition characterized by lipid accumulation, mitochondrial dysfunction, and reduced thermogenic capacity. This review synthesizes mechanistic and translational evidence linking obesity-associated microbiota alterations to BAT dysfunction through integrated gut-adipose and gut-liver communication. We discuss how microbially derived metabolites (including short-chain fatty acids and secondary bile acids), endotoxin-driven inflammation, and bile acid receptor signaling (FXR/TGR5) may converge on sympathetic tone, mitochondrial biogenesis, and lipid flux to favor BAT whitening. We further evaluate nutrition- and lifestyle-based strategies (dietary fiber and polyphenols, exercise, pre/pro/postbiotics, and bile acid-targeted approaches) that modulate microbial ecology and metabolic outputs, with potential to preserve BAT thermogenic identity and improve metabolic health. Clarifying the causal pathways and clinically actionable microbial signatures within this gut-adipose-liver network may inform future nutrition-oriented interventions for obesity and related metabolic disorders.

Introduction

Obesity, metabolic dysregulation, and the role of gut microbiota

Obesity is a global public health challenge determined by a multifactorial interplay of genetic susceptibility, environmental exposures, behavioral patterns, and metabolic adaptations. Obesity involves excessive fat accumulation and ongoing low-grade inflammation. Beyond excess adiposity, obesity is increasingly recognized as a state of chronic, low-grade inflammation that promotes insulin resistance and elevates the risk of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD) [1, 2]. Although sustained positive energy balance remains a proximal determinant, accumulating evidence indicates that host-microbe interactions in the gastrointestinal tract contribute meaningfully to metabolic homeostasis and the trajectory of obesity-related complications [3–5].

The gut microbiota constitutes a dense and metabolically active ecosystem that shapes nutrient processing, energy harvest, lipid handling, and immune-endocrine signalling [6, 7]. Dysbiosis, broadly defined as disruption of microbial diversity, composition, and function, has been repeatedly associated with obesity and its comorbidities. Mechanistically, dysbiotic configurations may increase dietary energy extraction, favor lipogenic pathways, impair satiety and appetite-related hormonal signalling, and compromise intestinal barrier integrity, thereby amplifying systemic inflammatory tone. Importantly, these microbiota-derived influences extend beyond classical metabolic organs and may modulate adipose tissue biology, including the activity of BAT [8–10].

BAT is a specialized thermogenic organ that dissipates energy as heat via mitochondrial uncoupling (primarily through UCP1), thereby contributing to whole-body energy expenditure and glucose–lipid homeostasis. In obesity, however, BAT frequently exhibits a functional and morphological decline characterized by reduced thermogenic signalling, diminished mitochondrial density, and the emergence of enlarged unilocular lipid droplets, a phenotype commonly referred to as BAT whitening [10, 11]. BAT whitening is not merely a histological hallmark; it reflects a shift from an energy-dissipating toward an energy-storing state that can further worsen metabolic inflexibility and facilitate progression of insulin resistance and hepatic steatosis.

Recent studies propose that gut microbiota and their metabolites act as upstream regulators of BAT function through convergent pathways involving inflammatory signalling (e.g., endotoxemia and cytokine networks), neuroendocrine control of sympathetic outflow, and metabolite- and bile acid-dependent receptor signaling that integrates gut, adipose tissue, and liver physiology [12]. Nevertheless, a key unresolved issue is whether microbiota alterations actively drive BAT whitening as a causal component of obesity pathogenesis, or whether they predominantly mirror established metabolic dysfunction. Clarifying this directionality and mapping the intermediates that connect the gut to BAT and liver, has substantial therapeutic relevance.

In this review, we synthesize emerging evidence linking gut microbial dysregulation to obesity-associated BAT whitening, with an emphasis on mechanistic crosstalk across the gut-adipose and gut-liver axes. We highlight microbe-derived metabolites and bile acid signaling as integrative nodes, discuss inflammatory and neuroendocrine pathways that suppress thermogenic programs, and evaluate lifestyle and microbiota-targeted interventions that may preserve or restore BAT function. By framing BAT whitening within a multi-organ communication network, we aim to identify tractable targets and translational considerations for developing next-generation strategies against obesity and its metabolic sequelae.

Despite substantial progress in microbiome and adipose tissue research, critical gaps remain in defining how gut dysbiosis mechanistically contributes to obesity-related metabolic dysfunction. In particular, BAT whitening is increasingly recognized as a marker of impaired energy dissipation, yet it remains unclear whether microbiota-derived signals actively drive this phenotypic transition or primarily reflect downstream consequences of chronic inflammation and nutrient excess. Moreover, existing studies often address gut microbiota, BAT, and liver metabolism in isolation, limiting mechanistic integration and translational relevance. This review advances an integrative perspective by positioning BAT whitening as a dynamic and potentially reversible node within a coordinated gut-adipose-liver axis. By synthesizing evidence across inflammatory, neuroendocrine, and bile acid-dependent pathways, and by explicitly distinguishing associative from mechanistically supported links, we propose a conceptual framework that highlights microbiota, BAT interactions as actionable targets for restoring thermogenic capacity and metabolic flexibility in obesity.

Gut microbiota dysbiosis in obesity: mechanistic insights and metabolic consequences

The gut microbiota comprises a dense and metabolically active community of trillions of microorganisms that contribute to host physiology through fermentation of dietary fibers, vitamin synthesis, immune modulation, and regulation of energy metabolism. Under healthy conditions, this microbial ecosystem exists in a dynamic mutualistic equilibrium with the host. In obesity, however, this balance is disrupted, leading to gut dysbiosis characterized by reduced microbial diversity, alterations in the Firmicutes-to-Bacteroidetes ratio [13], and an increased abundance of pro-inflammatory microbial taxa [14]. These compositional changes are increasingly recognized as integral components of obesity pathophysiology rather than passive bystanders.

A prominent feature of obesity-related dysbiosis is an enhanced microbial capacity to extract energy from otherwise indigestible dietary polysaccharides, leading to increased production of short-chain fatty acids (SCFAs). Depending on the microbial and metabolic context, SCFAs may either support metabolic homeostasis or contribute to lipid accumulation and energy storage [15]. While SCFAs play essential roles in maintaining gut barrier integrity and exerting anti-inflammatory actions, excessive acetate production, particularly under conditions of microbial imbalance, has been linked to hyperinsulinemia, stimulation of de novo lipogenesis, and increased adiposity. In parallel, dysbiotic microbial communities promote elevated expression of host genes involved in triglyceride synthesis and fatty acid uptake, thereby facilitating lipid accumulation and body weight gain [16–18]. These observations highlight a shift from metabolically adaptive to maladaptive microbe-host interactions under conditions of chronic nutrient excess.

Beyond altered energy harvest, gut dysbiosis contributes to obesity through disruption of intestinal barrier function and activation of systemic inflammation. Increased gut permeability enables translocation of microbial products, most notably lipopolysaccharide (LPS), into the circulation, a process referred to as metabolic endotoxemia. Elevated circulating LPS activates toll-like receptor 4 (TLR4) signaling and induces pro-inflammatory cytokines such as TNF-α and IL-6. This chronic low-grade inflammatory state exacerbates insulin resistance and impairs mitochondrial function in metabolically active tissues, including BAT and skeletal muscle, thereby reducing energy expenditure and thermogenic capacity [19, 20].

