The channels act like conduits that speed signals across the gaps between clusters of cells — similar to the way a group email reaches several people at once. The study, recently published in Cell Metabolism , also found that beige fat, unlike the better-known white and brown fat, has interesting anti-diabetic effects on blood sugar metabolism that seem independent of temperature regulation.

Impaired glucose metabolism is a hallmark of diabetes. Scherer added. Fat, once considered merely a storage area for excess calories, is now appreciated as a dynamic tissue that comes in several forms with different functions that are still being identified.

White fat is used mainly for energy storage. Brown fat, the classic heat-generating fat, helps regulate body temperature, especially in newborns. Some white fat cells are capable of transforming into a third kind of fat, beige. Both brown and beige fat get their color from increased mitochondria that are added in response to cold and other environmental stimuli, he said.

To study the metabolic effects of beige fat, the researchers compared mice with Cx43 that are able to make beige fat normally to mice unable to make Cx43, meaning their white fat seldom got the message to change to beige in response to cold.

After three weeks in cold temperatures, the mice were returned to normal temperatures and analyzed for glucose blood sugar metabolism. The mice that produced Cx43 showed greater improvement in glucose metabolism, Dr.

Scherer said. Yet, both groups of animals were still able to regulate body temperature, apparently through their brown fat stores, he said. Scherer, who holds the Gifford O.

Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research. Study co-authors from the Touchstone Diabetes Center included lead author Dr. Yi Zhu, a postdoctoral fellow and employee of Eli Lilly and Co.

Caroline Tao; postdoctoral researchers Dr. Mengle Shao and Dr. Shangang Zhao; Dr. Olga Gupta, Assistant Professor of Pediatrics and Internal Medicine and a Dedman Family Scholar in Clinical Care; and Dr. William Holland and Dr. Rana Gupta, both Assistant Professors of Internal Medicine.

Tiemin Liu, Instructor of Internal Medicine; Dr. Joel Elmquist, Chief of the Division of Hypothalamic Research, Professor of Internal Medicine, Pharmacology and Psychiatry, and holder of the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr.

Roy A. Brinkley, and the Carl H. Westcott Distinguished Chair in Medical Research; and Dr. Kevin Williams, Assistant Professor Internal Medicine in the Division of Hypothalamic Research.

The research was supported by the NIH, the Cancer Prevention and Research Institute of Texas CPRIT ; a Lilly Innovation Fellowship Award; a China Scholarship Council Scholarship, and the American Heart Association.

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Automated external defibrillators AEDs are underutilized during cardiac arrest episodes despite laws in some states requiring their availability in high-risk areas such as athletic facilities, researchers at UT Southwestern Medical Center found. Although the critical role of ATGL in lipolysis is undisputed, the distinct biochemical functions of its most closely related family members—PNPLA1, PNPLA3, PNPLA4 and PNPLA5—remain equivocal.

While an unambiguous assignment of their primary physiological substrates is still missing, some of these enzymes are directly involved in disease development. PNPLA1 is a amino-acid protein specifically expressed in differentiated keratinocytes of the skin , It is an established causative gene for autosomal recessive congenital ichthyosis ARCI , which is characterized by a severe defect in the development of the epidermal corneocyte lipid envelope CLE and the transepithelial water barrier in the skin in humans and dogs The clinical presentation essentially phenocopies the deficiency of CGI in the skin , arguing for a common involvement of both proteins in the formation of the CLE.

PNPLA1 is a transacylase that specifically transfers linoleic acid from TG to ω-hydroxy ceramide, thus giving rise to ω- O -acylceramides , These skin-specific lipids are essential for the generation of the CLE and an intact skin permeability barrier. Transacylation of FAs requires a hydrolysis reaction that is coupled with an esterification reaction.

CGI interacts with PNPLA1 and recruits the enzyme onto cytosolic LDs where PNPLA1 utilizes TG-derived FAs for ω-hydroxy ceramide acylation , PNPLA1 mutations leading to ARCI may additionally impair autophagy, arguing for a potential role of PNPLA1 in lipophagy-mediated degradation of LDs In humans, PNPLA3 is less abundant in adipocytes, but highly expressed in hepatocytes Key transcription factors responsible for the expression of PNPLA3 include CHREBP in response to carbohydrates and SREBP1c in response to insulin , PNPLA3 localizes to LDs and exhibits various enzymatic activities including TG-, DG-, MG- and retinyl ester hydrolase activity, PLA 2 activity and transacylase activity 8 , , , It remains unclear which of these activities are physiologically relevant in adipose tissue and in the liver The fact that PNPLA3-KO mice have essentially no abnormal phenotype with normal plasma and hepatic TG concentrations , argued against a major role of PNPLA3 in lipid homeostasis.

