Cytosolic versus Lysosomal Lipolysis in Adipose Tissue: Opposing Roles in Cardiometabolic Disease

Abstract

Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the two primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by adipose triglyceride lipase (ATGL/PNPLA2), and the lysosomal pathway governed by lysosomal acid lipase (LAL/LIPA). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.

Graphical Abstract

Adipose Tissue: A Dynamic Metabolic Commander

The global pandemic of obesity, a condition of chronic energy surplus, is a principal driver of cardiometabolic disease morbidity and mortality. In obese states, the buffering capacity of adipose tissue to safely store excess nutrients as triglycerides (TGs) is often exceeded, leading to adipocyte hypertrophy, inflammation, and profound metabolic dysfunction¹. A central feature of this pathology is deranged adipose tissue lipolysis, characterized by elevated basal rates and an impaired anabolic (i.e. anti-lipolytic) response to insulin. Concomitantly, a profound dysregulation of lipid storage is observed, marked by aberrant activity of lipoprotein lipase (LPL), the key enzyme for fatty acid (FA) uptake from circulating lipoproteins. Alterations in paracrine control by inhibitors like angiopoietin-like 4 (ANGPTL4) additionally impair the adipocyte’s fundamental role in buffering of excess lipids. Dysregulation of the various nodes of lipid metabolism and handling in adipose tissue results in chronic and excessive efflux of free FAs into the circulation¹. The overabundance of circulating FA promotes ectopic lipid accumulation in non-adipose tissues like the liver, skeletal muscle, and heart, a phenomenon termed lipotoxicity, which interferes with insulin signaling pathways and fosters systemic insulin resistance. The cascade of events, originating from dysfunctional adipose tissue, is a key instigator of the spectrum of metabolic derangements including type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD), which collectively contribute to the pathogenesis of cardiometabolic and cardiovascular disease (CVD)².

At the center of this pathology, adipose tissue is a multifaceted organ central to systemic energy homeostasis, acting as both a primary caloric reservoir and a dynamic endocrine system³. Its normal metabolic function is rooted in the process of lipolysis, the regulated hydrolysis of stored TGs into FAs and glycerol, which are mobilized to supply energy to other tissues during periods of metabolic demand, such as exercise, cold exposure, or fasting⁴. This vital activity is complemented by the tissue’s endocrine role, secreting a host of adipokines like leptin and adiponectin that modulate appetite and systemic metabolism³. The functional diversity of adipose tissue is highlighted by its heterogeneity, comprising distinct subtypes: white adipose tissue (WAT) for energy storage, and brown adipose tissue (BAT) and beige adipose tissues for thermogenic energy expenditure³.

Adipocyte TG Catabolism: Cytosolic and Lysosomal Lipolysis

It is important to distinguish the intracellular TG catabolism discussed here from the extracellular hydrolysis of circulating TGs. The latter is mediated by the LPL system, which can be regulated by adipocytes (e.g. via ANGPTL4) but primarily functions at the vascular endothelium to facilitate FA uptake (Figure 1A)⁵. This review focuses specifically on the intracellular mobilization of stored TGs, a process termed lipolysis. Lipolysis is governed by a defined series of reactions, that involve the stepwise removal of each FA from TG. The canonical pathway, involving the trio of enzymes adipose triglyceride lipase (ATGL/PNPLA2), hormone-sensitive lipase (HSL/LIPE), and monoglyceride lipase (MGL/MGLL), occurs in the adipocyte cytosol at the surface of the lipid droplet⁴ (Figure 1B). Despite the clear importance of this pathway, evidence in animal models suggests the existence of alternative and complementary mechanisms since TG hydrolysis is still observed, albeit at diminished levels, in the absence of either ATGL^6,7 or HSL⁸. Interestingly, alternative lipolytic pathways are also suggested when considering enhanced lipolysis in adipose tissue during states of obesity⁹, yet protein expression and activity of ATGL remain suppressed¹⁰. Furthermore, while thermogenesis is impaired in mice with systemic ATGL deficiency^11,12, it remains intact when ATGL is deleted in BAT despite the need for a FA fuel source⁷. These observations highlight the need to identify and characterize non-canonical pathways in order to understand adipocyte lipolysis more holistically in the context of metabolic disease. In this regard, an underappreciated mechanism for TG catabolism occurs within the lysosome via lysosomal acid lipase (LAL/LIPA) and has been proposed as a potential alternative pathway (Figure 1B)¹³. This review aims to provide a comprehensive overview of the current understanding of adipose tissue lipolysis and its impact on systemic metabolism and metabolic diseases.

