The progressive expansion and remodeling of adipose tissue in response to nutritional demands ultimately converge on a tightly controlled biological process: adipogenesis. Defined as the differentiation of precursor cells into mature adipocytes capable of storing lipids and exerting endocrine functions, adipogenesis is a highly orchestrated cascade that is critical for maintaining adipose tissue homeostasis [11]. This process occurs within specialized adipose tissue depots that are functionally and metabolically distinct, and the health of adipose tissue depends on its ability to expand in a well–regulated state and safely store excess energy.

Under physiological conditions, efficient and tightly regulated adipogenesis enables the expansion of subcutaneous adipose tissue (SAT) and maintains adipose tissue homeostasis by supporting hyperplastic growth, preserving insulin sensitivity, and preventing ectopic lipid deposition, thereby protecting non–adipose organs from lipotoxic injury. Conversely, impaired adipogenesis disrupts these protective mechanisms by compromising the molecular cascade responsible for adipocyte differentiation and favoring hypertrophic, inflamed, and metabolically rigid adipose depots. Understanding these processes is therefore essential to contextualize adipose tissue plasticity and its systemic metabolic consequences in obesity.

Classically, adipogenesis unfolds through distinct but interdependent stages, including lineage commitment, early and intermediate differentiation, and terminal maturation. Each of these stages is governed by specific cellular, hormonal, and transcriptional regulatory mechanisms.

Cellular Origin and Lineage Commitment

Adipogenesis begins within the stromal vascular fraction (SVF) of adipose tissue, where mesenchymal stem cells (MSCs) and stromal progenitors gradually restrict their multipotency and become increasingly biased toward an adipocyte lineage rather than alternative differentiation programs such as osteogenesis (bone), myogenesis (muscle), and chondrogenesis (cartilage), a stage referred to as early commitment. As lineage restriction progresses, these progenitors transition into pre–adipocytes, fibroblast–like cells that retain proliferative capacity but are primed to initiate a coordinated, multistep differentiation program driven by hormonal cues and a core adipogenic transcriptional cascade [11, 12].

The early commitment phase is controlled by transcriptional regulators such as zinc finger protein (Zfp)423 and early B-cell factor (Ebf)1 and Ebf2, which establish adipogenic competence and distinguish adipocyte–fated progenitors from other mesenchymal lineages. These factors modulate chromatin accessibility, creating a transcriptional environment that enables subsequent activation of the core adipogenic program, thereby defining the earliest molecular signature of adipocyte commitment [13, 14].

Once adipogenic competence is established, adipocyte–fated progenitors are specified but do not yet distinguish between white and brown adipocyte lineages. Several studies have demonstrated that most white adipocytes derive predominantly from mesenchymal precursor cells of an adipogenic lineage lacking myogenic factor (Myf)5 expression (Myf5−), indicating a developmental pathway distinct from the myogenic program. These Myf5− progenitors differentiate into pre–adipocytes and subsequently mature adipocytes under appropriate endocrine and nutritional conditions [15,16,17]. In contrast, classical brown adipocytes originate from a Myf5+ lineage shared with skeletal muscle progenitors, reflecting their closer developmental relationship with myogenic tissues [16]. This developmental dichotomy underlies the distinct metabolic and thermogenic functions of white adipose tissue (WAT) and brown adipose tissue (BAT).

In addition to white and classical brown adipocytes, beige adipocytes represent a third inducible thermogenic population. These cells originate from Myf5− precursors within white adipose depots and can also emerge through the recruitment or transdifferentiation of mature white adipocytes in response to specific stimuli (Fig. 1) [18].