Gut dysbiosis further perturbs host metabolism by altering bile acid composition and signaling [21]. Microbiota-driven modifications of the bile acid pool influence activation of the farnesoid X receptor (FXR) and the G protein–coupled bile acid receptor TGR5, both of which play central roles in lipid and glucose homeostasis [22]. Disrupted bile acid signalling contributes to hepatic steatosis and compromises adaptive thermogenesis, in part by attenuating BAT activation. Collectively, these metabolic and inflammatory alterations underscore the complex involvement of gut microbiota in energy balance and fat accumulation, positioning dysbiosis as both a contributor to and a consequence of obesity [23].

As mechanistic insight into host-microbe interactions has expanded, it has become evident that obesity-associated dysbiosis is best defined by reproducible functional signatures rather than isolated taxonomic changes. In a comprehensive meta-analysis, Zhao et al. integrated multi-cohort gut microbiome datasets from thousands of obese and lean individuals and identified consistent microbial alterations linked to obesity. Their analysis revealed a reproducible reduction in microbial diversity in obese subjects, enrichment of genera such as Ruminococcus gnavus, Dorea, and Blautia, and depletion of beneficial taxa including Akkermansia muciniphila, Bifidobacterium adolescentis, and Faecalibacterium prausnitzii. Functional profiling demonstrated upregulation of microbial genes involved in energy harvest, endotoxin biosynthesis, and branched-chain amino acid metabolism, alongside suppression of butyrate-producing and anti-inflammatory pathways. Importantly, these functional signatures were conserved across populations and sequencing platforms, suggesting a universal microbial metabolic shift that reinforces obesity-associated inflammation and energy surplus [24].

Consistent with these findings, a large-scale meta-analysis published in Nature Communications by Qin et al. reanalyzed metagenomic datasets from over 2,000 individuals across multiple diseases. Obesity was consistently associated with reduced microbial gene richness and enrichment of energy-harvesting and pro-inflammatory taxa, including Ruminococcus gnavus and Clostridium symbiosum, alongside depletion of commensals such as Faecalibacterium prausnitzii and Akkermansia muciniphila. Notably, the authors identified a shared “core dysbiosis signature” encompassing pathways related to LPS biosynthesis, amino acid degradation, and oxidative stress responses across metabolic and inflammatory diseases, underscoring the systemic relevance of functional microbial alterations in obesity [25].

Further integrative metagenomic analyses by Yang et al. extended these observations by incorporating bacteriome, virome, and functional pathway profiling. Obese individuals exhibited reduced microbial alpha diversity, enrichment of energy-harvesting and pro-inflammatory taxa (Ruminococcus gnavus, Dorea longicatena, Blautia obeum), and depletion of mucin-degrading and butyrate-producing species such as Akkermansia muciniphila, Roseburia intestinalis, and Faecalibacterium prausnitzii. These compositional shifts were accompanied by upregulation of carbohydrate-active enzymes and lipid biosynthetic pathways and suppression of SCFA-producing routes. Importantly, alterations in bacteriophage populations suggested that viral-bacterial interactions may further destabilize microbial ecosystems in obesity, amplifying dysbiosis and metabolic dysfunction [26].

At the metabolite level, a systematic review by García-Mena et al. synthesizing over 120 human and animal studies demonstrated that obesity-associated dysbiosis is accompanied by profound changes in microbial metabolite profiles. These include reductions in beneficial SCFAs such as butyrate and propionate, alongside elevations in branched-chain amino acids (BCAAs), trimethylamine N-oxide (TMAO), and secondary bile acids. Such metabolic shifts influence lipid and glucose metabolism, insulin sensitivity, and appetite regulation through gut–liver and gut-brain signaling pathways. Reduced SCFA availability compromises intestinal barrier integrity and sustains low-grade inflammation, whereas increased TMAO and secondary bile acids promote oxidative stress and metabolic endotoxemia. Collectively, these findings establish microbial metabolites as key molecular mediators linking gut dysbiosis to systemic metabolic disturbances in obesity [27].

Collectively, the alterations summarized in Table 1 illustrate that obesity-associated gut dysbiosis is defined by coordinated functional shifts rather than isolated taxonomic changes. Expansion of microbial groups with enhanced energy-harvesting and endotoxin-producing capacity coincides with depletion of barrier-protective and anti-inflammatory taxa, thereby promoting systemic inflammation and metabolic inflexibility. These convergent microbial functions bias host metabolism toward lipid storage while impairing thermogenic and mitochondrial pathways in peripheral tissues. Importantly, such functional reprogramming provides a mechanistic link between gut dysbiosis and downstream suppression of BAT activity, creating a permissive environment for BAT whitening. These gut-derived inflammatory mechanisms linking dysbiosis to impaired thermogenic function are schematically summarized in Fig. 1.

Table 1.

Functional organization of gut microbial alterations in obesity

	Microbial Taxa/Phylum	Observed change in obesity	Primary functional role	Associated metabolic effects	Inflammatory consequences
Functional category	Energy harvest and lipogenesis
	Firmicutes	↑ Increased abundance	SCFA production, energy harvest	Increased energy absorption, lipogenesis	Induction of chronic low-grade inflammation via LPS
	Prevotella spp.	↑ in high-carbohydrate diets	Complex carbohydrate metabolism	Increased circulating BCAAs	Altered Th17 cell balance
	Lactobacillus spp.	Variable (↑ in some cases)	Lactic acid production, lipid absorption modulation	Altered lipid uptake and storage	Strain-dependent immune effects

Functional category	Barrier integrity and anti-inflammatory functions
	Akkermansia muciniphila	↓ Decreased abundance	Mucin degradation, gut barrier maintenance	Reduced GLP-1 and PYY secretion, glucose dysregulation	Increased gut-derived endotoxin-driven inflammation
	Faecalibacterium prausnitzii	↓ Decreased abundance	Anti-inflammatory butyrate producer	Loss of anti-inflammatory SCFAs, metabolic regulation	Reduced IL-10 and gut tolerance
	Clostridium cluster XIVa	↓ or altered abundance	Butyrate production, colonocyte energy supply	Reduced fatty acid oxidation, impaired satiety	Reduced Treg stimulation
	Bifidobacterium spp.	↓ Decreased abundance	Acetate/lactate production, immune modulation	Increased insulin resistance, dyslipidemia	Decreased IL-10, increased IL-6 and TNF-α
	Bacteroidetes	↓ Decreased abundance	Fiber fermentation, anti-inflammatory metabolites	Reduced SCFA production, impaired gut barrier	Higher intestinal permeability

Functional category	Endotoxemia and pro-inflammatory expansion
	Enterobacteriaceae (e.g. E. coli)	↑ Blooming in dysbiosis	Opportunistic pathogens, endotoxin release	Promotes insulin resistance and hepatic steatosis	Strong LPS-mediated inflammatory activation
	Desulfovibrio spp.	↑ Increased abundance	Sulfate reduction, hydrogen sulfide production	Mucosal damage, oxidative stress	Promotes intestinal inflammation

Fig. 1.

Gut microbiota-driven inflammatory signaling contributing to brown adipose tissue (BAT) whitening in obesity. Obesity-associated gut dysbiosis promotes increased intestinal permeability and expansion of endotoxin-producing microbial communities, leading to elevated circulating lipopolysaccharide (LPS) and pro-inflammatory cytokines. This state of chronic low-grade systemic inflammation suppresses mitochondrial activity and thermogenic gene expression in BAT, resulting in reduced energy dissipation and a phenotypic shift toward BAT whitening. Solid arrows indicate mechanistically supported pathways

Building on this gut-derived metabolic and inflammatory landscape, the next section focuses on the molecular and cellular mechanisms underlying BAT dysfunction and whitening in obesity.