Figure 1. Adipocyte lipid handling via extracellular uptake and intracellular lipolysis.

A. Illustration depicting the main pathways for lipid flux in adipocytes. Fatty acids (FAs) are acquired from circulating triglyceride (TG)-rich lipoproteins (e.g., VLDL, chylomicrons). This uptake is primarily mediated by lipoprotein lipase (LPL), which is anchored to the capillary endothelium by GBIHBP1 and hydrolyzes TGs. Adipocyte-secreted angiopoietin-like 4 (ANGPTL4) acts as a local inhibitor of LPL activity. Lipoproteins may also be taken up via endocytosis. B. Illustration of two primary systems for TG hydrolysis in adipocytes. In Cytosolic Lipolysis (top panel), TGs stored in the central lipid droplet are sequentially broken down by three enzymes: adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL). This cascade releases free fatty acids (FAs) and glycerol into the cytosol. ATGL activity is positively regulated by its co-activator CGI-58 and negatively regulated by the inhibitors G0S2 and HILPDA. In Lysosomal Lipolysis (bottom panel), the content of lipid droplets is engulfed by membranous vesicles and delivered to the lysosome through a process called lipophagy. Within the acidic lysosomal lumen, lysosomal acid lipase (LAL) hydrolyzes the TGs into FAs and glycerol.

Cytosolic Lipolysis: The ATGL-HSL-MGL Cascade

The canonical pathway for mobilizing FAs from TGs stored in adipocyte lipid droplets (LDs) involves the sequential action of three key neutral lipases: ATGL, HSL, and MGL⁴. This enzymatic cascade occurs at the surface of the LD¹⁴, releasing one FA molecule at each step and ultimately converting a TG into three FAs and one glycerol molecule. In adipose tissue, the coordinated action of ATGL and HSL has been shown to be responsible for the majority of TG hydrolysis^15,16.

• Adipose Triglyceride Lipase (ATGL/PNPLA2):

ATGL/PNPLA2 is the primary enzyme that catalyzes the initial and rate-limiting step in cytosolic TG hydrolysis, converting TGs into diacylglycerol (DG) and a free FA⁴. The critical role of ATGL for both basal and hormone-stimulated lipolysis is evident from the phenotype of ATGL-deficient mice, which exhibit significant TG accumulation in multiple tissues and impaired cold tolerance¹⁷.

The activity of ATGL is tightly controlled through a multi-layered regulatory system. Its maximal activity requires interaction with a co-activator protein, comparative gene identification-58 (CGI-58, also known as ABHD5)¹⁸. Conversely, ATGL activity is inhibited by direct binding to the protein G0/G1 switch gene 2 (G0S2)¹⁹ or hypoxia-inducible lipid droplet-associated protein (HILPDA)²⁰. Furthermore, its activity can be modestly increased by post-translational modification, such as phosphorylation by Protein Kinase A (PKA) during stimulated lipolysis (e.g., during fasting or exercise)²¹. At the transcriptional level, ATGL expression is nutritionally regulated, induced during fasting²² and by glucocorticoids²³, while suppressed by insulin²⁴. In the context of human obesity, this regulation appears more complex and likely deranged, as reduced ATGL protein levels and activity are often observed in adipose tissue despite normal or even elevated mRNA expression^10,25,26, suggesting significant influence from post-transcriptional control.