Fig. 1

Adipocyte lineage commitment and differentiation. Mesenchymal stem cells (MSC) differentiate into adipogenic and myogenic lineages. Within the adipogenic lineage, Myf5⁻ progenitors commit to white or beige pre-adipocytes through zinc finger protein (Zfp)423 and B-cell factor(Ebf)1 and Ebf2, while inflammatory cytokines impair adipogenic commitment. White adipocytes differentiate via CCAAT/enhancer–binding protein (C/EBP) and peroxisome proliferator–activated receptor (PPAR)γ signaling and can transdifferentiate into beige adipocytes in response to cold exposure, exercise, or β-adrenergic activation. In parallel, Myf5⁺ progenitors give rise to brown adipocytes under bone morphogenic proteins (BMP)7- and PR domain–containing protein 16 (PRDM16)-dependent cues. Beige and brown adipocytes are characterized by increased uncoupling protein 1 (UCP1) expression and thermogenic capacity. Created in https://BioRender.com

Other regulators such as T–box (TBX)15, PR domain–containing protein 16 (PRDM16, particularly relevant for beige adipocyte differentiation), and specific homeobox (HOX) gene clusters further contribute to depot–specific adipocyte identity. Subcutaneous progenitors exhibit higher HOXA5 expression, which is associated with a more insulin–sensitive phenotype, whereas visceral progenitors preferentially express HOXC9, a profile linked to increased inflammatory potential. In parallel with these molecular programs, adipocyte precursor cells are also heterogeneous across depots, with SAT enriched in adipogenic progenitors, while visceral adipose tissue (VAT) contains a higher proportion of fibro–inflammatory precursors with reduced differentiation capacity [19, 20]. These intrinsic molecular and cellular differences help explain the distinct metabolic behaviors of SAT and VAT and their differential susceptibility to adipose tissue dysfunction.

During the progression toward lineage commitment, pre–adipocytes gradually lose multipotency and adopt a fibroblast–like morphology. At this stage, pre–adipocytes express characteristic surface markers such as platelet–derived growth factor receptor (PDGFR)α, cluster of differentiation (CD)34, and CD29. The commitment phase is also highly sensitive to inflammatory cues, including tumor necrosis factor (TNF)–α, interleukin (IL)–1β, and interferon (IFN)–γ, which suppress early adipogenic regulators such as Zfp423 and members of the Ebf family. Persistent inflammatory signaling impairs adipocyte recruitment and favors hypertrophic expansion of existing adipocytes (Fig. 1) [21, 22].

Beyond cytokine-mediated effects, immune–stromal interactions strongly influence adipose progenitor fate and tissue remodeling. Adipose tissue macrophages (ATM), the predominant immune population within WAT, exert important regulatory effects on adipogenesis. Under lean conditions, alternatively activated M2-like ATMs support progenitor proliferation and adipogenic competence through anti-inflammatory IL-10 and transforming growth factor (TGF)-β, thereby promoting healthy hyperplastic expansion. In contrast, obesity promotes the accumulation of pro-inflammatory M1-like ATMs and lipid-laden metabolically activated ATMs, which secrete inflammatory mediators that suppress early adipogenic regulators such as Zfp423 and Ebf family members, impairing adipogenic commitment and shifting depot expansion toward pathological hypertrophy [23].

Adaptive immune cells also contribute to the regulation of progenitor cells. Regulatory T cells (Tregs) and invariant natural killer T (iNKT) cells maintain an anti-inflammatory microenvironment that preserves progenitor adipogenic potential and supports metabolic homeostasis. Their reduction in obesity amplifies inflammatory signaling, decreases hyperplastic capacity, and promotes extracellular matrix (ECM) deposition. Conversely, Th1-polarized T cell responses enhance ATM activation and fibrosis, further restricting adipose expandability [24]. In parallel, innate lymphoid cells (ILC)2 also modulate adipose plasticity by producing IL-5 and IL-13, which sustain eosinophil recruitment and M2 polarization, indirectly promoting beige adipocyte recruitment and thermogenic remodeling. Loss of ILC2 activity in obesity impairs this thermogenic axis and reduces progenitor response to browning stimuli, contributing to depot-specific dysfunction [25].

