Lipid availability in reproductive systems exhibits marked heterogeneity, with distinct patterns across germ and somatic cells as well as species-specific adaptations. For instance, while oocytes in lipid-rich species like pigs, cows, and humans amass numerous cytoplasmic LDs that confer opacity and fuel early embryogenesis through β-oxidation and membrane synthesis, murine oocytes maintain lower lipid reserves, highlighting metabolic divergences (9-12). In somatic support cells, LD profiles are tailored to functional demands: Sertoli cells show cyclic LD accumulation tied to phagocytosis and spermatogenic cycles (15-17), whereas granulosa and luteal cells prioritize cholesteryl ester storage for sustained steroidogenesis under hormonal regulation (20-22).

In addition to spatial heterogeneity, LDs exhibit notable temporal regulation throughout reproductive processes. During oocyte growth, LD content increases as neutral lipids are synthesized or imported and stored in preparation for fertilization and early embryonic development (11,12). Following fertilization, maternally inherited LDs undergo redistribution and partial consumption during cleavage divisions, reflecting a shift from lipid storage to utilization (13,31).

Similar temporal patterns are evident in reproductive somatic cells: In Sertoli cells, LD abundance fluctuates across the spermatogenic cycle, increasing during periods of active germ cell turnover and phagocytosis of residual bodies (16,17,45,46). In granulosa cells, LD accumulation intensifies during follicular maturation and peaks following luteinization, coinciding with maximal steroidogenic activity (24,47,48). These dynamic changes indicate that LDs are not static lipid depots but responsive organelles whose formation and turnover are associated with developmental timing and hormonal cues.

Once accumulated, lipids stored within LDs serve as key metabolic substrates. Triacylglycerols can be hydrolyzed to release fatty acids (FAs) that fuel mitochondrial β-oxidation, providing ATP during energetically demanding processes such as oocyte maturation, early embryonic cleavage and spermatogenic support by Sertoli cells (11,13,49). In parallel, LD-derived lipids contribute to membrane biogenesis, ensuring sufficient phospholipid supply during rapid cell division and cellular remodeling (50).

The balance between lipid storage and mobilization is regulated. Excessive lipid accumulation leads to lipotoxicity and oxidative stress, whereas insufficient lipid reserves compromise energy availability and developmental competence (14,51). Reproductive cells therefore rely on coordinated control of lipid synthesis, lipolysis and oxidation to maintain metabolic homeostasis across fluctuating physiological demands (49,50).

Beyond their metabolic roles, LDs integrate lipid metabolism with signaling and regulatory pathways. The controlled release of bioactive lipid species from LDs influences nuclear receptor activation, including peroxisome proliferator-activated receptors (PPARs), thereby modulating transcriptional programs associated with cell differentiation and developmental progression (52,53). In steroidogenic cells, LDs store cholesteryl esters that are rapidly mobilized in response to gonadotropic stimulation, coupling lipid storage directly to hormone biosynthesis (20-22).

LDs also engage in notable physical and functional interactions with other organelles. Increasing evidence supports the existence of membrane contact sites between LDs and mitochondria or the ER, enabling efficient lipid transfer, metabolic channeling and coordination of redox homeostasis (54,55). Ultrastructural evidence supports the concept of LDs as metabolic hubs: Electron microscopy studies have revealed tight membrane contact sites between LDs and mitochondria or the ER, indicating that these organelles are physically connected rather than randomly juxtaposed (54-57). Such contacts are hypothesized to facilitate efficient lipid transfer, metabolic channeling and coordinated regulation of energy production and lipid metabolism, providing a structural basis for the functional interactions illustrated in schematic models (58,59). Through these interactions, LDs serve not merely as passive reservoirs but as dynamic hubs that synchronize energy metabolism, signaling and cell adaptation during reproduction (2,10).

Accumulating evidence indicates that the LD-mitochondria interface represents a physically tethered unit rather than a transient or stochastic association (58,60). Ultrastructural analyses have revealed well-defined membrane contact sites that anchor LDs to mitochondria, thereby establishing stable platforms for lipid transfer and metabolic coordination (54,55,61,62). These contact sites are mediated by specific tethering proteins that physically link the organelles. Among these, PLIN5 is a LD-associated protein that promotes sustained LD-mitochondria coupling and facilitates the channeling of FAs from LDs to mitochondria for β-oxidation. In parallel, mitoguardin 2, a mitochondrial outer membrane protein, forms physical bridges between mitochondria and LDs, coordinating lipid trafficking and mitochondrial energy metabolism (54,63,64). Together, these tethering mechanisms support a model in which LDs and mitochondria serve as integrated metabolic units, providing a structural and molecular basis for the metabolic hub concept in reproductive cells.