• Hormone-Sensitive Lipase (HSL/LIPE):

HSL/LIPE is a key multifunctional enzyme in lipolysis, primarily responsible for hydrolyzing DG to produce monoacylglycerol (MG) and the second FA. In fact, HSL exhibits broader substrate specificity than ATGL, also hydrolyzing TGs²⁷ (though 11-fold less efficiently than DGs), cholesteryl esters^28,29, and retinyl esters³⁰. The phenotype of HSL-null mice supports its crucial role in DG hydrolysis, as these mice show only partially reduced stimulated lipolysis but accumulate substantial amounts of DG in adipose tissue^31,32. HSL contributes to both basal and particularly, hormone-stimulated lipolysis^33,34, although non-enzymatic roles for HSL have also been reported³⁵ which points to the complicated and multifaceted functions of HSL.

The activity of HSL is acutely and robustly regulated by reversible phosphorylation³⁶. During stimulated lipolysis, catecholamines activate PKA, which phosphorylates HSL³⁴, markedly increasing its catalytic activity and promoting its translocation to the LD surface in a process often facilitated by interaction with Perilipin 1³⁷. Conversely, insulin exerts a potent anti-lipolytic effect by activating phosphodiesterase 3B³⁸, which reduces cAMP levels and thereby reverses the PKA-mediated activation of HSL^39,40. HSL activity can also be inhibited by phosphorylation by AMP-activated protein kinase, potentially linking lipolysis to cellular energy status^36,41. Other kinases like PKC and ERK may also contribute to HSL regulation⁴². In states of obesity and insulin resistance, the expression and activity of HSL in adipose tissue are often found to be decreased^26,43, highlighting its importance in metabolic health.

• Monoglyceride Lipase (MGL/MGLL):

MGL/MGLL catalyzes the terminal step in the cytosolic lipolytic cascade by hydrolyzing MGs to release glycerol and the final FA⁴⁴. Accumulating evidence has shown that MGL is involved in the development of obesity, regulating systemic glucose metabolism and energy expenditure⁴⁵, as well as participating in carcinogenesis^46,47. Beyond this function, MGL plays a crucial and distinct role in the endocannabinoid system by degrading 2-arachidonoylglycerol, a major endocannabinoid⁴⁸. This dual function directly links lipid metabolism with neuronal signaling and inflammation^49–51, and also supplies arachidonic acid^52,53, a key precursor for prostaglandins and other eicosanoids⁵⁴. While the acute regulation of MGL in adipocyte lipolysis is not as well-defined as that of other lipases⁵⁵, its critical role in terminating endocannabinoid signaling has established it as a significant therapeutic target⁵⁶. Consequently, MGL inhibitors are under active development for treating conditions related to pain, neurodegeneration, and inflammation^57,58.

Lysosomal Lipolysis: Key Role of LAL

Complementing the enzymatic cascade the constitutes the cytosolic pathway, lipolysis also occurs within the acidic lumen of lysosomes, a process mediated exclusively by lysosomal acid lipase (LAL/LIPA)⁵⁹. LAL’s primary function is to hydrolyze TGs and cholesteryl esters (CEs) delivered to the lysosome from two main sources: extracellular lipoproteins, such as low-density lipoprotein (LDL), acquired via receptor-mediated endocytosis, and intracellular LDs engulfed through autophagy, a specific process termed lipophagy⁵⁹. The enzyme is synthesized and trafficked via the mannose-6-phosphate (M6P) receptor pathway, which directs it from the Golgi to the lysosome⁶⁰. This M6P-dependent mechanism is not only critical for endogenous LAL targeting⁶⁰ but also forms the basis for enzyme replacement therapy (sebelipase alfa), as externally administered LAL can be taken up by neighboring cells⁶¹.