Together, these immune–stromal interactions integrate inflammatory tone, progenitor fate decisions, and adipose tissue plasticity, highlighting immune–metabolic crosstalk as a central regulatory axis in obesity-associated adipose dysfunction [26].

While the classical Myf5⁺/Myf5⁻ developmental framework has been fundamental for establishing the foundations of adipocyte lineage relationships, recent advances in single-cell RNA sequencing and spatial transcriptomics have considerably expanded this view [27]. Emerging evidence demonstrates that adipose progenitor populations are highly heterogeneous, comprising functionally distinct subsets with divergent adipogenic, fibrotic, inflammatory, and thermogenic potentials. These studies also revealed substantial lineage plasticity and strong microenvironmental influences on progenitor fate determination, supporting a more dynamic, plastic, and spatially organized model of adipose tissue development and remodeling [28].

These approaches revealed that adipose progenitors are far from a homogeneous population but instead comprise multiple specialized subsets, including DPP4⁺ interstitial progenitors with high self-renewal capacity, ICAM1⁺ committed pre-adipocytes with strong adipogenic potential, PDGFRβ⁺/Ly6C⁺ fibro-inflammatory progenitors, and beige-competent thermogenic precursors [27,28,29]. Spatial mapping further demonstrated that these populations occupy discrete micro-niches shaped by vascular proximity, ECM composition, and local inflammatory cues [30].

Together, these findings shift the current understanding from a binary Myf5⁺/Myf5⁻ model toward a more dynamic, heterogeneous, and spatially organized view of adipose tissue development. Rather than representing a uniform differentiation process, adipogenesis is now understood as a context-dependent and depot-specific phenomenon shaped by progenitor diversity, local inflammatory signals, ECM composition, and metabolic status. This refined framework helps explain depot-specific differences in adipogenic capacity and provides mechanistic insight into how microenvironmental signals influence progenitor fate, a concept that directly links lineage heterogeneity to the signaling pathways governing adipogenesis. Importantly, this conceptual shift also offers a more comprehensive framework for understanding adipose tissue dysfunction and pathological remodeling in obesity.

Adipogenesis Signaling Pathways

The initiation and progression of adipogenesis are determined by a complex interplay of extracellular and intracellular signaling pathways that regulate the transition from lineage commitment to terminal differentiation. These pathways include hormonal, nutritional, and inflammatory cues that collectively determine whether adipocyte progenitors enter, sustain, or inhibit the adipogenic program. Broadly, adipogenic signaling pathways can be categorized into pro– and anti–adipogenic, reflecting their capacity either to promote activation of the core adipogenic transcriptional cascade or to restrain differentiation and maintain progenitors in an undifferentiated or alternative lineage state.

Pro–Adipogenic Pathways

Pro–adipogenic pathways comprise a set of signaling cascades that actively promote adipocyte differentiation by inducing the transcriptional machinery required for adipogenesis and coordinating the metabolic remodeling necessary for the development of mature adipocytes. Although multiple signals can promote adipogenic differentiation under specific physiological or experimental contexts, only a limited number of pathways are consistently recognized as central drivers of the adipogenic program, operating from lineage commitment to terminal maturation.

A defining early event in the adipogenic program is lineage commitment, which is primarily driven by bone morphogenic protein (BMP) signaling, particularly BMP4 and BMP7. BMP4 phosphorylates suppressor of mother against decapentaplegic (SMAD)1/5/8 and establishes a transcriptional state permissive for adipogenic differentiation, directing multipotent stromal cells away from osteogenic or myogenic programs and toward the adipocyte lineage [31]. In contrast, BMP7 selectively promotes brown adipocyte differentiation, inducing mitochondrial biogenesis, uncoupling protein 1 (UCP1) expression, and thermogenic programming via SMAD and p38 mitogen-activated protein kinase (MAPK) pathways. This commitment phase sets the foundation upon which subsequent differentiation signals act, ensuring that progenitor cells acquire the transcriptional and chromatin landscape necessary to respond effectively to pro–adipogenic hormonal stimuli [32]. Thus, BMP signaling functions as a key early determinant of adipocyte identity, preceding and enabling the initiation of the adipogenic transcriptional cascade (Fig. 1).