This view changed dramatically when Hobbs and colleagues reported that a single amino acid exchange at position from isoleucine to methionine in PNPLA3 p.

IM strongly associates with NAFLD This association was replicated in numerous studies and extended to associations of the mutation with steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma Important progress concerning the function of PNPLA3 was achieved by recent studies suggesting that excess PNPLA3 on the surface of LDs competes with ATGL for its coactivator CGI refs.

PNPLA3-IM has higher affinity to CGI than does wild-type PNPLA3 ref. This leads to reduced ATGL activity, which may explain the fatty liver disease in people carrying the variant. Additionally, the IM variant may promote increased TG synthesis via a transacylation reaction PNPLA4 was originally identified as gene sequence 2 GS2 in the human genome and is also found in other mammalian species but not in mice The PNPLA4 gene is located on the X chromosome between the genes encoding steroid sulfatase and Kallmann Syndrome The human PNPLA4 protein comprises amino acids and is expressed in numerous tissues, including adipose tissue, skeletal and cardiac muscle, kidney, liver and skin , Similar to PNPLA3, various enzymatic activities have been attributed to PNPLA4, including TG and retinyl ester hydrolase, phospholipase and transacylase activities 8 , , Genetic analyses have suggested that PNPLA4 is involved in the development of two rare congenital disorders: combined oxidative phosphorylation deficiency COXPD and X-linked intellectual disability , COXPD arises from a hemizygous nonsense mutation resulting in a C-terminally-truncated protein Rter and defective assembly of complexes I, III and IV of the respiratory electron transport chain.

Whether the enzymatic activity of PNPLA4 is involved in the pathogenesis of COXPD is unknown. Fortunately, small-molecule inhibitors have recently been developed that may help to elucidate the biochemical function of PNPL4 and its role in patho- physiology PNPLA5 also named GS2-like is a amino-acid protein that is ubiquitously expressed and, unlike PNPLA4, is present in both mice and humans PNPLA5 exerts hydrolytic activities towards multiple lipid substrates, including TGs and retinyl esters, but has also been shown to exhibit transacylase activity , Notably, PNPLA5-dependent hydrolysis of LD-associated TGs has been suggested to affect autophagosome biogenesis Furthermore, rare variants of PNPLA5 strongly associate with LDL cholesterol levels in humans They catalyse the hydrolysis of a wide range of endogenous substrates and xenobiotics CES family members that exhibit neutral TG hydrolase activity include human CES1 also called human cholesterylesterhydrolase-1, hCEH and CES2, and mouse Ces1d also called Ces3 or TG hydrolase-1 , Ces1g also called Ces1 or esterase-X and Ces1c.

The previously confusing nomenclature of human and murine CES enzymes has recently been revised for more clarity The carboxylesterase 1 CES1 gene in the human genome encodes a kDa protein with high abundance in liver and intestine and lower abundance in kidney, adipose tissue, heart and macrophages , CES1 preferably hydrolyses CEs and TGs , Hepatocyte-specific overexpression of human CES1 in transgenic mice increases hepatic TG hydrolase activity; lowers TG, FA and cholesterol content; and reduces reactive oxygen species ROS , apoptosis and inflammation, which cumulatively protect mice from western-diet- or alcohol-induced steatohepatitis Both hepatocyte- and macrophage-specific overexpression of CES1 in mice decrease atherosclerosis susceptibility in LDL-receptor-deficient mice and, consistent with this finding, treatment of THP-1 macrophages with a CES1 inhibitor caused accumulation of CE Hence, the role of human CES1 in lipid metabolism remains controversial.