The diverse and sometimes contradictory functions of LDs can be reconciled by viewing them as organelles with multiphase activities that are dynamically regulated across developmental and physiological contexts. In a storage phase, LDs primarily accumulate neutral lipids, serving as reservoirs that buffer energy availability and protect cells from lipid overload. During metabolic phases, LDs undergo controlled lipolysis, releasing FAs that fuel mitochondrial β-oxidation and support membrane biosynthesis. In signaling phases, LD-derived lipid species serve as bioactive molecules that engage nuclear receptors, such as PPARs, thereby influencing transcriptional programs associated with cell fate decisions and developmental progression (2,60,65).

The transition between these phases is not fixed but context-dependent, shaped by developmental timing, hormonal cues and cellular energy demands. This multiphase framework provides a conceptual basis for understanding how the same LD population alternately serves as a protective storage depot, a metabolic fuel source or a signaling platform during reproduction (2,41,48,66).

LD biogenesis in oocytes is a tightly orchestrated process that coincides with folliculogenesis. Throughout the growing phase, oocytes accumulate neutral lipids via both de novo synthesis and uptake of exogenous FAs, which are esterified and stored in LDs (37,68). During oocyte growth, LDs primarily operate in a storage phase, ensuring sufficient lipid reserves for subsequent developmental transitions. In large antral follicles, LDs become prominent cytoplasmic features (68). Their abundance and distribution vary across species: Porcine and bovine oocytes are lipid-rich and visibly opaque, whereas murine and human oocytes have fewer LDs and a clearer cytoplasm (41,42,70,71). These differences reflect fundamental differences in lipid metabolism, sensitivity to in vitro conditions and developmental strategies (49,72). For example, lipid-rich oocytes in porcine and bovine species rely heavily on β-oxidation of stored lipids for energy during early embryogenesis, as shown by reduced developmental rates when β-oxidation inhibitors are applied in culture (11). In contrast, murine oocytes exhibit greater dependence on glycolysis, making them less sensitive to lipid perturbations but more vulnerable to glucose fluctuations in vitro (73). Human oocytes, while lipid-moderate, show intermediate sensitivity, with in vitro maturation success influenced by media supplements that mitigate oxidative stress from lipid peroxidation (74). These variations underscore species-specific reproductive adaptations, where lipid-rich strategies buffer against nutrient scarcity post-fertilization, whereas lipid-poor ones prioritize rapid external nutrient uptake (49).

Oocyte capacity to accumulate and mobilize LDs is associated with the ability to resume meiosis and support embryo development (72,75). Disruptions in LD formation, either through inhibition of DGAT1/2 or alterations in FA composition, impair nuclear maturation and decrease blastocyst yield, underscoring the role of LDs in establishing developmental competence (49,69,76).

LDs undergo dynamic spatial reorganization during meiotic maturation. In many species, LDs are dispersed throughout the oocyte cytoplasm at the germinal vesicle (GV) stage, then undergo clustering or partial consumption during GV breakdown and metaphase II transition (31,37,49,77). These changes may reflect a metabolic switch: As the oocyte transitions from quiescence to a highly active biosynthetic state, lipid oxidation increases, supported by mitochondrial redistribution and enhanced FA flux (67,68).

Moreover, LD remodeling is typically coordinated with organelle positioning. In mammalian oocytes, LDs have been observed in proximity to mitochondria and ER-derived vesicles, suggesting metabolic crosstalk and potential transfer of lipid species (54,55,61,62). These interactions may be key for shaping mitochondrial function, as lipid overload or misdistribution is associated with increased ROS production and mitochondrial dysfunction, which are detrimental to fertilization and embryo cleavage (63,64,71).

The functional integrity of LDs in oocytes is governed by a tightly regulated network of enzymes and structural proteins (37,69). DGAT2, which catalyzes TAG synthesis, is enriched in growing oocytes, and its inhibition leads to decreased lipid storage and impaired oocyte maturation (69,76). Similarly, the LD surface protein PLIN2 is abundantly expressed in lipid-rich oocytes, and is hypothesized to stabilize LDs by preventing premature lipolysis (78-80). Knockdown or pharmacological interference with PLIN2 results in dysregulated lipid metabolism and altered oocyte developmental trajectories (69,81).