Once commitment is established, the early induction of adipogenesis strongly depends on cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. Elevated intracellular cAMP activates PKA, which phosphorylates the cAMP response element–binding protein (CREB), leading to its activation and subsequent binding to DNA sequences that regulate early adipogenic gene transcription, most notably CCAAT/enhancer–binding protein (C/EBP)β, the earliest transcriptional activator of the adipogenic program [11]. This early signal also facilitates mitotic clonal expansion, coupling cell proliferation with transcriptional priming in preparation for terminal adipocyte differentiation [33].

The progression from transcriptional initiation to mature adipocyte identity is driven by the insulin–like growth factor (IGF)–1/phosphoinositide 3–kinase (PI3K)/protein kinase B (Akt) pathway, which integrates hormonal and metabolic inputs to sustain adipogenesis. IGF–1 binds to its receptor, activating insulin receptor substrate (IRS) proteins that recruit and activate PI3K, leading to the production of phosphatidylinositol (3,4,5)–trisphosphate (PIP3), a critical step enabling full Akt activation [34]. Activated Akt enhances glucose uptake, stimulates lipogenic enzyme expression, inhibits anti–adipogenic regulators, and stabilizes peroxisome proliferator–activated receptor (PPAR)γ, consolidating the pro–adipogenic transcriptional program. Inhibition of PI3K or Akt blocks differentiation even after early transcriptional events have occurred, underscoring the indispensable anabolic role of this pathway [35].

Downstream of Akt, mammalian target of rapamycin complex (mTORC)1 operates as a master regulator of metabolic remodeling during adipocyte maturation. mTORC1 promotes protein synthesis, de novo lipogenesis, and organelle biogenesis, in part by activating sterol regulatory element-binding protein (SREBP)1c and other lipogenic transcriptional factors. This ensures that differentiating adipocytes acquire the metabolic capacity for triacylglycerides (TGs) synthesis, lipid droplet expansion, and endocrine functionality. Inhibition of mTORC1 markedly impairs lipid accumulation and suppresses the expression of late adipogenic genes, confirming its essential role in terminal differentiation [36].

Collectively, pro–adipogenic pathways create a hierarchical and cooperative network. BMP signaling establishes lineage commitment, cAMP/PKA/CREB initiates the transcriptional cascade, IGF–1/PI3K/Akt stabilizes and amplifies adipogenic identity, and mTORC1 drives the metabolic maturation required for functional adipocyte formation. These pathways ensure the coordinated acquisition of both transcriptional and metabolic features of the mature adipocyte.

Anti–Adipogenic Pathways

Anti–adipogenic pathways include signaling mechanisms that oppose adipocyte differentiation by inhibiting lineage commitment, blocking the activation of adipogenic transcription factors, or impairing the metabolic remodeling required for terminal differentiation.

Among all inhibitory regulators, adenosine monophosphate activated protein kinase (AMPK) is the most prominent. Acting as a master sensor of cellular energy stress, AMPK is activated under conditions of low adenosine triphosphate (ATP) availability and shifts metabolism toward catabolic processes. Through inhibition of mTORC1, suppression of lipogenic enzymes, phosphorylation–mediated suppression of PPARγ, and downregulation of C/EBPα, AMPK counteracts the anabolic and transcriptional requirements for differentiation. Its anti–adipogenic effects also extend to lipid metabolism, promoting fatty acid oxidation and reducing TGs synthesis, directly opposing the metabolic profile of mature adipocytes [36].

In addition to AMPK, the MAPK family, namely extracellular signal–regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, acts as a central mediator linking extracellular cues to nuclear transcriptional programs. In obesity, MAPK cascades regulate appetite, adipocyte differentiation, thermogenic capacity, and inflammatory processes, acting both as pro–adipogenic (ERK) and anti–adipogenic (JNK and p38 MAPK) [37].