Ces1d is highly expressed in adipose tissue and liver where it localizes to the lumen of the ER In adipose tissue, Ces1d is additionally associated with LDs and may contribute to basal lipolysis , In mouse hepatocytes, transgenic overexpression or pharmacological inhibition of Ces1d increased or decreased VLDL assembly and secretion, respectively , , In accordance with these findings, liver-specific and global Ces1d deficiency in mice lowers VLDL production and plasma TG and CE concentrations , Despite strong evidence for a role of Ces1d in hepatic VLDL assembly and secretion, it remains unclear how an enzyme residing in the lumen of the ER actually contributes mechanistically to lipoprotein synthesis.

Interestingly, while global Ces1d deficiency leads to TG accumulation in isolated hepatocytes, conditional Ces1d knockout in liver cells does not. In fact, they are actually protected from high-fat-diet-induced hepatic steatosis , The protective effect of Ces1d deficiency in the liver might be due to reduced FA-synthase activity and increased hepatic FA oxidation , Moreover, mice with global, but not liver-specific, Ces1d deficiency exhibit improved insulin sensitivity and glucose tolerance , The recent finding that Ces1d deficiency does not affect CE hydrolysis or bile-acid synthesis in mice argues against an important role for CES1 enzymes in cholesterol homeostasis see previous paragraph.

The second murine ortholog to human CES1 with established TG hydrolase activity is Ces1g. Overexpression of Ces1g increases TG hydrolase activity and reduces TG content in cultured rat hepatoma cells and livers of transgenic mice , Conversely, global- and liver-specific Ces1g-KO mice exhibit hepatic steatosis and hyperlipidemia , Restoration of hepatic Ces1g expression reverses hepatic steatosis, hyperlipidemia and insulin resistance in global Ces1g-deficient mice Several studies suggest that the lipid phenotype observed in Ces1g-deficient mice results from diminished FA signalling to restrain SREBP1c activation, leading to reduced FA oxidation and increased de novo lipogenesis , , CES2 preferably hydrolyses esters with a large alcohol group and a small acyl group, and as for Ces2c, TG and DG hydrolase activities have been reported , CES2 is abundantly expressed in the small intestine, colon and liver and is decreased in mice and humans with obesity and NAFLD , , Adenoviral overexpression of human CES2 in the liver of mice prevents genetic- and diet-induced steatohepatitis by increasing TG hydrolase activity and FA oxidation and reduces SREBP1c mediated lipogenesis, inflammation, apoptosis and fibrosis.

Murine Ces2c is a highly abundant TG, DG and MG hydrolase in liver and intestine , Its expression is decreased in livers of mice with diet- or genetically induced obesity , Loss of hepatic Ces2c in chow- or western-diet-fed mice causes hepatic steatosis Conversely, increasing hepatic Ces2c expression ameliorated obesity and hepatic steatosis, and improved glucose tolerance and insulin sensitivity Mechanistically, FAs released by Ces2c enter FA oxidation and concomitantly inhibit SREBP1 activity to decrease de novo lipogenesis in the liver Similarly, intestine-specific transgenic expression of Ces2c in mice also promotes intestinal TG hydrolysis and FA oxidation, and ameliorates high-fat-diet-induced obesity and NAFLD Moreover, an increased re-esterification rate of MGs and DGs may contribute to the generation of large chylomicrons that undergo accelerated postprandial TG clearance Taken together, the physiological function of both human CES2 and murine Ces2c render this enzyme an attractive target for the treatment of metabolic liver disease.

The putative enzyme is mainly expressed in BAT, WAT, liver, heart and macrophages of atherosclerotic lesions The LDAH ortholog in D.

melanogaster CG facilitates lipid packaging and regulates LD clustering in cell and tissue cultures of salivary glands , Unfortunately, only conflicting data exist on the physiological function of the enzyme in mammalian cells.

Goo et al. The same group also showed that LDAH promotes LD accumulation by affecting ATGL ubiquitinylation and degradation In other studies, however, LDAH overexpression did not affect CE, TG and retinyl ester hydrolase activity, and LDAH ablation did not change CE turnover in bone-marrow-derived macrophages Also, mice globally lacking LDAH exhibit normal CE, TG and whole-body energy metabolism, suggesting that LDAH either plays only a minor role in lipid metabolism or when absent is replaced by effective compensatory mechanisms Notably, genetic studies revealed that loss of LDAH may be associated with prostate cancer and sensorineural hearing loss Without a better functional characterization of this putative lipase, it is currently impossible to assess its role in lipid and energy homeostasis or cancer development.