BAT dysfunction in obesity

Molecular and cellular regulation of BAT thermogenesis

BAT is a specialized thermogenic organ that dissipates chemical energy as heat through non-shivering thermogenesis, a process critically dependent on high mitochondrial content and the expression of uncoupling protein 1 (UCP1). Unlike white adipose tissue, which primarily functions as an energy storage depot, BAT actively contributes to whole-body energy expenditure, thermoregulation, and glucose homeostasis. In adult humans, metabolically active BAT is predominantly localized to the supraclavicular, cervical, and perirenal regions and can be recruited by cold exposure and sympathetic nervous system activation [28].

At the cellular level, BAT thermogenic activity is primarily regulated by β-adrenergic signaling pathways. Upon cold exposure, norepinephrine released from sympathetic nerve terminals activates β3-adrenergic receptors on brown adipocytes, stimulating cyclic AMP (cAMP) production and downstream protein kinase A (PKA) signaling. This cascade promotes phosphorylation of transcriptional regulators such as cAMP response element-binding protein (CREB) and induction of thermogenic gene programs, including Uncoupling Protein 1 (UCP1) expression [29–31]. Maintenance of the brown adipocyte phenotype further relies on transcriptional coactivators such as peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) and PR domain containing 16 (PRDM16), which coordinate mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation [32–34]. Through these tightly regulated molecular networks, BAT sustains high metabolic flexibility and energy-dissipating capacity under physiological conditions.

Mechanisms of BAT whitening in obesity

Collectively, inflammatory, hormonal, vascular, and microbiota-derived mechanisms converge to destabilize brown adipocyte identity and promote the progressive whitening of BAT in obesity.In the context of obesity, BAT undergoes profound functional and structural remodeling that culminates in a marked reduction of thermogenic capacity. Downregulation of thermogenic genes, including Ucp1 and other mitochondrial genes, may facilitate impaired energy dissipation, reduced glucose uptake, and diminished metabolic flexibility. Concomitantly, brown adipocytes exhibit a morphological transition from multilocular to unilocular lipid droplets, a process commonly referred to as BAT whitening. This phenotypic shift reflects a reprogramming from an energy-dissipating toward an energy-storing state and contributes to positive energy balance and systemic metabolic dysfunction [35].

Multiple convergent mechanisms drive BAT dysfunction in obesity. Chronic low-grade inflammation, a hallmark of obesity, suppresses thermogenic gene expression and mitochondrial activity through sustained exposure to pro-inflammatory cytokines such as TNF-α and IL-1β [36–38]. In parallel, insulin and leptin resistance disrupt hypothalamic regulation of sympathetic outflow to BAT, further attenuating thermogenic activation [39, 40]. Structural alterations also play a critical role; obesity induces vascular rarefaction within BAT, resulting in reduced capillary density, local hypoxia, and impaired nutrient and oxygen delivery. These vascular defects exacerbate mitochondrial dysfunction and promote BAT whitening by limiting oxidative capacity and angiogenic signaling [41].

Emerging evidence further implicates gut microbiota, derived metabolites and endotoxins as upstream modulators of BAT activity. Through inflammatory and energy-sensing pathways, microbial signals can blunt thermogenic responsiveness and reinforce the inflammatory milieu that suppresses BAT function [42]. Together, inflammatory, hormonal, vascular, and microbial factors converge to destabilize BAT identity and functionality in obesity.

Evidence from human studies and experimental models

Human imaging studies provide compelling in vivo evidence for the physiological relevance of BAT in metabolic health. Using ^18F-fluorodeoxyglucose positron emission tomography-computed tomography (^18F-FDG PET-CT), Cypess et al. detected cold-activated BAT in 48% (125 of 260) of healthy adults following controlled cold exposure. BAT positivity was more prevalent in younger, leaner, and female individuals and was inversely associated with adiposity-related parameters, including body mass index, body fat mass, and abdominal fat area. Importantly, multivariate analyses demonstrated that BAT was independently associated with lower fasting glucose and HbA1c levels, even after adjustment for age, sex, and body fatness [43]. In contrast, studies in morbidly obese individuals consistently demonstrate a marked reduction in BAT detectability and cold-induced glucose uptake, with metabolically active BAT observed in only a minority of subjects (e.g., 3 of 15 individuals) following cold exposure, underscoring a profound attenuation of BAT thermogenic responsiveness in severe obesity [44].

Experimental models have provided mechanistic insight into both the drivers and reversibility of BAT dysfunction. Aerobic exercise restores BAT thermogenic capacity in diet-induced obese mice by reversing whitening, enhancing mitochondrial density, and upregulating the protein expression of UCP1, PGC-1Α, and PRDM16 [45]. These effects are mediated, at least in part, through cyclooxygenase-2 (COX2)-dependent activation of vascular endothelial growth factor (VEGF) signalling, which improves BAT vascularization and oxygen delivery. Consistently, restoration of angiogenic signalling preserves BAT thermogenic phenotype and systemic glucose tolerance, whereas endothelial dysfunction accelerates BAT inactivation [41].

Beyond inflammation and vascular impairment, recent studies have identified additional immunometabolic pathways contributing to BAT dysfunction. Activation of local coagulation signaling within BAT, particularly through tissue factor–protease-activated receptor 1 (TF-PAR1) pathways, induces mitochondrial dysfunction, inflammatory remodeling, and lipid accumulation in both murine and human BAT [46]. Transcriptomic profiling further reveals extensive inflammatory and fibrotic reprogramming of obese BAT, characterized by coordinated suppression of mitochondrial and thermogenic gene programs alongside activation of immune, hypoxia-responsive, and extracellular matrix remodelling pathways that destabilize brown adipocyte identity [47].

Interventional studies targeting BAT activation highlight both the promise and limitations of BAT-centered therapeutic strategies. Meta-analyses of cold exposure studies in humans demonstrate robust activation of BAT and increased lipid mobilization; however, short-term interventions produce modest or inconsistent improvements in systemic glucose and lipid parameters, particularly in obese individuals with attenuated BAT responsiveness [48]. These findings suggest that sustained, multimodal interventions may be required to overcome obesity-associated constraints on BAT plasticity.

Cellular stress responses and maladaptive remodeling underlying BAT whitening

BAT whitening represents a maladaptive cellular response to sustained metabolic stress in obesity, characterized by a progressive loss of thermogenic identity and a shift toward lipid storage. This process is not merely a passive consequence of reduced energy demand but reflects the activation of stress-responsive pathways that actively dismantle mitochondrial integrity, disrupt lipid handling, and reprogram brown adipocytes toward a white-like phenotype. Understanding these cellular failure mechanisms is critical for defining how obesity converts BAT from an energy-dissipating to an energy-storing tissue [49, 50].

A central driver of BAT whitening is mitochondrial dysfunction. In obesity, chronic nutrient overload, oxidative stress, and inflammatory signaling impair mitochondrial quality control, leading to reduced mitochondrial number, diminished membrane potential, compromised electron transport chain activity, and suppression of thermogenic gene expression, including Ucp1 and Cidea [11, 49]. Damaged mitochondria generate excessive reactive oxygen species (ROS), further amplifying cellular stress and triggering apoptotic or lipogenic differentiation programs [51].Rather than adaptive remodeling, this mitochondrial decline reflects a collapse of oxidative capacity that precedes overt structural whitening.

In addition to mitochondrial dysfunction and autophagic imbalance, disturbed proteostasis represents a major intrinsic stress pathway contributing to BAT whitening. Brown adipocytes rely on efficient protein quality control systems, including chaperone networks, the ubiquitin, proteasome system, and mitochondrial proteases, to preserve mitochondrial integrity and thermogenic competence. When proteostasis is disrupted, misfolded and damaged proteins accumulate within mitochondria, exacerbating oxidative stress and impairing respiratory chain function. This proteotoxic stress further suppresses thermogenic gene expression and accelerates the transition toward a white adipocyte–like phenotype [52].