In addition to synthesis and stabilization, lipid mobilization is precisely timed. Lipolytic enzymes such as ATGL and HSL are activated in peri-ovulatory periods, allowing controlled release of FAs for β-oxidation and membrane synthesis (82-85). An imbalance in this process, either via excessive lipid accumulation or hyperactive lipolysis, compromises oocyte viability (86).

LD content and composition in the oocyte are not solely determined by intrinsic metabolic programs. Surrounding cumulus and granulosa cells contribute to the oocyte lipid profile through paracrine signaling and metabolite transfer (41,87,88). Cumulus-oocyte complexes exhibit extensive gap junction communication, allowing transfer of small lipophilic molecules such as FAs and sterols (89-92). Cumulus cells express lipoprotein receptors, FA transporters and lipogenic enzymes, and can modulate the lipid environment of the oocyte in response to gonadotropic stimulation or dietary lipid availability (41,91,93).

Alterations in cumulus cell metabolism, such as those seen in high-fat diet models or PCOS, lead to excessive lipid accumulation in oocytes and are associated with lower fertilization and blastocyst rates (71,77,93). These findings emphasize that LD metabolism in the oocyte must be understood in the context of the follicular microenvironment (41,87,88).

Because LD content reflects metabolic history and readiness for fertilization, it is increasingly studied as a biomarker of oocyte competence (31,94,95). Non-invasive imaging modalities, such as CARS microscopy, have made it possible to quantify LD content in live oocytes and demonstrate its association with subsequent embryo development (31,96-99). Moreover, interventions aimed at modifying LD metabolism through culture media supplementation with oleic acid or antioxidants have shown potential to rescue poor-quality oocytes by rebalancing lipid profiles (96-99).

Altogether, LDs in oocytes serve as more than static energy stores; they are dynamic organelles whose content, composition and spatial behavior are critical determinants of oocyte maturation and developmental success (37,69). Their regulation is multifactorial, involving intrinsic enzyme systems, extrinsic paracrine input and inter-organelle coordination. Understanding and manipulating LD biology in the oocyte may thus represent a promising avenue for improving assisted reproduction outcomes (96,100,101).

During the early phases of spermatogenesis, including in spermatogonia and early spermatocytes, LDs are readily observed and serve as temporary energy reserves and platforms for lipid remodeling (15,102,103). As germ cells differentiate toward the elongated spermatid stage, LD content typically declines, which is associated with cytoplasmic condensation and organelle removal (15,102). However, disturbances in lipid storage and LD homeostasis during these early stages impair germ cell differentiation and decrease sperm output (43,104,105).

Model organisms such as Drosophila and C. elegans are key in dissecting LD function during spermatogenesis (43). For example, the Drosophila homolog of ATGL, Brummer, localizes to LDs in testicular germ cells and its deletion results in massive LD accumulation and spermatogenic arrest (43). Similarly, in mammals, ATGL and HSL are functionally important in lipid mobilization during spermatogenic progression (43,106). Deficiency in these enzymes leads to abnormal lipid accumulation, disrupted spermatid elongation and reduced fertility (106).

While studies in C. elegans have uncovered genetically conserved roles of LD in embryonic integrity (25,107,108), mammalian systems exhibit additional layers of complexity, particularly in steroidogenesis and hormonal regulation. For instance, LDs in mammalian reproductive cells integrate with hormone-responsive lipases to mobilize cholesterol for steroid hormone synthesis and interact with organelles such as mitochondria for enhanced metabolic channeling, features modulated by endocrine signals absent in simpler models (Table I).

Sertoli cells provide structural and metabolic support to developing germ cells (46,109-111). Sertoli cells contain abundant LDs, the composition and abundance of which fluctuate in response to the spermatogenic cycle and phagocytic activity (45,46,110). One notable source of LDs in Sertoli cells is the engulfment of residual bodies (cytoplasmic fragments shed by spermatids during final maturation) (17,46,110,112). Lipid-rich components of these residual bodies are internalized and sequestered into LDs within Sertoli cells, where they may be catabolized via β-oxidation or lipophagy to fuel Sertoli cell metabolism (15,17,46).