DDH domain-containing protein 2 DDHD2, also named KIAA or iPLA1γ belongs to the mammalian intracellular phospholipase A1 iPLA1 family which consists of three paralogs—DDHD1, DDHD2 and SEC23IP. All members share a conserved GXSXG lipase motif and a DDHD domain named after a characteristic amino acid signature within the domain , DDHD2 exhibits DG and TG hydrolase activity, and DDHD2 deficiency in mice causes TG accumulation in the brain , , , The protein localizes to the cytosol, Golgi apparatus and ER , In humans, loss-of-function mutations in DDHD2 lead to hereditary spastic paraplegia , , , a neurodegenerative disorder associated with lipid accumulation in the brain and characterized by spasticity in the lower limbs Additionally, short-hairpin-RNA-mediated DDHD2 knockdown was shown to impair phospholipid synthesis and sensory axon regeneration after sciatic nerve crush , emphasizing a crucial role for lipolysis in neuron function.

Moreover, genome-wide analyses identified DDHD2 as a candidate risk gene for other neurological diseases, including autism and schizophrenia , Whether these diseases are directly linked to the enzymatic activity of DDHD2 is currently investigated. Arylacetamide deacetylase AADAC is a kDa esterase that harbours a typical GXSXG motif and exhibits considerable sequence homology to HSL in its presumed active site AADAC localizes to the ER and is mainly expressed in liver and intestine with much lower expression in adrenal glands and pancreas , AADAC preferably hydrolyses cholesteryl acetate and DGs over TGs , Its diurnal expression pattern is identical to hepatic VLDL secretion in mice and depends on transcriptional regulation by PPARα ref.

Overexpression of AADAC in human HepG2 and rat McA hepatoma cells increases TG secretion and reduces TG accumulation, respectively, indicating that it might play a role in lipid mobilization for VLDL synthesis , Another study has demonstrated that, although hepatic AADAC activity is decreased in humans with obesity, there was no association to the homeostasis model assessment HOMA index or with DG species, and knockdown of endogenous AADAC did not affect FA oxidation in primary human hepatocytes Accordingly, the role of AADAC in lipid metabolism in vivo is still elusive.

Extracellular vesicles EVs represent a recently discovered mechanism for the utilization of TG stores. In contrast to lipolysis and lipophagy, EV-mediated TG utilization does not involve TG hydrolysis and subsequent FA distribution.

Instead, LDs are directly released from cells within EVs. A familiar, unique subclass of EVs containing large amounts of TGs are milk fat globules. They originate from cuboidal epithelial cells of lactating mammary glands and are secreted into milk ducts Apart from the very distinct milk fat globules, EVs are generally secreted from almost all cell types and are found in interstitial fluid and many other body fluids.

After their release, EVs are internalized by other cells, enabling the horizontal transfer of cargo from donor to recipient cells. The nature of their cargo is manifold and includes proteins, nucleic acids, various metabolites and even intact organelles EVs have thus been attributed diverse biological functions ranging from immunomodulation to tissue differentiation and cancer development Importantly, Ferrante and colleagues reported that adipocyte-derived EVs are able to transport TGs to adipose-tissue-resident macrophages Similar to all EVs, TG-containing exosomes are enclosed by a phospholipid bilayer derived from the plasma membrane of EV-producing cells Additionally, a phospholipid monolayer engulfs the hydrophobic core of enclosed LDs Fig.

Adipocyte-derived exosomes are almost exclusively taken up by macrophages and may thus represent an alternative pathway for local intercellular lipid distribution in adipose tissue. Through this process, macrophages may adapt to their local adipose tissue environment, consistent with similar findings in other tissues Whether adipocyte-derived EVs can transport TG cargo to cells and tissues other than macrophages remains to be elucidated.

TGs are shuttled from adipocytes to macrophages in adipose tissue via exosomes. Exosomes comprise a phospholipid bilayer and phospholipid monolayer engulfing the hydrophobic core of enclosed LDs and harbour exosomal marker proteins, such as CD63, and LD proteins, such as perilipins or ATGL.

Sebocytes represent another cell type secreting large amounts of mostly neutral lipids including TGs. These lipids accumulate in LDs during sebocyte differentiation but in contrast to adipocytes, lipid mobilization occurs via sebocyte necrosis instead of lipolysis or exosome-mediated pathways Sebum hypersecretion is associated with increased fat catabolism in adipose tissue and associated with adipose tissue loss in a TSLP transgenic mouse model.