In the central nervous system, ERK1/2 activation enhances anorexigenic signaling by increasing the expression of pro–opiomelanocortin (POMC)–derived neuropeptides, thereby promoting satiety [38]. In contrast, within adipose tissue, MAPK signaling exhibits significant tissue– and time–specificity. Transient early ERK1/2 activation provides essential support during the induction phase of adipogenesis. Short–lived ERK signaling enhances C/EBPβ expression and facilitates mitotic clonal expansion, thereby contributing to the successful initiation of the adipogenic program [39].

Nevertheless, sustained or chronic ERK activity suppresses adipogenesis by inhibiting PPARγ, demonstrating that MAPK pathways can either promote or restrain adipocyte formation depending on cellular and temporal context. This temporal dichotomy is further illustrated by the requirement of ERK1 for terminal adipocyte differentiation, while prolonged MAPK activation remains inhibitory, highlighting the need for precisely timed ERK signaling throughout the adipogenic process [39, 40].

On the other hand, JNK and p38 MAPK play central roles in obesity–associated inflammation signaling. Their activation in adipocytes and resident ATM stimulates the production of pro–inflammatory cytokines that disrupt insulin receptor signaling, thereby exacerbating insulin resistance. These inflammatory responses establish MAPK signaling as a critical contributor to metabolic deterioration and impaired adipose tissue remodeling [41].

The TGF–β superfamily, particularly TGF–β1 and activins, also acts as a potent inhibitory signaling pathway in adipogenesis. Unlike BMPs, which promote adipogenic commitment, TGF–β1 signals through SMAD2/3 to repress PPARγ expression and maintain progenitor cells in an undifferentiated state. TGF–β signaling disrupts early adipogenic induction and interferes with C/EBPβ activation, effectively blocking the initiation of the adipogenic cascade [42]. In vivo, elevated TGF–β1 levels are associated with fibrosis and reduced adipose tissue expandability, further underscoring its inhibitory role (Fig. 1) [43].

Additionally, canonical wingless–related integration site (Wnt)/β–catenin exerts strong anti–adipogenic effects. Wnt activation stabilizes β–catenin and prevents the expression of PPARγ and C/EBPα, thereby maintaining progenitors in a pre–adipogenic or fibroblastic state (Fig. 1). While inhibition of adipogenesis may limit adipose expansion, chronic Wnt activation restricts the formation of beige adipocytes, impairs tissue remodeling, and promotes hypertrophic and dysfunctional adipocytes [44]. Wnt signaling also regulates incretin secretion in the gastrointestinal tract, linking this pathway to systemic glucose metabolism [45]. Notch signaling similarly restricts adipogenic differentiation by inducing Hes/Hey transcriptional repressors that interfere with adipogenic gene networks. Although sustaining progenitor proliferation, experimental studies showed that Notch signaling inhibits the cell–cycle exit required for terminal differentiation, leading to the loss of C/EBPα and PPARγ induction [46].

In parallel with canonical anti–adipogenic signaling pathways, endocrine regulators arising from the gastrointestinal tract also influence adipose tissue remodeling and systemic energy balance. Among these, glucagon–like peptide (GLP)–1 acts primarily through the gut-brain axis to suppress appetite, reduce calorie intake, and improve metabolic homeostasis. In addition to these central effects, GLP–1 receptor agonists have been associated with indirect modulation of adipose tissue function, including improved insulin sensitivity, activation of AMPK–related pathways, reduced inflammation, and increased thermogenic potential [47, 48]. However, the extent to which GLP–1 exerts direct anti-adipogenic effects in adipocytes remains incompletely understood and is still under debate. Thus, GLP-1 is best understood as an endocrine regulator that indirectly affects adipose tissue expandability rather than a canonical intracellular anti-adipogenic pathway.