The products of LAL-mediated hydrolysis, FAs and free cholesterol, are transported to the rest of the cell to fulfill essential metabolic roles. LAL-derived cholesterol is crucial for maintaining cellular cholesterol homeostasis by regulating endogenous cholesterol synthesis and uptake pathways⁶². Meanwhile, the liberated FAs serve as energy substrates for β-oxidation^63,64 and as signaling molecules that can activate nuclear receptors like peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR)^65,66, thereby influencing gene expression related to lipid metabolism and inflammation. This is particularly evident in immune cells, where LAL-derived FAs are essential fuels for processes such as M2 macrophage polarization⁶⁴ and metabolic reprogramming in lymphocytes⁶³. Beyond individual cells, LAL’s influence extends to systemic lipid balance by modulating very low-density lipoproteins (VLDL) secretion in hepatocytes and degrading aggregated LDL within atherosclerotic plaques⁶⁷. Moreover, emerging evidence highlights a crucial role for LAL in adipose tissue, where it helps mediate the mobilization of energy stores during prolonged fasting⁶⁸ and modulates thermogenesis and systemic glucose homeostasis in the context of diet-induced obesity¹³.

The non-redundant role of LAL is underscored by the severe consequences of its genetic deficiency, which causes a rare autosomal recessive lysosomal storage disorder⁶⁹. Complete loss of LAL function results in Wolman disease, a fatal infantile disorder marked by massive TG and CE accumulation in the liver, spleen, and other organs⁷⁰. Partial deficiency leads to Cholesteryl Ester Storage Disease (CESD), a less severe condition presenting later in life with hepatomegaly, progressive liver disease, dyslipidemia, and accelerated atherosclerosis^69,70. Even more localized and relative LAL deficiency states (e.g. in arterial smooth muscle cells) promotes conversion into lipid-laden foam cells and a propensity toward atherosclerotic plaque formation⁷¹. Beyond these rare diseases where LAL function is significantly altered, genome-wide association studies have identified the LIPA locus as a risk factor for coronary heart disease, suggesting that more nuanced variations in LAL activity contribute to cardiovascular risk in the general population⁷². Thus, LAL functions as a critical gatekeeper, linking lysosomal degradation of endocytosed and autophagocytosed lipids to the control of cellular energy metabolism, cholesterol homeostasis, and systemic lipid balance.

Adipose Lipolysis and its Role in Cardiometabolic Disease

Adipose lipolysis has been proposed as a potential therapeutic target to treat cardiometabolic diseases⁷³ (Figure 2). The dysregulation of adipose lipid storage and mobilization establishes a critical nexus between obesity, inflammation, and the pathogenesis of cardiovascular disorders⁷⁴. This crosstalk is particularly relevant in the development of atherosclerosis and heart failure, where the cytosolic and lysosomal lipolytic pathways may play distinct roles.

Figure 2. Consequences of dysregulated adipose lipolysis in obesity and impact on cardiometabolic disease.

In the state of obesity, dysregulated adipose tissue lipolysis leads to pathological consequences that impair cardiometabolic health. The excessive release of lipids from dysfunctional adipocytes promotes (1) Adiposopathic Dyslipidemia, leading to ectopic fat storage in organs like the liver; (2) Systemic Inflammation, driven by pro-inflammatory factors released from adipose tissue; and (3) Direct Toxicity to cells in the heart and other organs. Collectively, these factors contribute to cardiovascular disease. The figure highlights that the lipolytic pathways (ATGL and LAL) are key therapeutic targets. Selective pharmacological modulation of these pathways, inhibiting the detrimental effects of cytosolic lipolysis while promoting the beneficial effects of lysosomal lipolysis, represents a novel strategy for treating cardiometabolic disorders.

Mechanisms in Cardiometabolic Dysfunction

It is crucial to frame this pathology within the context of the heart’s unique metabolic demands. The healthy adult heart is a metabolic omnivore but preferentially utilizes FAs, which supply 60–90% of its vast energy needs⁷⁵. This reliance on circulating FAs is essential for physiologic cardiac function. Indeed, pathological states that force a chronic substrate switch away from FA oxidation and towards reliance on glucose utilization are associated with metabolic inflexibility, energy deficits, and maladaptive remodeling⁷⁵. The cardiometabolic dysfunction associated with obesity however, is strongly driven by a state of chronic and excessive FA overload caused by dysregulated lipolysis. Such toxic oversupply, or lipotoxicity, leads to the following interconnected mechanisms driving pathology (Figure 2):