Considering the essential role of lipolytic enzymes in systemic and tissue-specific energy homeostasis, the inhibition of lipolysis may offer potential treatment opportunities for various metabolic, and possibly even infectious, diseases. Example target diseases are described below and in Box 1.

Viruses are obligate intracellular pathogens that hijack host cells and create an intracellular metabolic niche to facilitate efficient replication and virion production.

Striking examples of such hostile takeovers include positive-stranded RNA viruses that rewire lipid metabolism to form membrane platforms, so called replication compartments RCs providing a structural framework for RNA synthesis , , These RCs additionally enable local accrual of viral macromolecules and hinder host defence mechanisms.

Flaviviruses including dengue virus, West Nile virus and hepatitis C virus HCV , as well as severe acute respiratory syndrome coronavirus SARS-CoV , exploit ER membranes for RC formation. Picornaviruses, a large family of positive-stranded RNA viruses, stimulate phospholipid—especially phosphatidylcholine—biosynthesis to form RCs Accordingly, virus-infected cells upregulate FA uptake and CoA activation Notably, however, exogenous FAs do not directly enter phospholipid synthesis but are first esterified to TGs by DGAT1 and deposited in LDs On demand, activation of lipolysis promotes FA release and subsequent RC-membrane synthesis.

During infection by enteroviruses, including rhinovirus, inhibition of DGAT1, ATGL or HSL largely reduces viral replication To access cellular lipid stores, viruses use newly formed membrane contact sites between LDs and RCs.

A direct interaction of viral proteins with ATGL and HSL at these contact sites may promote FA channelling towards RC synthesis Besides providing FAs for RC formation, LDs also serve as platforms for HCV and dengue virus-particle synthesis , , and inhibition of LD formation decreases dengue virus and HCV replication For both viruses, particle morphogenesis depends on the localization of the basic core protein to LDs, from which it is recruited for virus particle formation The interface between LDs and ER may serve as HCV assembly platforms Once bound to LDs, HCV core protein inhibits ATGL-mediated lipolysis to increase LD volume and number.

This process likely contributes to the hepatic steatosis commonly observed in people infected with HCV Similarly, accumulation of LDs was also observed in infected African green monkey kidney epithelial cells and in lungs of people infected with SARS-CoV-2, suggesting that SARS-CoV-2 pathogenesis also involves lipid metabolism Lipolysis of LD-associated TGs furthermore provides energy substrates for ATP production that are required for viral replication and virion formation.

In some cases, such as upon infection with the lymphocytic choriomeningitis LCM virus, activation of neutral lipolysis via ATGL and HSL is so pronounced that it contributes to the drastic reduction in mass of adipose tissue in infected mice Other viruses, such as dengue virus , influenza H3N2 virus and porcine reproductive and respiratory syndrome virus , activate lipophagy and acid lipolysis to mobilize FAs from LDs.

FAs are subsequently oxidized in mitochondria to fuel viral replication. Similarly, poliovirus , HCV and coxsackievirus B3 ref. Thus, virus infections inhibit or activate lipolysis depending on whether the virus utilizes LDs as an assembly and replication platform or as a source of FAs as an energy substrate, respectively.

HCV exploits the VLDL synthesis pathway to exit hepatocytes as lipo-viro-particles Knockdown of arylacetamide deacetylase AADAC , a putative lipase involved in VLDL synthesis, largely decreases virus production Moreover, HCV production depends on hepatic CGI ref.

Loss-of-function mutations in CGI, which are associated with NLSDI, diminish HCV production, indicating that the prolipolytic function of CGI, but not of ATGL, is required for HCV formation. The contradiction that the HCV life cycle depends on inactive ATGL but active CGI may be resolved by the identification of an ATGL-independent role of CGI in VLDL synthesis Finally, adipose tissue is also a refuge for several pathogenic parasites, including Trypanosoma cruzi , Trypanosoma brucei , Coxiella burnetiid , Rickettsia prowazekii and Mycobacterium tuberculosis cruzi causes Chagas disease and invades adipocytes, where it resides in close proximity to LDs, ensuring that the parasite has a continuous supply of FAs Adipose tissue represents a major reservoir for T.

brucei , which adapts to the lipid-rich environment by increased ATGL-mediated lipolysis and FA oxidation to satisfy their energy requirements This catabolic switch towards fat catabolism would also explain the weight loss in people and cattle with sleeping sickness caused by this parasite , Studies in Listeria monocytogenes -infected mice demonstrated a link between fasting and increased survival, and forced feeding of infected mice with a glucose-containing diet was lethal Apparently, lipolysis-associated metabolites like ketone bodies are essential for surviving L.

monocytogenes infections. Anorexia and even cachexia accompany most infections and may be seen as host defence mechanisms to mimic fasting and activate adipose-tissue FA mobilization for ketogenesis in the liver to improve immune function and increase the chance of survival.