The dynamic balance between LD formation and degradation in Sertoli cells is key for maintaining testicular homeostasis (103,113,114). Exposure to toxicants such as lead or cadmium disrupts lysosomal and autophagic pathways in Sertoli cells, leading to impaired LD clearance, lipid overload and testicular dysfunction (113). Furthermore, hormonal regulation, particularly by FSH, modulates LD content in Sertoli cells by stimulating lipid uptake and lipogenic gene expression (109). This endocrine-metabolic axis ensures that Sertoli cells are metabolically equipped to support the rapid turnover of lipids during active spermatogenesis (109,111,114).

While rodent models have provided insights into the metabolic coupling between Sertoli and germ cells, key differences exist between human and rodent spermatogenesis (115,116). Human spermatogenesis is characterized by a longer developmental timeline, distinct seminiferous epithelial organization and differences in hormonal regulation and metabolic demands compared with commonly used rodent models (117,118). Moreover, the dynamics of lipid metabolism and LD turnover in human Sertoli cells are less well characterized, in part due to limited access to human testicular tissue (115,117,119).

These species-specific features suggest that, although core principles of Sertoli-germ cell metabolic support are potentially conserved, direct extrapolation from rodent studies to human reproductive physiology should be approached with caution. Integrating findings from human tissue analyses, organoid systems and single-cell profiling is key to define the relevance of LD-mediated mechanisms in human spermatogenesis (120-123).

Although mature spermatozoa lack classical LDs (typical cytoplasmic organelles characterized by a hydrophobic core of neutral lipids encased in a phospholipid monolayer), lipid metabolism is key for their structural and functional integrity (43,124). The plasma membrane of sperm is rich in polyunsaturated FAs (PUFAs), which provide membrane fluidity necessary for motility and capacitation (124-130). The composition of these lipids is tightly regulated during epididymal maturation and influenced by prior LD metabolism in germ and Sertoli cells (43,103,124,131).

Enzymes such as acyl-CoA synthetase long-chain family members, which participate in FA activation and incorporation into complex lipids, are key for proper sperm development (75). Genetic disruption of these enzymes leads to altered lipid composition and defective sperm morphology (75). These findings suggest that early LD metabolism indirectly shapes sperm functionality by controlling the availability and remodeling of lipid precursors (43, 75,124).

Aberrant lipid metabolism in the testis is increasingly implicated in male reproductive disorder (43,104,105,132). In both mouse and rat models and human patients, disturbances in lipid homeostasis, manifested as altered LD dynamics, defective lipolysis or accumulation of cholesteryl esters, are associated with low sperm count, impaired motility and hormonal imbalance (43,104-106,132). Notably, mouse models with HSL knockout exhibit lipid-laden Leydig cells, decreased testosterone levels and oligospermia, underscoring the importance of intact LD mobilization for androgen synthesis and spermatogenic support (106,133,134).

Lipidomics and histological analyses of human testicular biopsies have revealed elevated LD accumulation in Sertoli and Leydig cells of infertile patients, often accompanied by disrupted mitochondrial morphology and increased oxidative stress markers (119,135-137). These observations further reinforce the idea that LD dysregulation contributes to male infertility not only through energy imbalance, but also by disrupting redox homeostasis, membrane remodeling and hormone production (43,104,106,132,138).

Sertoli cells are the central architectural and metabolic support for spermatogenesis, forming the blood-testis barrier, providing nutrients to developing germ cells and clearing apoptotic or senescent spermatocytes (139). These cells contain prominent LDs, particularly during periods of active spermatogenic turnover or high phagocytic activity (15).

A notable source of lipids for LD formation in Sertoli cells is the internalization of residual bodies and degenerating germ cells (17). These engulfed materials, rich in membrane and cytoplasmic lipids, are processed in lysosomes, with a portion of the liberated FAs and sterols re-esterified and stored in LDs. These droplets are mobilized for energy production via β-oxidation, allowing Sertoli cells to meet their metabolic demands while supporting adjacent spermatogenic cells (141).

The degradation of LDs in Sertoli cells involves not only cytosolic lipases (HSL) but also selective autophagy of LDs, known as lipophagy (142). This process is regulated by nutrient availability and endocrine factors. Under physiological stress or toxicant exposure (lead, cadmium), lysosomal dysfunction or autophagy impairment leads to LD accumulation, disrupted lipid homeostasis and impaired Sertoli cell function, contributing to testicular atrophy and infertility (143).