Concomitant with mitochondrial damage, profound alterations in intracellular lipid metabolism promote lipid droplet expansion and cellular remodeling. Under conditions of nutrient excess, brown adipocytes experience sustained exposure to elevated circulating free fatty acids and triglycerides, exceeding their oxidative capacity. This imbalance contributes to a metabolic shift away from fatty acid oxidation toward lipid storage, characterized by downregulation of genes involved in β-oxidation, such as Cpt1b and Acadm, alongside upregulation of lipogenic enzymes including fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) [51, 53, 54]. The resulting accumulation of large unilocular lipid droplets is a defining morphological feature of BAT whitening and reflects a fundamental reprogramming of cellular energy handling.

Defective vascular support further exacerbates BAT dysfunction during obesity. Using diet-induced obese mouse models, Shimizu et al. demonstrated that BAT whitening is preceded by vascular rarefaction, leading to reduced capillary density, impaired perfusion, and local hypoxia [55]. Hypoxic stress suppresses mitochondrial gene expression, promotes ROS accumulation, and activates mitophagy, accelerating mitochondrial loss. Importantly, restoration of vascularization through VEGF-A signaling rescued mitochondrial content and thermogenic capacity, establishing insufficient vascular supply as a causal contributor to stress-induced BAT remodeling rather than a secondary consequence.

Autophagy-dependent mitochondrial clearance represents another key maladaptive pathway driving BAT whitening. Under thermoneutral conditions, where sympathetic stimulation is minimal, Zhao et al. identified transcription factor EB (TFEB) as a critical mediator of excessive autophagy and mitophagy in brown adipocytes [56]. TFEB activation promoted lysosomal biogenesis and mitochondrial degradation, resulting in lipid droplet expansion and loss of thermogenic capacity. Genetic ablation of Tfeb in brown adipocytes preserved mitochondrial integrity and limited lipid accumulation, demonstrating that dysregulated autophagy actively enforces the whitening phenotype under conditions of reduced energetic demand.

Recent evidence has also uncovered mitochondria–nucleus communication pathways that lock brown adipocytes into a white-like state. Li et al. showed that impaired mitochondrial proteostasis in brown adipocytes lacking the mitochondrial protease CLPP promotes accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) [57]. Elevated D-2HG disrupted α-ketoglutarate–dependent epigenetic enzymes, inducing widespread histone and DNA hypermethylation and altering nuclear architecture. This epigenetic reprogramming weakened nuclear mechanics and promoted lipid droplet expansion, suppressing thermogenic gene expression despite preserved basal respiration. These findings reveal a previously unrecognized epigenetic locking mechanism by which mitochondrial stress irreversibly destabilizes brown adipocyte identity.

Notably, BAT exhibits extreme sensitivity to metabolic stress, even before overt obesity develops. Seoane-Collazo et al. demonstrated that as little as 24 h of high-fat diet exposure induces rapid lipid accumulation and insulin resistance in BAT, without changes in body weight [58]. Early suppression of insulin signalling and glucose uptake preceded transcriptional downregulation of thermogenic genes, indicating that metabolic and structural disturbances initiate BAT dysfunction before canonical markers of whitening become apparent. Prolonged exposure further intensified mitochondrial remodeling, inflammation, and lipid accumulation, reinforcing the progression toward a white-like phenotype.

Long-term obesity amplifies these stress responses into a self-reinforcing degenerative program. In a longitudinal study, Skop et al. showed that chronic high-fat feeding induces progressive mitochondrial loss, vascular regression, inflammatory infiltration, and fibrotic remodeling in BAT [35]. These changes culminate in diminished β-adrenergic responsiveness, impaired cold tolerance, and systemic metabolic inflexibility, confirming that sustained nutrient excess transforms BAT into a dysfunctional energy-storing depot.

Hormonal stressors can further accelerate BAT whitening. Chronic exposure to glucocorticoids, as demonstrated by Liu et al. in rabbit models, induces pronounced BAT lipid accumulation, mitochondrial suppression, and leptin resistance [59]. Disruption of leptin signaling within BAT impaired fatty acid oxidation and mitochondrial activity, synergizing with oxidative stress to promote thermogenic failure. These findings highlight how endocrine stress intersects with cellular damage pathways to enforce BAT inactivation.

Collectively, these studies demonstrate that BAT whitening arises from coordinated cellular stress responses rather than isolated molecular defects. Mitochondrial damage, lipid overload, vascular insufficiency, dysregulated autophagy, inflammatory remodeling, and epigenetic reprogramming converge to dismantle the thermogenic machinery of brown adipocytes. This maladaptive remodeling shifts BAT from an energy-dissipating to an energy-storing phenotype, contributing directly to reduced energy expenditure and metabolic deterioration in obesity. The convergent cellular stress pathways driving BAT whitening and their systemic metabolic consequences are schematically summarized in Fig. 2.

Fig. 2.

Integrative schematic of systemic triggers, cellular stress pathways, and functional outcomes underlying BAT whitening in obesity. (A) External/systemic stressors, including high-fat diet, gut microbiota dysbiosis, chronic low-grade inflammation, and hormonal or drug-induced alterations, initiate metabolic stress signals that impair brown adipose tissue (BAT) function. Microbial-derived lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), and inflammatory cytokines such as IL-6 and TNF-α propagate systemic inflammation and blunt sympathetic activation of BAT. (B) Within BAT, multiple interconnected cellular and molecular processes drive whitening: (a) attenuated sympathetic signaling reduces cAMP/PKA activation and thermogenic gene expression (UCP1, PGC‑1α); (b) mitochondrial dysfunction and ROS accumulation compromise oxidative metabolism; (c) TFEB-mediated autophagy and mitophagy dysregulation enhance mitochondrial clearance; (d) metabolic reprogramming favors lipogenesis (FAS, ACC) over fatty acid oxidation (CPT1β, ACADM); and (e) vascular rarefaction and hypoxia suppress angiogenic (VEGF‑A) and thermogenic gene expression.These maladaptive pathways collectively destabilize brown adipocyte identity and promote morphological conversion from multilocular to unilocular lipid droplets. (C) Functional readouts of BAT whitening include reduced thermogenesis, decreased glucose uptake measured by 18 F‑FDG PET/CT, and lower whole-body energy expenditure (O₂ consumption and CO₂ production). Systemically, BAT dysfunction contributes to insulin resistance, impaired AKT signaling, glucose intolerance, and hepatic steatosis. Together, these interactions link nutrient overload and gut dysbiosis to cellular stress–driven remodeling of BAT and systemic metabolic deterioration.

The gut-adipose axis: microbiota-driven regulation of BAT activity and lipid metabolism

This section integrates metabolic, inflammatory, and neuroendocrine pathways through which gut microbiota-derived signals converge on BAT to regulate thermogenic activity, lipid handling, and susceptibility to whitening in obesity.

The gut-adipose axis has emerged as a central regulatory network linking intestinal microbial ecology to peripheral adipose tissue function and systemic energy homeostasis. This bidirectional axis integrates microbial metabolites, immune mediators, and neuroendocrine signals to fine-tune thermogenesis, lipid handling, and adipocyte fate decisions across brown and white adipose depots. In obesity, dysbiosis-induced disruption of this axis profoundly impairs BAT activity and promotes maladaptive adipose tissue remodeling, thereby facilitating BAT whitening and metabolic inflexibility [12, 60, 61].