In addition to inflammatory and hormonal regulation, mechanical cues within the adipose microenvironment have emerged as key regulators of progenitor fate and adipose tissue expandability. ECM remodeling and fibrosis increase matrix stiffness during obesity, activating integrin–focal adhesion kinase (FAK) signaling and downstream Hippo pathways mechanosensors that suppress adipogenic differentiation. Increased ECM stiffness promotes nuclear translocation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which suppresses PPARγ activity, impairs adipogenic differentiation, and maintains progenitors in a fibro‑inflammatory state, thereby shifting adipose expansion toward hypertrophy rather than hyperplasia. Conversely, compliant ECM environments favor cytoplasmic retention of YAP/TAZ, enabling adipogenic commitment and supporting adaptive adipose tissue remodeling. These findings identify mechanotransduction and ECM-dependent signaling as critical regulators of adipose tissue plasticity and obesity-associated dysfunction [49, 50].

Taken together, anti–adipogenic pathways are a multilayered regulatory network that acts at distinct checkpoints of adipogenesis. AMPK restricts the metabolic shift required for differentiation, inflammatory cascades destabilize the adipogenic transcriptional machinery, TGF–β and Wnt signaling prevent lineage commitment and transcriptional progression, and sustained MAPK activation inhibits terminal maturation. These mechanisms ensure that adipogenesis proceeds only under favorable metabolic, hormonal, and environmental conditions.

Although signaling pathways determine whether adipogenesis is initiated or repressed, the execution of the differentiation process ultimately depends on a hierarchical transcriptional network that converts extracellular cues into stable adipocyte phenotype. Once progenitor cells receive appropriate hormonal and environmental signals, a tightly coordinated transcriptional cascade is activated, driving pre–adipocytes through early differentiation and toward a mature adipocyte phenotype.

Adipogenesis Core Transcription Cascade

Adipogenesis is driven by a highly ordered and tightly regulated transcriptional cascade that converts external hormonal, nutritional, and metabolic cues into a stable adipocyte–specific gene expression program. This core transcriptional machinery operates downstream of lineage commitment and upstream of terminal phenotypic differentiation, acting as a nuclear regulatory framework that irreversibly establishes adipocyte identity. In parallel, adipogenesis involves profound changes in cell morphology, insulin sensitivity, and the reprogramming of the secretory profile that defines the endocrine functions of mature adipocytes [19].

In mammalian cells, adipogenesis is primarily controlled by the sequential activation of C/EBP transcription factors, followed by the induction of PPARγ, which acts as the central regulator of adipocyte lineage determination [21]. Importantly, the activity of these transcriptional regulators is tightly modulated by the PI3K–Akt–mTOR signaling axis, which integrates insulin, lipid synthesis and transport, growth factor, and nutrient signals, whose coordinated activity ensures the proper initiation, amplification, and stabilization of adipocyte differentiation [19].

Early Transcriptional Initiation: C/EBPβ and C/EBPδ

C/EBP belongs to a family of conserved basic leucine zipper transcription factors comprising six distinct isoforms, among which C/EBPβ, C/EBPδ and C/EBPα play the most prominent roles in driving adipocyte differentiation [51].

The earliest phase of adipogenesis is marked by the rapid and transient induction of the transcription factors C/EBPβ and C/EBPδ, which act as the primary molecular links between extracellular adipogenic stimuli and the transcriptional events that commit cells to the adipocyte differentiation program [52].

In classical in vitro models such as 3T3–L1 pre–adipocytes, the expression of C/EBPβ and C/EBPδ is induced within the first hours of differentiation following hormonal stimulation, particularly in response to insulin (which promotes glucose uptake and subsequent TGs storage), glucocorticoids such as dexamethasone (which preferentially induces C/EBPδ expression), and agents that elevate intracellular cAMP levels (such as 3–isobutyl–1–methylxanthine, IBMX, which primarily induces C/EBPβ) [53,54,55].