Type 2 diabetes is a serious public-health concern that impairs quality and expectancy of life. Obesity represents the major risk factor for type 2 diabetes It is well accepted that an increased FA flux from hypertrophic adipose tissue to insulin-sensitive tissues contributes to insulin resistance and glucose intolerance Accordingly, reduced FA mobilization from adipose tissue in mice with global or adipocyte-specific deletion of ATGL, HSL or LAL leads to significantly increased glucose tolerance and improved insulin sensitivity 24 , 27 , , , , For HSL deficiency, the beneficial metabolic phenotype is present in old, but not young, mice, and may be due to a concomitant decline in ATGL activity, which strongly impairs FA mobilization from adipose stores in older animals Pharmacological inhibition of ATGL or HSL also improved glucose tolerance and insulin sensitivity in high-fat-diet-fed mice.

A shift towards glucose utilization upon reduced FA availability from adipose tissue, reduced hepatic acetyl-CoA levels and pyruvate carboxylase activity and, consequently, reduced hepatic glucose production contributes to increased glucose tolerance in mice with adipocyte-specific ATGL deficiency Hypoinsulinemia occurs in both ATGL- and HSL-deficient mice and likely contributes to the insulin-sensitive phenotype 27 , , , Insulin, secreted from pancreatic β-cells, regulates lipid versus carbohydrate utilization as fuel for energy.

β-cell-intrinsic lipolysis generates various lipid intermediates with signalling potential like MGs, FA-CoAs and FAs that were shown to regulate glucose-stimulated insulin secretion GSIS Studies in global- and β-cell-specific ATGL and HSL-deficient mice revealed impaired GSIS of isolated pancreatic islets and hypoinsulinemia 26 , 31 , , , , In contrast, inhibition of LAL in pancreatic β-cells indirectly potentiates GSIS by activating ATGL and HSL Several mechanisms have been proposed for impaired insulin secretion in ATGL-deficient β-cells, including 1 reduced availability of PPARδ ligands resulting in mitochondrial dysfunction 31 , 2 reduced generation of MGs that induce insulin exocytosis by binding to the vesicle priming protein Munc13—1 refs.

Moreover, FAs liberated from adipose tissue promote insulin secretion after β-adrenergic stimulation and reduced or diminished adipocyte ATGL or HSL activity perturbs insulin secretion from β-cells 27 , , , , Hence, specifically manipulating adipocyte lipolysis may represent a potential pharmacological approach to improve insulin sensitivity and glucose tolerance.

Obesity-associated NAFLD results from either increased de novo TG synthesis in the liver or increased flux of FAs from adipose tissue to the liver, or both Accordingly, reduced FA mobilization from adipocytes ameliorates hepatic steatosis, inflammation and fibrosis in high-fat-diet-fed mice that have adipocyte-specific ATGL deficiency or CGI deficiency or that have been treated with atglistatin , , Somewhat counterintuitively, overexpression of ATGL in adipocytes also improves hepatic steatosis in a transgenic mouse model However, evidence shows that enhanced FA oxidation in adipose tissues of adipocyte-specific ATGL transgenic mice reduces FA flux to the liver, resulting in decreased hepatic fat storage.