Among the most extensively characterized mediators of gut-BAT communication are SCFAs, including acetate, propionate, and butyrate, generated through microbial fermentation of dietary fibers [62–64]. Beyond their role as metabolic substrates, SCFAs function as signaling molecules that activate G-protein-coupled receptors such as GPR41 and GPR43 on adipocytes, immune cells, and peripheral neurons [65, 66]. Experimental evidence demonstrates that butyrate enhances mitochondrial biogenesis and thermogenic gene expression in BAT, including Ucp1 and Pgc-1α, thereby supporting oxidative metabolism and heat production [67, 68]. In parallel, SCFAs engage gut-brain-adipose neural circuits to augment sympathetic outflow to BAT, further reinforcing thermogenic activation and energy expenditure [69]. Dysbiosis-associated reductions in SCFA availability thus deprive BAT of critical upstream cues required to maintain thermogenic competence.

Gut microbiota also exert powerful control over BAT activity through modulation of bile acid metabolism. Intestinal bacteria convert primary bile acids into secondary species, reshaping the circulating bile acid pool and influencing downstream signaling through nuclear and membrane-bound receptors, most notably the FXR and the G protein-coupled bile acid receptor TGR5. Activation of TGR5 in BAT and skeletal muscle elevates intracellular cAMP levels and enhances thyroid hormone signaling, thereby promoting mitochondrial activity and adaptive thermogenesis [70, 71]. In obesity, dysbiosis-driven alterations in bile acid composition attenuate TGR5 signalling, contributing to suppressed thermogenic programs and facilitating BAT whitening [72].

Inflammatory signaling represents an additional mechanistic layer through which the gut microbiota modulates BAT function. Obesity-associated dysbiosis compromises intestinal barrier integrity, enabling translocation of LPS into the circulation. Systemic LPS activates TLR4-dependent inflammatory pathways in adipose tissue, triggering NF-κB signaling and chronic low-grade inflammation. This inflammatory milieu directly suppresses mitochondrial function and UCP1 expression in brown adipocytes, thereby impairing thermogenesis and promoting insulin resistance [73, 74]. These findings position gut-derived endotoxemia as a critical upstream driver of inflammation-mediated BAT dysfunction.

Neuroendocrine signaling further integrates gut microbial activity with central regulation of BAT. Gut-derived hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and ghrelin, modulate hypothalamic circuits that govern sympathetic output to BAT [75, 76]. Microbiota-dependent increases in GLP-1 signalling have been shown to enhance sympathetic tone and BAT thermogenesis, whereas dysbiosis disrupts enteroendocrine balance and dampens central pathways required for BAT activation [77–79]. Through these neurohormonal routes, gut microbes indirectly shape BAT responsiveness to environmental and nutritional cues.

Consistent with these mechanistic insights, specific microbial taxa have been repeatedly associated with preserved BAT function and metabolic health. Beneficial commensals such as Akkermansia muciniphila, Bifidobacterium, and selected Lactobacillus species enhance gut barrier integrity, reduce endotoxemia, and promote anti-inflammatory signaling, thereby creating a permissive environment for maintenance of brown adipocyte identity [80, 81]. Loss of these taxa in obesity correlates with diminished BAT activity and increased susceptibility to whitening.

Causal evidence for the gut microbiota as an upstream regulator of BAT thermogenesis has been provided by studies employing germ-free and antibiotic-treated animal models. Li et al. demonstrated that depletion of gut microbiota severely impairs cold-induced thermogenesis and energy expenditure, accompanied by reduced expression of thermogenic genes (Ucp1, Ppargc1α, Dio2) and morphological whitening of BAT [82]. Restoration of microbial communities or supplementation with SCFAs, particularly butyrate, rescued mitochondrial function and thermogenic gene expression, establishing microbial metabolites as indispensable drivers of adrenergic activation and adipose tissue energy dissipation.

Dietary and lifestyle interventions further underscore the therapeutic potential of targeting the gut-BAT axis. Multiple studies have shown that bioactive compounds such as nobiletin, genistein, and turmeric-derived polyphenols enhance BAT thermogenesis and adipose tissue browning by reshaping gut microbial composition and increasing SCFA production [83–85]. These effects are abolished by microbiota depletion and recapitulated by fecal microbiota transplantation, confirming microbiota-dependent mechanisms. Similarly, regular physical exercise preserves BAT function by remodeling the gut microbiota toward barrier-protective and anti-inflammatory profiles, thereby reducing systemic endotoxemia and inflammatory suppression of thermogenesis [86].

Finally, emerging evidence highlights bile acid–dependent pathways as key mediators of microbiota-driven BAT regulation. Chen et al. demonstrated that obesity-induced dysbiosis disrupts bile acid homeostasis, suppressing TGR5 signaling and impairing BAT thermogenic gene expression [87]. Restoration of bile acid profiles through probiotic intervention or bile acid supplementation reactivated BAT thermogenesis and improved systemic metabolic parameters, identifying the microbiota-bile acid-BAT axis as a critical control point in metabolic disease.

Collectively, these findings establish the gut microbiota as a central upstream regulator of BAT activity, integrating metabolic, inflammatory, and neuroendocrine signals to control thermogenic capacity and lipid metabolism. Disruption of this axis in obesity shifts BAT toward a white-like, energy-storing phenotype, thereby contributing to systemic metabolic dysfunction. The key pathways underlying microbiota-driven regulation of BAT thermogenesis and inflammation are summarized in Fig. 3.

Fig. 3.

The gut-brown adipose tissue axis in the regulation of thermogenesis and inflammation

This schematic illustrates how gut microbiota-derived metabolites modulate brown adipose tissue (BAT) thermogenic function and inflammatory status. Short-chain fatty acids (SCFAs; acetate, propionate, butyrate, succinate) and bile acids produced by the gut microbiota activate specific receptors such as GPR41/43, FXR, and TGR5, thereby enhancing cAMP signaling, mitochondrial biogenesis, and thermogenic gene expression (e.g., Ucp1, Pgc‑1α). In contrast, dysbiosis-associated lipopolysaccharide (LPS) engages TLR4-NF‑κB pathways, leading to increased pro-inflammatory cytokines (IL‑6, TNF‑α), suppression of thermogenesis, and promotion of BAT dysfunction and whitening. These microbial and inflammatory cues are integrated via the gut-brain axis and sympathetic output to BAT, ultimately influencing whole-body energy expenditure and the balance between white and brown adipocyte phenotypes.

The gut-liver axis: metabolic and inflammatory interactions influencing BAT whitening

The gut-liver axis represents a primary interface through which intestinal microbiota shape systemic metabolic homeostasis, inflammatory tone, and energy balance. A simplified schematic overview of these interactions and their impact on BAT function is provided in Fig. 4. Through the portal circulation, microbial metabolites and endotoxin-derived signals directly influence hepatic function, positioning the liver as a critical intermediary between gut dysbiosis and peripheral metabolic tissues, including BAT. In obesity, disruption of this axis amplifies hepatic inflammation and metabolic dysregulation, thereby creating endocrine and inflammatory conditions that favor BAT dysfunction and whitening [88–91].

Fig. 4.