Furthermore, hormonal regulation serves a key role in LD dynamics. FSH promotes lipid uptake and storage in Sertoli cells by upregulating lipoprotein receptors and lipogenic gene expression. This hormonally mediated lipid buffering ensures an adequate energy reserve during active spermatogenesis and facilitates metabolic synchronization between Sertoli and germ cells (109,144-146).

Granulosa cells, which surround and support the developing oocyte, undergo extensive metabolic reprogramming as follicles mature (147). In the pre-ovulatory phase, these cells proliferate, increase steroidogenic activity and accumulate LDs rich in cholesteryl esters (49). Following ovulation, granulosa cells differentiate into luteal cells, which are among the most steroidogenically active cells in the body (147). In both phases, LDs serve as central platforms for steroid hormone biosynthesis (148).

LDs in granulosa and luteal cells store cholesteryl esters that serve as substrates for estrogen and progesterone synthesis, respectively (149). Upon gonadotropin (FSH or LH) stimulation, HSL is activated and hydrolyzes cholesteryl esters into free cholesterol (148). The cholesterol is transported to mitochondria via steroidogenic acute regulatory protein, where it is converted to pregnenolone by CYP11A1, initiating the steroidogenic cascade (149).

Several studies have demonstrated that LD content and associated enzyme expression levels vary depending on follicular stage and endocrine environment (150-153). For example, mature preovulatory granulosa cells contain larger and more numerous LDs than their early antral counterparts, consistent with enhanced steroidogenic readiness (23). Disruption of lipid mobilization pathways via HSL inhibition, PLIN dysregulation or excessive lipid accumulation impairs estrogen and progesterone synthesis, follicular rupture and corpus luteum formation (150).

Proteomic and lipidomic profiling of granulosa cell LDs has identified key components of the steroid biosynthetic machinery localized to or enriched around LDs, including enzymes of the P450 family and mitochondrial contact proteins (90). These findings suggest that LDs are not passive lipid depots, but serve as biochemical scaffolds that facilitate rapid and localized hormone production (148).

Beyond their intrinsic functions, support cell LDs also influence germ cell development through metabolic coupling and paracrine interactions (154). Cumulus granulosa cells, which form the innermost layer of follicular somatic cells directly surrounding the oocyte, are metabolically connected to the oocyte via transzonal projections and gap junctions (155). These cells actively metabolize glucose and FAs, generating pyruvate, amino acids and lipid intermediates that are transferred to the oocyte to support growth and maturation (28,154).

LDs within cumulus cells reflect this metabolic activity (156). Their number and size increase with gonadotropin stimulation and they show dynamic responses to oxidative stress, FA exposure and endocrine disruption (157). Excess accumulation of saturated FAs in cumulus cell LDs, such as under high-fat diet or PCOS, alter oocyte lipid composition, increase ER stress and reduce developmental competence (156).

Therefore, somatic cell LDs contribute indirectly to oocyte quality by modulating the follicular lipid environment, buffering toxic lipid species and fine-tuning substrate availability for oocyte maturation (157). Disruption of these functions leads to broader metabolic dysfunction and subfertility, highlighting the need to consider support cell lipid metabolism in the assessment of reproductive health (89).

Upon fertilization, the zygote inherits LDs from the oocyte, which vary in size, number and lipid composition across species (72). Following fertilization, LDs transition toward a metabolic phase characterized by enhanced lipolysis and FA oxidation (FAO). In lipid-rich species such as pigs and cows, zygotes contain abundant LDs that are readily visualized by light microscopy, while in mice and humans LDs are smaller (159). These maternal LDs are progressively redistributed during the first cleavage divisions (42). Time-lapse imaging studies reveal that LDs undergo dynamic clustering, dispersion and partial lipolysis in synchrony with cell cycle progression (158,160-162). This remodeling reflects a shift from maternal lipid storage toward active use, enabling the embryo to meet energetic demands of rapid mitosis (31). Beyond serving as lipid reservoirs, LDs in early embryos also participate in the storage and regulation of non-lipid macromolecules. Johnson et al (126) demonstrated that LDs in early embryos serve as storage depots for maternal histones and selectively recruit RNA-binding proteins involved in post-transcriptional regulation. Through this mechanism, LDs contribute to the temporal control of mRNA translation during early embryogenesis, a developmental window characterized by limited zygotic transcription. These findings expand the functional scope of LDs beyond energy metabolism, positioning them as organizational platforms that coordinate lipid storage with proteostasis and translational control in the early embryo.