• Adiposopathic Dyslipidemia

The excessive release of FAs from hypertrophied adipocytes particularly from visceral depots, leads to an increased FA flux to the liver, a condition especially elevated during obesity^9,76. This serves as a substrate for increased hepatic production of VLDL-TGs and an overall deranged lipid profile termed “adiposopathic dyslipidemia,” characterized by elevated TGs, reduced high-density lipoprotein cholesterol (HDL-C), and an increased concentration of small dense LDL (sdLDL) particles⁷⁷. The formation of this atherogenic lipid profile is mechanistically driven by the elevated TG-rich lipoproteins in circulation. An enzyme called cholesteryl ester transfer protein facilitates the exchange of TGs from VLDL to LDL and HDL in return for CEs⁷⁷. The resultant TG enrichment of LDL and HDL particles renders them susceptible to hydrolysis by hepatic lipases, which ultimately generates smaller, denser particles like sdLDL⁷⁷. Such lipoprotein particles are especially pro-atherogenic due to their enhanced ability to penetrate the arterial intima and their lower affinity for the LDL receptor which leads to longer circulation times and increased susceptibility to oxidative modification⁷⁸. These TG-rich lipoproteins and their remnants are considered a causal risk factor for atherosclerosis and heart failure^79,80.

• Systemic Inflammation

Expanding and progressively dysfunctional WAT becomes a major source of pro-inflammatory factors, including several cytokines such as TNF-α and IL-6 and chemokines such as MCP-1³. There is a clear link between adipose-derived lipids and inflammation as evidenced by increased recruitment of macrophages into the adipose tissue and their activation. Specifically, hypertrophied adipocytes can undergo apoptosis or necrosis, triggering a robust inflammatory response which often leads to the formation of “crown-like structures” characterized by macrophages surrounding dead adipocytes³. Moreover, saturated FAs (SFAs) like palmitate can directly act as ligands for Toll-like receptor 4 and other pattern recognition receptors on immune cells, thereby activating downstream signaling pathways that activate NF-κB and enhanced transcription of pro-inflammatory genes⁸¹. An important example of this is palmitate-induced NLRP3 activation and IL-1β secretion in macrophages⁸² and the polarization of macrophages to pro-inflammatory states⁸³. The local inflammation in WAT contributes to a state of chronic systemic inflammation that directly affects cardiometabolism by impairing insulin signaling in distant organs and development of vascular endothelial dysfunction⁸⁴.

• Direct Lipotoxicity

The specific FAs released from adipocytes, particularly SFAs (e.g., palmitate) can exert direct toxic effects on the cardiovasculature. These effects manifest as cytotoxic injury to critical cells, such as cardiomyocytes⁸⁵, vascular smooth muscle cells⁸⁶, and endothelial cells⁸⁷, and as an exacerbation of atherosclerotic plaque vulnerability⁸⁸. Excess FA uptake overwhelms mitochondrial β-oxidation capacity, leading to the accumulation of toxic lipid intermediates such as DGs and ceramides⁸⁵. Ceramides are potent activators of apoptotic pathways and considered a key mediator of lipoapoptosis⁸⁵. In vitro studies show that palmitate induces cell death due to reactive oxygen species (ROS)-activated apoptosis and endoplasmic reticulum stress⁸⁹. The overload of FAs in mitochondria also leads to incomplete fatty acid oxidation, further increasing ROS production and causing mitochondrial dysfunction, which impairs cardiac energy production and contractile function⁹⁰. This suggests that the products of adipose lipolysis can directly contribute to the cardiomyocyte apoptosis and cardiac damage seen in heart failure.