Gut-liver-brown adipose tissue (BAT) axis dysfunction linking microbial dysbiosis to BAT whitening in obesity. (a) Gut microbiota dysbiosis increases intestinal permeability, facilitating portal translocation of microbial products and metabolites, including lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), branched-chain amino acids (BCAAs), and bile acid derivatives. (b) In the liver, gut-derived endotoxin-driven inflammation, mediated in part by LPS-TLR4 signaling, induces pro-inflammatory cytokine production (TNF-α, IL-6, IL-1β), promotes hepatic steatosis and insulin resistance, and disrupts bile acid receptor signaling (FXR/TGR5). These hepatic alterations impair endocrine outputs, including reduced FGF19 and dysregulated FGF21 secretion, generating a systemic inflammatory and metabolic milieu that suppresses BAT thermogenic programs. (c) Consequently, reduced UCP1 and PGC-1α expression, impaired mitochondrial biogenesis, and altered bile acid-TGR5 signaling in BAT drive lipid accumulation, diminished thermogenic capacity, and the phenotypic transition of brown adipocytes toward BAT whitening

A central mechanism linking gut dysbiosis to hepatic and BAT impairment is metabolic endotoxemia (Fig. 4a), whereby obesity-associated increases in intestinal permeability facilitate translocation of LPS into the portal vein, where it activates Toll-like receptor 4 (TLR4) signaling in hepatocytes and Kupffer cells. This activation triggers NF-κB, dependent inflammatory cascades and the release of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, into the systemic circulation. These cytokines impair mitochondrial biogenesis and suppress thermogenic gene expression in brown adipocytes, thereby promoting lipid accumulation and loss of thermogenic identity characteristic of BAT whitening [92, 93]. These integrated gut-liver-BAT interactions illustrate how microbiota-driven hepatic inflammation and endocrine disruption converge to suppress BAT thermogenesis and promote whitening.

In parallel, hepatic metabolic adaptations to microbial signals indirectly modulate BAT function through alterations in lipid flux and bile acid signaling (Fig. 4b). Obesity-induced hepatic steatosis and insulin resistance are frequently accompanied by dysregulated bile acid synthesis and enterohepatic circulation [94, 95]. Microbiota-driven remodeling of bile acid composition alters activation of key receptors, particularly the G protein–coupled bile acid receptor TGR5 and the nuclear receptor FXR, in both hepatic and extrahepatic tissues [96]. Attenuated TGR5 signaling reduces intracellular cAMP production and mitochondrial activation in BAT, thereby suppressing thermogenic programs and facilitating whitening. Concurrent FXR dysregulation disrupts lipid clearance and promotes ectopic lipid deposition, further reinforcing metabolic stress in both liver and BAT [23, 97–99].

Endocrine mediators arising from the gut-liver axis, particularly FGF19 and FGF2, provide an additional regulatory layer linking hepatic metabolism to BAT thermogenesis (Fig. 4c). Fibroblast growth factor 19 (FGF19), an enterokine induced by intestinal FXR activation, plays a pivotal role in coordinating hepatic lipid metabolism, glucose homeostasis, and energy expenditure [100–102]. In obesity, impaired FXR signaling reduces FGF19 secretion, contributing to hepatic lipid accumulation and diminished systemic metabolic efficiency. Reduced FGF19 availability further dampens BAT thermogenic tone, highlighting its role as a hormonal link between intestinal bile acid sensing and peripheral energy dissipation [103–105].

Beyond bile acids and endotoxins, gut microbiota-derived metabolites such as TMAO, BCAAs, and indole derivatives modulate hepatic insulin sensitivity and inflammatory status [106, 107]. Elevated circulating TMAO levels have been associated with hepatic steatosis and insulin resistance, generating an endocrine milieu that indirectly suppresses BAT activity. In turn, impaired BAT thermogenesis exacerbates whole-body energy surplus, increasing lipid burden on the liver and reinforcing metabolic dysfunction [108, 109].

Hepatokines further mediate bidirectional communication between the liver and BAT. Obesity-associated increases in fetuin-A and reductions in fibroblast growth factor 21 (FGF21) are linked to systemic inflammation and diminished BAT activity. FGF21, in particular, enhances mitochondrial function and thermogenic gene expression in BAT, and its deficiency contributes to thermogenic decline and adipose tissue whitening in metabolic disease [110–112].

Consistent with these mechanistic insights, integrative reviews and experimental studies have delineated a gut-liver-BAT inflammatory axis underlying metabolic disease progression. Dysbiosis-driven endotoxemia, impaired bile acid signaling, and disrupted SCFA production converge to promote hepatic inflammation, lipid accumulation, and systemic cytokine release, which collectively suppress BAT thermogenesis and accelerate whitening [113–115]. Importantly, this axis is bidirectional: recent evidence demonstrates that activation of BAT can alleviate hepatic steatosis and inflammation by enhancing lipid clearance and energy expenditure, as exemplified by studies identifying BAT-derived endocrine factors such as neuregulin 4 (Nrg4) that directly inhibit hepatic lipogenesis and inflammatory signaling [116].

Collectively, these findings position the gut-liver axis as a critical regulatory hub integrating microbial, metabolic, and inflammatory cues that shape BAT function. Chronic activation of hepatic inflammatory pathways, combined with disrupted bile acid and hepatokine signaling, establishes a feed-forward loop that promotes BAT whitening and systemic metabolic deterioration. The following section will examine how dietary and lifestyle interventions may modulate the gut microbiota and disrupt this pathogenic axis to preserve BAT thermogenic capacity in obesity.

Dietary and lifestyle modulation of gut microbiota and BAT whitening

Dietary habits and lifestyle behaviors represent major upstream determinants of gut microbial composition and metabolic output, thereby exerting powerful regulatory effects on BAT activity and its susceptibility to whitening. In obesity and metabolic disorders, maladaptive dietary patterns and physical inactivity disrupt gut microbial ecology, promoting endotoxemia, chronic inflammation, and mitochondrial dysfunction that collectively impair BAT thermogenic competence.

Emerging evidence indicates that these lifestyle-driven alterations reshape multiple microbiota-dependent signaling pathways that directly influence brown adipocyte metabolism. These include microbial short-chain fatty acids that regulate mitochondrial biogenesis and sympathetic responsiveness, bile acid-TGR5 signaling that modulates thermogenic gene expression, and microbiota-controlled inflammatory cascades that alter adipose tissue remodeling. Through these interconnected mechanisms, the gut microbiota acts as a key intermediary linking environmental exposures to BAT metabolic plasticity. Conversely, targeted dietary strategies, regular physical activity, and microbiota-modulating interventions can restore gut-adipose signaling and preserve brown adipocyte identity [91, 117, 118].

Dietary patterns and microbiota-derived signals regulating BAT thermogenic integrity

Diet composition critically shapes gut microbial diversity and metabolite production, thereby influencing BAT metabolism. Western-style diets rich in saturated fats and refined carbohydrates reduce microbial diversity and promote the expansion of pro-inflammatory taxa such as Enterobacteriaceae, leading to increased circulating LPS levels, impaired intestinal barrier integrity, and suppression of BAT thermogenesis [118–121]. These changes favor lipid accumulation and accelerate BAT whitening.

In contrast, diets enriched in dietary fiber, polyphenols, and resistant starch promote the growth of beneficial microbes including Bifidobacterium, Lactobacillus, and Akkermansia muciniphila. These taxa enhance the production of SCFAs, particularly acetate and butyrate, which activate GPR41/43 signaling, support mitochondrial biogenesis, and sustain UCP1-driven thermogenic programs in BAT [122–124]. In addition, dietary phytochemicals indirectly modulate β-adrenergic and PPAR signaling pathways through microbiota-derived metabolites, reinforcing adipose tissue browning and metabolic flexibility.

Together, these findings indicate that dietary composition modulates BAT thermogenic competence largely through microbiota-derived metabolites that influence mitochondrial function, inflammatory tone, and sympathetic signaling within brown adipocytes. Collectively, these findings underscore dietary composition as a primary upstream regulator of microbiota-dependent thermogenic signaling, positioning nutritional modulation as a strategic approach to preserve BAT identity and prevent whitening in obesogenic states.