The extent of LD remodeling is sensitive to culture conditions and external nutrient availability (163). Embryos cultured in vitro often display altered LD number and distribution compared with in vivo counterparts, which has been linked to reduced developmental potential (164). These findings highlight LDs as sensitive indicators of embryo metabolic state (71).

During cleavage, embryos rely primarily on pyruvate and lactate metabolism, but FAO becomes increasingly important as development proceeds to the blastocyst stage (49). LDs provide a readily accessible pool of FAs through controlled lipolysis (165). Inhibition of FAO enzymes such as carnitine palmitoyltransferase 1 (CPT1) leads to developmental arrest, underscoring the importance of LD-derived FAs in sustaining blastocyst formation (166).

Mitochondrial-LD interactions are central to this process (37). In mouse and bovine embryos, LDs are typically found close to mitochondria, facilitating efficient FA transfer and oxidation (13). This spatial proximity suggests that LDs and mitochondria form functional units that coordinate energy production and redox regulation during early development (167).

An additional context in which LD-mitochondria interactions may be relevant is ovarian aging. Advanced maternal age is associated with progressive mitochondrial dysfunction in oocytes, including decreased oxidative capacity, altered mitochondrial dynamics and increased oxidative stress (168,169). Emerging evidence suggests that aged oocytes often display abnormal LD accumulation and altered lipid distribution, raising the possibility that impaired mitochondrial FA utilization contributes to LD dysregulation during aging (69,170,171).

Whether aberrant LD accumulation in aged oocytes represents a compensatory response to mitochondrial insufficiency or a maladaptive process that compromises oocyte quality remains unresolved. Clarifying how mitochondrial dysfunction intersects with LD storage, mobilization and oxidative stress control during ovarian aging is key for understanding age-associated declines in oocyte competence and embryo developmental potential.

In addition to their roles in energy metabolism and signaling, LDs have recently been implicated in protecting embryos from lipid peroxidation and ferroptotic cell death (172-174). PUFAs, while essential for membrane synthesis and developmental signaling, are susceptible to oxidative damage. Sequestration of PUFAs within LDs limits their availability for uncontrolled lipid peroxidation, thereby decreasing oxidative stress and ferroptosis during early embryonic development (174-177).

Recent studies have highlighted LDs as key buffers that spatially compartmentalize PUFAs away from pro-oxidant environments, particularly under conditions of heightened mitochondrial activity and reactive oxygen species production (175,176,178). This protective function may be key during early embryogenesis, when antioxidant capacity is limited and metabolic demands rapidly increase. Together, these findings position LDs not only as metabolic hubs but also as key guardians of redox homeostasis and embryo survival.

While FA β-oxidation is a notable pathway through which LD-derived lipids support reproductive processes, its flux is constrained by a rate-limiting step: The transport of long-chain FAs into mitochondria (179-181). This process is mediated by the carnitine shuttle system, which consists of CPT1 on the outer mitochondrial membrane and CPT2 on the inner membrane (2,179,182,183). CPT1 catalyzes the conversion of long-chain acyl-CoAs into acyl-carnitines, enabling their translocation across the mitochondrial membranes, whereas CPT2 reconverts acyl-carnitines into acyl-CoAs within the mitochondrial matrix for β-oxidation (180,184-186).

In oocytes and early embryos where mitochondrial oxidative capacity is tightly coupled with developmental competence, disruption of carnitine-dependent FA transport leads to impaired energy production and developmental arrest, underscoring the importance of this regulatory checkpoint in lipid utilization (49,166). Notably, supplementation with L-carnitine or acetyl-L-carnitine improves mitochondrial function, enhances FAO and increases blastocyst yield in multiple assisted reproduction settings (187,188). These findings suggest that the carnitine shuttle not only represents a biochemical bottleneck of LD-derived energy metabolism, but also constitutes a clinically actionable node linking LD biology to gamete quality and embryo developmental outcomes.