Numerous GWAS and candidate-gene studies have demonstrated that the PNPLA3-IM variant represents a strong genetic risk factor for steatohepatitis, fibrosis and HCC ASO-mediated silencing of PNPLA3 improved NAFLD and fibrosis in a mutant knock-in mouse model harbouring the PNPLA3-IM mutation Moreover, PNPLA3-IM sequesters CGI from its interaction with ATGL and impairs its hydrolytic activity for LD-associated TGs This therapeutic concept is corroborated by the finding that diet-induced hepatic steatosis is prevented by adenovirus-mediated overexpression of ATGL in murine livers Chronic heart failure HF is a common disease resulting from any structural or functional impairment of ventricular filling or ejection of blood HF represents a leading cause of death and can basically be subdivided into two distinct groups: HF with preserved ejection fraction HFpEF and HF with restricted ejection fraction HFrEF The healthy heart exhibits high flexibility to use FA, glucose and ketone bodies as energy substrates During cardiac failure, metabolic flexibility is reduced, and the heart increasingly uses glucose as energy fuel However, a chronic activation of the sympathetic nervous system and an increase in natriuretic peptides augments adipose FA mobilization, which competes with glucose utilization and aggravates oxidative stress during HF , , Accordingly, adipocyte-specific ATGL deficiency or atglistatin treatment protected mice from pressure-induced cardiac hypertrophy and cardiac fibrosis , Similarly, ATGL inhibition promoted a cardioprotective effect in a mouse model of catecholamine-induced cardiac damage It has been suggested that inhibition of adipocyte ATGL activity improves cardiac energy metabolism by further shifting substrate utilization from FAs towards glucose and by changing the cardiac membrane lipid composition Considering the current lack of effective therapeutics, the pharmacological inhibition of ATGL, and possibly other lipases in adipose tissue, may represent a promising approach to treat HFpEF.

Importantly, however, the inhibition of lipolysis must be restricted to adipose tissue because concomitant suppression of lipolysis in cardiac myocytes, hepatocytes and other non-adipose tissues may result in steatosis and organ dysfunction, as present in people with global ATGL 21 , 23 or CGI deficiency Cachexia is a severe wasting disorder accompanying the late stage of various diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, burn-induced trauma or cancer The occurrence of cachexia in any of these maladies drastically decreases treatment options and chances of survival.

Cachexia is a hypermetabolic disorder characterized by systemic inflammation and an unintended loss of body weight due to a reduction in adipose tissue and skeletal muscle mass that cannot be reversed by increased nutritional intake , To date, the multifactorial mechanisms causing cachexia are yet insufficiently understood and effective treatments are not available.

Adipose tissue loss often precedes muscle loss in cachexia, and some studies have provided evidence that halting fat depletion also preserves muscle mass , Mechanistically, adipose tissue undergoes a switch towards catabolism that is initiated by proinflammatory cytokines and amplified by β-adrenergic signals , This catabolic reprogramming elevates lipolysis and futile cycling, but reduces lipogenesis and fat accumulation, leading to adipose tissue atrophy , Reducing lipolysis by pharmacological or genetic inhibition of ATGL , or by targeting the erroneously prolipolytic signals, like the β3-adrenergic signal or the AMPK—CIDEA axis , prevented adipose-tissue loss in murine cachexia models of burn-induced trauma or cancer.

Interestingly, ATGL blockade not only reduced lipolysis but also prevented browning of WAT and fatty-liver development post burn injury and muscle atrophy in some mouse models of cancer cachexia The mechanisms underlying the tumour—adipose tissue—muscle crosstalk in cachexia and the question of whether lipolysis inhibition affects cachexia in humans await future clarification.

Discoveries in the past two decades have turned intracellular TG catabolism from a relatively simple, single-enzyme reaction by HSL to a complex, highly regulated pathway that affects energy homeostasis on numerous levels.

While canonical lipolysis of intracellular lipid stores is by now relatively well-characterized, the contribution of noncanonical enzymes and the role of lysosomal acid lipolysis for cytoplasmic LD degradation require comprehensive characterization.

In many cases, the enzymatic function of these proteins as well as their placement in lipid metabolism and physiology remain unclear, despite compelling evidence for their relevance in disease development.

A good example for such dreadful lack of knowledge relates to the crucial yet unsettled function of PNPLA3 in lipid metabolism and liver disease. Another exciting topic of future research will address the therapeutic potential of lipolytic enzymes to treat metabolic disorders.

Examples include inhibition of ATGL and possibly HSL to treat or prevent type 2 diabetes, fatty liver disease, lethal heart failure or cachexia. While preclinical experiments in mice are promising, their potential in humans remains completely unknown.

Similarly, it is of utmost interest to find out whether inhibition of PNPLA3 prevents NASH, liver cirrhosis and liver cancer in humans.

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