Physical activity and lifestyle factors as microbiota-dependent modulators of BAT function

Physical activity exerts potent BAT-preserving effects that extend beyond increased energy expenditure and involve microbiota-mediated mechanisms. Exercise-induced adaptations in host metabolism may further interact with the gut microbiota through the release of myokines and alterations in substrate availability within the intestinal environment. These changes can promote the expansion of metabolically beneficial microbial taxa and increase the production of SCFAs and secondary bile acids that support thermogenic signaling in BAT. Regular exercise enhances gut microbial diversity and enriches butyrate-producing bacterial populations, resulting in reduced systemic inflammation and improved mitochondrial efficiency in adipose tissues [86, 125]. Experimental studies demonstrate that voluntary or structured exercise preserves BAT thermogenic capacity and prevents whitening even in the absence of dietary modification, through enhanced sympathetic output and SCFA-mediated signaling [126, 127].

Lifestyle factors such as circadian alignment and sleep quality further modulate the gut microbiota-BAT axis. Disruption of circadian rhythms induces dysbiosis, alters bile acid metabolism, and blunts sympathetic activation of BAT, leading to reduced thermogenic responsiveness. Conversely, restoration of circadian rhythmicity through optimized sleep hygiene and meal timing improves microbial oscillations and supports BAT metabolic plasticity [128–130].

Mechanistic evidence from microbiota-targeted interventions and metabolic surgery

Beyond observational associations, several experimental and translational studies provide direct evidence that microbiota-targeted interventions can modulate BAT thermogenic capacity and susceptibility to whitening. Compelling mechanistic studies establish a causal role for the gut microbiota in mediating the effects of lifestyle interventions on BAT function. Zhang et al. demonstrated that structured exercise training prevents obesity-associated BAT whitening by reshaping gut microbial composition, enhancing intestinal barrier integrity, and suppressing LPS-TLR4-NLRP3 inflammatory signaling within BAT. Microbiota transfer experiments confirmed that these thermogenic benefits are transmissible, highlighting a microbiota-dependent mechanism underlying exercise-induced BAT preservation [86].

Similarly, Chen et al. showed that HFD-induced dysbiosis disrupts bile acid homeostasis and suppresses TGR5 signaling, resulting in impaired BAT mitochondrial function and whitening. Restoration of bile acid pools via tauroursodeoxycholic acid supplementation or probiotic-mediated microbiota remodeling rescued BAT thermogenesis and improved systemic metabolic parameters [87].

Bariatric surgery provides a translational proof-of-concept for microbiota-driven BAT activation. Surgical procedures such as sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and sustained remodeling of gut microbial communities, enhance bile acid-TGR5 and FXR-FGF15 signaling, and increase BAT volume and metabolic activity in both humans and experimental models. Fecal microbiota transplantation from post-surgery donors recapitulates these thermogenic effects, underscoring gut microbiota reprogramming as a central mediator of surgery-induced metabolic benefits [131].

Integrative perspective and therapeutic implications

Collectively, dietary composition, physical activity, and broader lifestyle factors converge on a shared mechanistic axis linking gut microbial metabolites, inflammatory tone, and endocrine signaling to BAT thermogenic integrity. By reshaping gut microbial ecosystems and their metabolic outputs, these interventions mitigate systemic inflammation, preserve mitochondrial function, and prevent the maladaptive conversion of BAT into lipid-storing tissue. These insights position the gut microbiota as a modifiable therapeutic target through which non-pharmacological and adjunctive strategies may restore metabolic homeostasis and counteract BAT whitening in obesity. Future therapeutic strategies may therefore focus on precision modulation of the gut microbiome, including targeted probiotics, metabolite-based therapies, and personalized dietary interventions designed to restore BAT thermogenic resilience. In the following section, we will discuss emerging therapeutic approaches that leverage this gut-adipose-liver network to treat obesity and its associated metabolic disorders.

Potential therapeutic strategies targeting the Gut-BAT and Gut-liver axes

The growing recognition of gut microbiota as a central regulator of BAT thermogenic integrity has opened new therapeutic avenues for obesity and related metabolic disorders. Rather than targeting adipose tissue or hepatic metabolism in isolation, emerging strategies aim to modulate the integrated gut-BAT and gut-liver networks to attenuate inflammation, restore mitochondrial function, and reverse adipose tissue whitening. These approaches encompass microbiota-directed interventions, metabolite-based therapies, receptor-targeted pharmacology, and next-generation biotherapeutics designed to reshape host-microbe interactions.

Microbiota-directed interventions: restoring upstream metabolic control

Among the most direct therapeutic strategies are interventions that restore gut microbial homeostasis through probiotics, prebiotics, and synbiotics [132–134]. Specific probiotic strains, including Akkermansia muciniphila, Bifidobacterium longum, and Lactobacillus plantarum, have demonstrated the capacity to strengthen intestinal barrier integrity, suppress systemic endotoxemia, and enhance BAT thermogenic gene expression in preclinical and early clinical studies [135–138]. These effects are mechanistically linked to increased SCFA production and improved bile acid signaling, which activate key thermogenic regulators such as TGR5 and FXR in BAT and liver [160, 161]. Prebiotics such as inulin and resistant starch further potentiate these benefits by selectively enriching beneficial taxa, while synbiotic formulations may provide more sustained metabolic improvements [139, 140].

Fecal microbiota transplantation (FMT) offers compelling proof-of-concept for microbiome-driven metabolic reprogramming. Although still experimental in obesity, FMT from lean donors has been shown to improve insulin sensitivity, alter hepatic lipid metabolism, and increase thermogenic gene expression in adipose tissues [141, 142]. Notably, Cao et al. demonstrated that FMT administered during diet cycling attenuates weight regain and lipid accumulation by enhancing propionate production and reprogramming hepatic lipid metabolism, thereby indirectly reducing energy storage and adipose rebound [143]. Despite regulatory and ethical challenges, these findings highlight the therapeutic potential of microbiota replacement strategies.

Metabolite- and bile acid-based therapeutic approaches

Microbial metabolites represent a second mechanistic tier of intervention. SCFAs, particularly butyrate and propionate, directly promote mitochondrial biogenesis and UCP1 expression in brown adipocytes, positioning them as attractive candidates for metabolite-based therapies [144–146]. Parallel efforts focus on modulating bile acid signaling, given its pivotal role in linking gut microbiota to BAT and liver metabolism. Pharmacological activation of TGR5 enhances cAMP-dependent thermogenic pathways in BAT, whereas FXR agonists normalize bile acid synthesis and improve hepatic lipid handling [71–148]. However, given the pleiotropic actions of these receptors, achieving tissue specificity and minimizing off-target effects remain critical challenges.

Consistent with this framework, Liu et al. comprehensively reviewed therapeutic strategies targeting the gut microbiota-bile acid axis, highlighting the potential of probiotics, bile acid sequestrants, FXR modulators, and engineered microbes to restore coordinated gut-liver-BAT metabolic signaling. By enhancing bile acid receptor activation and reducing inflammatory spillover, these approaches can simultaneously improve hepatic lipid metabolism and preserve BAT thermogenic capacity [149].

Pharmacological repurposing and next-generation biotherapeutics

Interestingly, several drugs originally developed for glycemic control also exert secondary effects on the gut microbiota and BAT function. Agents such as metformin, GLP-1 receptor agonists, and SGLT2 inhibitors reshape gut microbial composition, reduce endotoxemia, and indirectly enhance BAT thermogenesis, illustrating the interconnected nature of host metabolism and microbial ecology [150–152]. These pleiotropic effects suggest that combining classical metabolic pharmacology with microbiota modulation may yield synergistic benefits.