Harnessing the Opposing Roles of Adipose Lipolysis for Therapeutical Applications

Comparing the function of bioactive lipids:

Aside from serving as a fuel source, lipids also function as potent signaling molecules, mediating communication both within the adipose tissue and systemically⁹¹. For example, both ATGL and HSL have been shown to be involved in regulation of cellular metabolism by generating the lipid ligands for the PPAR family of receptors and Retinoid X receptors⁹¹. In addition, ATGL participates in the generation of fatty acid ester of hydroxyl fatty acid (FAHFA), an adipocyte-derived lipokine which has been reported to be involved in systemic insulin sensitivity via affecting hepatic signaling⁹². On the other hand, LAL is capable of generating not only FAs and glycerol but also cholesterol⁹³, which is involved in the regulation of activity of the sterol regulatory element-binding proteins (SREBPs) and LXRs. Moreover, cholesterol is an important component of all cellular membranes and an essential precursor for steroid hormones⁹⁴, suggesting roles for lysosomal lipolysis that involve more complex downstream signaling and physiology.

Opposing functions of ATGL versus LAL inhibition:

Although both cytosolic and lysosomal lipolysis in adipose tissue are necessary for maintaining systemic lipid homeostasis, the roles of ATGL and LAL, informed by phenotypes of ATGL- and LAL-deficient mouse models when challenged by metabolic stress, are starkly different. First, the expression of only LAL and not the three lipases mediating cytosolic lipolysis¹⁶, is stimulated under metabolic stressor such as obesity and fasting even though LAL expression is extremely low under baseline homeostatic conditions¹³. This suggests the recruitment of lysosomal lipid metabolism in order to meet the demands of severe metabolic states. Furthermore, in the context of diet-induced obesity, adipose ATGL deficiency does not affect body weight and fat mass albeit improvements in hepatic lipid and systemic glucose metabolism are seen. On the other hand, adipose LAL deficiency exacerbates obesity, causing gains in body weight and fat mass with disrupted hepatic lipid and systemic glucose metabolism. A deficiency in either lysosomal or cytosolic lipolysis in adipose tissue enhances the respiratory exchange ratio (RER), indicating a metabolic switch toward carbohydrate use rather than lipid; yet, only the LAL-deficient setting shows lower energy expenditure, a change not observed in the ATGL-deficient setting under conditions of nutrient excess^13,16. This highlights a different workload and physiological contribution between lysosomal and cytosolic lipolysis in adipocytes, particularly under metabolic stressors such as obesity which would have opposing effects on the cardiometabolic disease spectrum.

Targeting lipolysis for treating cardiovascular disease:

Pharmacological inhibition of ATGL in adipose tissue with agents like Atglistatin has been shown to be cardioprotective in animal models of catecholamine-induced myocardial injury⁹⁵ and β-adrenergic agonist-stimulated adverse cardiac remodeling⁹⁶. Furthermore, adipose-specific ATGL deficiency has been shown to prevent the development of obesity-related heart failure with preserved ejection fraction (HFpEF)⁹⁷. By preventing the release of toxic lipid species and reducing systemic inflammation, targeting adipose tissue cytosolic lipolysis offers a novel approach to treating cardiometabolic diseases. Although no direct evidence indicates the effect of lysosomal lipolysis in adipose tissue on cardiometabolic diseases, mice with adipose LAL deficiency exhibit exacerbated obesity and related complications¹³, implying an opposing, detrimental role for LAL inhibition on cardiometabolism, in clear contrast to the protective effects of ATGL inhibition.

Interestingly, overexpressing LAL in adipocytes shows an anti-obesity effect with improved glucose metabolism and lower adipose tissue inflammation⁶², reinforcing the notion that LAL activation provides cardiometabolic benefits in adipose tissue. While such over-activation models in mice are protective, it is notable that no such naturally occurring gain-of-function variants of LAL have been identified in humans. Known and characterized human LIPA mutations are largely loss-of-function variants, which cause severe metabolic storage diseases as previously discussed (i.e. Wolman’s Disease and CESD). It should be noted that adipose overexpression of transcription factor EB (TFEB), a major positive regulator of lysosomal function that induces the expression of LAL⁵⁹, protects against metabolic dysfunction in the context of diet-induced obesity⁹⁸. The activation of TFEB is itself highly sensitive to nutrient status and is differentially modulated by distinct FA species; for instance, the saturated FA palmitate reportedly diminishes TFEB content, an inhibitory effect not observed with polyunsaturated FAs⁹⁹. The influence of carbohydrates is similarly complex and appears structurally specific. While common dietary sugars, abundant in high-fat/high-sucrose diets, are associated with reduced nuclear TFEB in vivo⁹⁹, a stark contrast is observed with a less common natural disaccharide called trehalose¹⁰⁰. Trehalose functions as a known TFEB activator and has demonstrated anti-obesity effects¹⁰⁰, implying a potential strategy to improve cardiometabolic health by harnessing adipose lysosomal lipolysis. This evidence highlights that the TFEB-LAL axis is susceptible to dietary modulation, though the specific nutrient-sensing mechanisms in adipocytes that distinguish between these different carbohydrate structures require further investigation.