This hormonal cocktail activates the adipogenic program, leading to an early transcriptional response that precedes the activation of PPARγ and marks the first decisive molecular transition toward adipogenic commitment and subsequent differentiation. In vitro studies have shown that the loss of C/EBPβ and C/EBPδ significantly disrupts adipogenesis, inhibiting the proper induction of downstream regulators such as C/EBPα, PPARγ, and fatty–acid binding protein 4 (FABP4). Notably, in vivo studies have demonstrated that although adipogenesis can be initiated in the absence of C/EBPβ and C/EBPδ, adipose tissue development is severely compromised, indicating that adipocyte differentiation follows a tightly ordered transcriptional hierarchy in which the expression of C/EBPα and PPARγ, despite being essential, cannot independently support the formation of fully functional mature adipocytes [56].

Once induced, C/EBPβ and C/EBPδ bind to regulatory regions of multiple adipogenic genes, most notably those encoding PPARγ and C/EBPα, thereby initiating the transcriptional cascade that ultimately drives terminal adipocyte differentiation. Although both factors are expressed at this early stage, C/EBPβ plays a predominant role, whereas C/EBPδ functions mainly as a cooperative regulator that reinforces the adipogenic signal. Importantly, the transcriptional activity of C/EBPβ is not immediate, as it requires sequential post–translational modifications, including phosphorylation by MAPK and glycogen synthase kinase (GSK)3β, which are essential for its full DNA–binding capacity and transactivation potential [37, 57]. This temporal regulation ensures that cell–cycle progression during mitotic clonal expansion is properly coordinated with the onset of differentiation.

In addition to activating the core adipogenic regulators, C/EBPβ and C/EBPδ control a set of early–response genes involved in cell–cycle regulation, chromatin remodeling, and the initial metabolic adaptation of differentiating cells [58]. During mitotic clonal expansion, C/EBPβ supports the expression of cyclins and other proliferation–associated factors while simultaneously priming the chromatin landscape for subsequent PPARγ–driven transcription. Through this dual function, C/EBPβ serves as a key integrator of proliferative signals and differentiation cues during the early stages of adipogenesis [11, 33].

The expression, activity, and stability of C/EBPβ and C/EBPδ are tightly regulated by upstream signaling pathways, particularly the PI3K/Akt, MAPK/ERK, and cAMP/PKA cascades, which integrate hormonal, nutritional, and energy–related signals. Perturbations in these pathways markedly affect early adipogenic commitment by altering C/EBPβ and C/EBPδ induction or activation, thereby compromising PPARγ expression and subsequent adipocyte formation [11, 59]. Together, these early transcription factors define the entry point of the adipogenic program and play a decisive role in determining both the timing and efficiency of adipocyte differentiation.

Adipocyte Identity: PPARγ as the Master Regulator

The establishment of adipocyte identity is critically dependent on PPARγ, which functions as the central regulator of the adipogenic transcriptional program. Following the early induction of C/EBPβ and C/EBPδ, the activation of PPARγ marks the transition from a permissive differentiation state to a stable and irreversible mature adipocyte phenotype. At this stage, differentiation becomes self-sustaining, as PPARγ initiates a robust transcriptional network that consolidates both the morphological and metabolic features of mature adipocytes [59].

PPARs are ligand–dependent transcription factors of the nuclear hormone receptor family that regulate gene expression by binding to specific DNA response elements in target genes. Within the PPAR family, three main isoforms have been identified, PPARα, PPARβ (also known as PPARδ), and PPARγ, which display distinct tissue distributions and complementary metabolic functions. PPARα is highly expressed in metabolically active tissues such as the liver, heart, and brown adipose tissue, where it promotes fatty acid uptake and oxidation, ketogenesis, and metabolic adaptation to fasting. PPARβ/δ is ubiquitously expressed and acts as a key regulator of metabolic flexibility, coordinating lipid and glucose utilization, mitochondrial function, and oxidative metabolism across multiple tissues, including skeletal muscle and adipose tissue. In addition to its metabolic role, PPARβ/δ exerts anti-