Beyond repurposed drugs, next-generation biotherapeutics, including engineered probiotics, microbial enzyme inhibitors, and synthetic microbial consortia, are being developed to deliver defined metabolic functions such as SCFA production or bile acid transformation with greater precision [82, 153, 154]. Experimental studies, including those by Fuchs et al., demonstrate that microbiota-modulating compounds can suppress adipose inflammation, restore mitochondrial function, and preserve BAT thermogenic gene expression by reducing endotoxemia and rebalancing bile acid signaling [155]. Such targeted approaches aim to overcome the variability and modest efficacy observed in earlier probiotic trials.

Translational evidence and clinical considerations

Systematic analyses of clinical trials underscore both the promise and limitations of microbiota-targeted therapies. Tomé-Castro et al. reported that probiotic supplementation in overweight and obese adults yields modest but consistent improvements in body composition, lipid profiles, and inflammatory markers, largely through enhanced gut barrier function, increased SCFA production, and favorable modulation of bile acid metabolism [156]. However, substantial heterogeneity in strains, dosing, and study design highlights the need for standardized formulations and mechanistic endpoints, including direct assessment of BAT activity.

Collectively, these findings support a paradigm shift in obesity treatment, from symptom-oriented metabolic control toward upstream modulation of gut-derived signals that govern BAT thermogenic integrity and hepatic lipid handling. By targeting the gut-BAT and gut-liver axes, emerging therapies offer an integrated strategy to attenuate chronic inflammation, restore mitochondrial function, and reactivate BAT as a physiological energy sink. The following section will outline key research gaps and future directions required to translate these concepts into effective, personalized clinical interventions.

Future perspectives and research directions

The expanding recognition of the gut microbiota-BAT-liver network as a central regulator of metabolic homeostasis has fundamentally reshaped obesity research. Despite substantial advances, critical mechanistic gaps remain that limit the translation of experimental findings into effective clinical strategies. Addressing these challenges will require integrative, multi-disciplinary approaches that combine systems biology, precision medicine, and human-relevant translational models to fully harness the therapeutic potential of microbiota-driven modulation of BAT function.

A primary unresolved challenge is the identification of causal microbial signatures and metabolites that directly regulate BAT activity in humans. Although preclinical studies have established roles for SCFAs, bile acids, and other microbial-derived metabolites in thermogenic regulation, their relevance, dose dependency, and durability in human BAT remain incompletely defined. Future investigations should prioritize longitudinal and interventional studies across diverse populations to identify reproducible microbiota–metabolite profiles associated with BAT activation or whitening. Parallel efforts to isolate and functionally validate specific microbial strains will be essential for the rational development of next-generation probiotics and precision postbiotic therapies [70, 82, 157].

Systems-level approaches will be indispensable for resolving the complexity of gut-BAT-liver interactions. Integrated metagenomics, metabolomics, transcriptomics, and epigenomics can enable simultaneous mapping of microbial ecology, host inflammatory signaling, mitochondrial function, and thermogenic gene networks. Emerging technologies such as single-cell RNA sequencing and spatial transcriptomics hold particular promise for dissecting cellular heterogeneity within brown and beige adipose depots, clarifying how distinct adipocyte subpopulations respond to microbial and metabolic cues under physiological and pathological conditions [158–160].

Personalized microbiota-targeted therapies represent a key frontier in obesity management. Given the pronounced inter-individual variability in microbiome composition, host genetics, and metabolic responsiveness, uniform interventions are unlikely to achieve consistent efficacy. Future therapeutic strategies will likely require stratification of patients based on baseline microbiome profiles, metabolic phenotypes, and genetic risk. Machine learning and predictive modeling approaches will be central to integrating multi-omics datasets, enabling the identification of responder subgroups and the design of individualized interventions optimized to enhance BAT thermogenic capacity and metabolic resilience [161, 162].

Translational barriers between animal models and human physiology remain a major limitation. Species-specific differences in BAT distribution, microbiota composition, diet, and environmental exposure necessitate the use of humanized mouse models, organoid platforms, and advanced imaging modalities to validate mechanistic insights. Non-invasive technologies, including ^18F-FDG PET/CT, infrared thermography, and emerging wearable metabolic sensors, will be critical for dynamic, real-time assessment of BAT activity and therapeutic response in clinical studies [163–166].

Finally, future research should extend beyond classical metabolic pathways to incorporate chronobiology, sleep, psychosocial stress, and life-stage-specific factors. Circadian misalignment and sleep disruption profoundly influence gut microbial oscillations and thermogenic responsiveness, yet remain underexplored in BAT-focused interventions. Moreover, early-life microbial exposure and age-associated shifts in microbiota composition may exert long-lasting effects on adipose tissue plasticity and metabolic health, underscoring the need for lifespan-oriented research frameworks [167–172].

Collectively, advancing the field will require coordinated efforts bridging basic science, computational biology, and clinical investigation. By integrating mechanistic insight with patient-specific profiling, future research can move beyond associative findings toward actionable strategies that exploit the gut-BAT and gut-liver axes to prevent and reverse obesity.

Conclusion

Obesity and its associated metabolic disorders constitute a persistent global health burden that demands therapeutic strategies extending beyond caloric restriction and physical activity alone. Accumulating evidence underscores the pivotal role of gut microbiota in governing BAT thermogenic activity and susceptibility to whitening, revealing a tightly integrated network linking microbial ecology, inflammation, mitochondrial function, and systemic energy balance across the gut-adipose-liver axis.

Alterations in gut microbial composition and metabolic output profoundly influence BAT phenotype through multiple convergent mechanisms, including endotoxemia-driven inflammation, bile acid signaling, and modulation of mitochondrial function. Importantly, dietary interventions, lifestyle modification, pharmacological agents, and emerging microbiome-based therapies demonstrate that these pathways are modifiable, offering the opportunity to restore BAT thermogenic competence and counteract adipose tissue whitening. Microbial metabolites such as SCFAs and bile acids emerge as central mediators of host metabolic adaptation, positioning them as promising targets for therapeutic intervention.

Despite these advances, significant translational challenges remain. Defining causal microbial drivers, establishing durable clinical efficacy, and integrating multi-omics data into personalized treatment paradigms are critical next steps. Addressing these challenges will be essential to translate mechanistic insight into scalable, safe, and effective interventions.

In summary, the gut microbiota-BAT axis represents a fundamental regulatory system in metabolic health with substantial implications for obesity treatment. Strategic modulation of this interconnected network holds the potential not only to restore metabolic balance but also to provide durable protection against obesity-related diseases by reactivating endogenous thermogenic pathways.

Abbreviations

BAT

Brown Adipose Tissue

UCP1

Uncoupling Protein 1

PGC-1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

LPS

Lipopolysaccharide

SCFAs

Short-chain fatty acids

FGF19/FGF21

Fibroblast growth factor 19/21

TGR5

G protein-coupled bile acid receptor 1

FXR

Farnesoid X receptor

TMAO

Trimethylamine N-oxide

TLR4

Toll-like receptor 4

Author contributions

M.G. and M.F. conceived the review and wrote the original draft. M.K., S.E.Z., S.A.R., S.S.M.G., M.M.V., A.G., N.M., M.A., and Z.K. contributed to literature review, critical revision, and editing. M.F. and M.B. conceptualized and designed the figures. A.J.T. provided clinical and translational input. M.B. supervised the work and finalized the manuscript. M.G. and M.F. contributed equally as co-first authors. All authors reviewed and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.