Conclusion

The regulation of lipid metabolism within adipose tissue is a critical determinant of systemic metabolic health. While the canonical cytosolic lipolytic cascade has long been the focus of research, it is now clear that the lysosomal pathway, mediated by LAL, represents a distinct and functionally divergent system for lipid catabolism. This review highlights an emerging, opposing relationship: inhibiting cytosolic ATGL-mediated lipolysis appears protective against cardiometabolic disease, whereas enhancing lysosomal LAL-mediated lipolysis is what offers protective benefits. Understanding their distinct functions and relative contributions is essential, yet many critical questions remain. At the heart of the discussion is how two lipolytic systems liberate overlapping FA species yet result in opposing metabolic effects?

Future research must elucidate the precise molecular mechanisms, including how specific dietary nutrients (e.g., FAs and sugars) are sensed and impinge on signaling pathways to regulate TFEB and LAL as opposed to ATGL in adipocytes, particularly in response to metabolic stress. This requires a deeper understanding of how the cytosolic and lysosomal lipolytic pathways interact and are co-regulated. The precise impact of aging on the functional balance between these lipolytic pathways also represents a critical open question. This is highly relevant given recent work identifying the lysosomal pathway as central to the adaptive fasting response⁶⁸, a metabolic program now known to be highly interconnected with the genetic networks of aging and age-related diseases.

Key questions remain regarding the precise kinetics of LAL-mediated FA release, the depot-specific (e.g., visceral vs. subcutaneous) distinctions between these pathways, and the functional implications of LAL’s secretion versus the strictly cytosolic nature of ATGL. Most importantly, a critical challenge is to identify the full spectrum of unique, bioactive lipid molecules generated by each pathway and their distinct endocrine effects on distal tissues, especially at the cardiac and vascular tissue beds. Furthermore, identifying the molecular machinery, such as autophagy receptors that target lipid droplets for lipophagy in adipocytes, could provide novel therapeutic targets. Leveraging this knowledge can aid development of strategies to selectively modulate adipose tissue to control the release of lipid intermediates which maximize cardiometabolic health. The ultimate goal is a new era of mechanism-based therapies that precisely correct the lipolytic imbalances driving cardiovascular pathology.

Highlights.

• Adipose tissue utilizes two distinct lipolytic pathways: the canonical cytosolic pathway driven by ATGL and the lysosomal pathway mediated by LAL.

• Dysregulated lipolysis drives adiposopathic dyslipidemia and lipotoxicity, with cytosolic lipolysis exerting detrimental effects while lysosomal lipolysis acts as a protective counterbalance, representing a functional antagonism that critically determines cardiometabolic disease progression.

• Targeting the TFEB-LAL axis represents a novel, pathway-specific therapeutic strategy to correct the lipolytic imbalances in metabolic diseases.

Abbreviations

ATGL/PNPLA2

Adipose triglyceride lipase

HSL/LIPE

Hormone-sensitive lipase

MGL/MGLL

Monoglyceride lipase

LAL/LIPA

Lysosomal acid lipase

TGs

Triglycerides

DG

Diacylglycerol

MG

Monoacylglycerol

FAs

Fatty acids

TFEB

Transcription factor EB

ANGPTL4

Angiopoietin-like 4

LPL

Lipoprotein lipase

CVD

Cardiovascular disease

WAT

White adipose tissue

BAT

Brown adipose tissue

sdLDL

Small dense LDL

SFAs

Saturated FAs