Beyond energy supply, LDs also protect early embryos from lipotoxicity and oxidative stress (2). Excess accumulation of saturated FAs in culture or maternal metabolic disorders can trigger ER stress and apoptosis in embryos (69). By sequestering potentially toxic lipids into LDs, embryos buffer against lipotoxic insult (189). Moreover, LDs can serve as sinks for peroxidized lipids, thereby limiting propagation of oxidative damage (190). This detoxification role is key during preimplantation, when embryonic antioxidant defenses are developing (161).

As embryos reach the blastocyst stage, LD distribution becomes asymmetric between inner cell mass (ICM) and trophectoderm (TE) (42). TE cells, which contribute to the placenta, contain more and larger LDs than ICM cells, suggesting lineage-specific metabolic requirements (42,158,191). This differential LD allocation may reflect the TE role in steroidogenesis, nutrient transport and implantation, which demand robust lipid metabolism (158).

In pluripotent ICM cells, LDs are fewer but metabolically active, supporting a glycolysis-dominant phenotype typical of stem cells (192). Manipulating LD metabolism in vitro influences stem cell fate: Pharmacological activation of lipolysis promotes differentiation, while stabilizing LDs maintains pluripotency (193). These findings position LDs as regulators of cell fate transitions in the embryo (194).

Understanding LD biology in embryos has practical implications (72). In assisted reproductive technology, embryo selection is typically based on morphology, yet LD content and dynamics may provide more sensitive biomarkers of viability (31). Non-invasive imaging techniques such as CARS microscopy have been applied to quantify LDs in live embryos, revealing an association between lipid distribution and implantation success (160).

In stem cell biology, insights into LD regulation in early embryos inform strategies to maintain pluripotency in vitro and direct differentiation (49). For example, modulating lipid availability or LD turnover influences epigenetic programming, since acetyl-CoA and lipid-derived metabolites serve as cofactors for chromatin-modifying enzymes. Thus, LDs not only support metabolic needs but also contribute to epigenetic landscapes that govern developmental trajectories (195).

LD biogenesis begins with the synthesis of neutral lipids within the ER, a process primarily mediated by enzymes such as DGAT1 and DGAT2 for triacylglycerols and acyl-CoA cholesterol acyltransferases (ACATs) for cholesteryl esters (140). In reproductive cells, these enzymes facilitate metabolic readiness: In oocytes, DGAT2 activity underlies the accumulation of lipid stores necessary for meiotic progression (196), while in granulosa and luteal cells, ACAT-mediated cholesterol esterification establishes a pool of precursors for steroid hormone synthesis (149). Disruption of these synthetic pathways reduces oocyte competence and compromises hormone production, highlighting their key role in reproductive physiology (150).

Once formed, LDs are stabilized and functionally tuned by coat proteins, most prominently the PLIN family (197). PLIN2, highly abundant in lipid-rich oocytes and granulosa cells, prevents uncontrolled lipolysis and ensures lipids remain available for developmental cues (37,48,68). PLIN3, enriched in steroidogenic cells, contributes to cholesterol storage and supports rapid progesterone synthesis following LH stimulation (22,24,47). These surface proteins not only regulate LD size and stability but also serve as molecular scaffolds that recruit lipases or tether LDs to partner organelles, integrating storage with utilization (2).

Mobilization of LD lipids is mediated by lipolytic enzymes, whose activity is coupled to reproductive events (148). ATGL initiates triacylglycerol breakdown, providing FAs for mitochondrial β-oxidation, which is key for oocyte maturation and embryonic cleavage (166). HSL plays a dual role, hydrolyzing both TAGs and cholesteryl esters. In luteal cells, LH-induced phosphorylation of HSL rapidly liberates cholesterol for progesterone synthesis, directly linking lipolysis to endocrine function (147). Failure of these pathways, as seen in mouse knockout models of ATGL or HSL deficiency, results in lipid accumulation, impaired gametogenesis and subfertility (106,133).

The transcriptional and hormonal control of LD regulators provides another layer of coordination (143). Sterol regulatory element-binding proteins activate the expression of lipogenic enzymes, ensuring reproductive cells adapt to energy demand and steroidogenic flux (198). PPARs fine-tune lipid storage and oxidation, with PPARγ promoting lipid accumulation in granulosa cells and PPARα enhancing FA use in embryos (199). Endocrine signals, particularly FSH and LH, further dictate LD dynamics: FSH promotes lipid uptake and storage in Sertoli and granulosa cells, while LH triggers lipolysis and cholesterol mobilization, exemplifying how systemic hormonal cues converge on LD regulation (20,109,200).