TYPE Review

PUBLISHED 13 September 2022

DOI 10.3389/fendo.2022.1000739

Potential lipolytic regulators

OPEN ACCESS derived from natural products
EDITED BY
Bruno Melo Carvalho,
Universidade de Pernambuco, Brazil
as effective approaches to
REVIEWED BY
Monica Colitti,
treat obesity
University of Udine, Italy
Alisson Oliveira,
Federal University of Xi-Ding Yang 1,2, Xing-Cheng Ge 3, Si-Yi Jiang 4
Pernambuco, Brazil
and Yong-Yu Yang 1,5*
*CORRESPONDENCE
Yong-Yu Yang
1
Department of Pharmacy, Second Xiangya Hospital of Central South University, Changsha, China,
yongyuyang@csu.edu.cn 2
Phase I Clinical Trial Center, The Second Xiangya Hospital of Central South University,
Changsha, China, 3 Xiangxing College, Hunan University of Chinese Medicine, Changsha, China,
SPECIALTY SECTION 4
Department of Pharmacy, Medical College, Yueyang Vocational Technical College, YueYang, China,
This article was submitted to 5
Hunan Provincial Engineering Research Central of Translational Medical and Innovative Drug, The
Obesity,
Second Xiangya Hospital of Central South University, Changsha, China
a section of the journal
Frontiers in Endocrinology

RECEIVED 22 July 2022

ACCEPTED 23 August 2022
PUBLISHED 13 September 2022 Epidemic obesity is contributing to increases in the prevalence of obesity-
CITATION
related metabolic diseases and has, therefore, become an important public
Yang X-D, Ge X-C, Jiang S-Y and health problem. Adipose tissue is a vital energy storage organ that regulates
Yang Y-Y (2022) Potential lipolytic whole-body energy metabolism. Triglyceride degradation in adipocytes is
regulators derived from natural
products as effective approaches to called lipolysis. It is closely tied to obesity and the metabolic disorders
treat obesity. associated with it. Various natural products such as flavonoids, alkaloids, and
Front. Endocrinol. 13:1000739.
terpenoids regulate lipolysis and can promote weight loss or improve obesity-
doi: 10.3389/fendo.2022.1000739
related metabolic conditions. It is important to identify the specific secondary
COPYRIGHT
© 2022 Yang, Ge, Jiang and Yang. This metabolites that are most effective at reducing weight and the health risks
is an open-access article distributed associated with obesity and lipolysis regulation. The aims of this review were to
under the terms of the Creative
identify, categorize, and clarify the modes of action of a wide diversity of plant
Commons Attribution License (CC BY).
The use, distribution or reproduction secondary metabolites that have demonstrated prophylactic and therapeutic
in other forums is permitted, provided efficacy against obesity by regulating lipolysis. The present review explores the
the original author(s) and the
copyright owner(s) are credited and regulatory mechanisms of lipolysis and summarizes the effects and modes of
that the original publication in this action of various natural products on this process. We propose that the
journal is cited, in accordance with
discovery and development of natural product-based lipolysis regulators
accepted academic practice. No use,
distribution or reproduction is could diminish the risks associated with obesity and certain
permitted which does not comply with metabolic conditions.
these terms.

KEYWORDS

adipose tissue, insulin resistance, lipolysis, natural product, obesity

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Yang et al. 10.3389/fendo.2022.1000739

1 Introduction summarize a wide diversity of plant secondary metabolites

that have demonstrated anti-obesity effects via the promotion
Obesity is excessive lipid accumulation in adipose tissue. It is of lipolysis. We also focus on the progress of research on
caused by an imbalance between energy intake and energy inhibitors of lipolysis with different mechanisms of action in
consumption. According to the World Health Organization adipose tissue dysfunction. This review provides insight into the
(WHO), more than 650 million adults over 18 years of age precise biochemical and molecular mechanisms by which plant
were obese as of 2016 (1). Obesity is a risk factor for secondary metabolites inhibit the onset and/or progression of
cardiovascular disease (CVD), insulin resistance (IR), type 2 obesity and, by extension, its related co-morbidities. In addition,
diabetes mellitus (T2DM), hypertension, dyslipidemia, and it highlights the potential of lipolysis as a therapeutic target for
certain cancers (2). Increased adipocyte number (hyperplasia) obesity and its complications.
and size (hypertrophy) are morphological manifestations of
obesity (3). Adipose tissue is classified into three distinct types:
white (WAT), brown (BAT), and beige (4). WAT stores excess 2 Triglyceride biosynthesis and
energy in the form of triglycerides (TG), whereas BAT and beige metabolism
adipose tissues catabolize TG into heat (5). Adipose tissue also
functions as an endocrine organ and filler tissue and cushions, Adipose tissue, the liver, and skeletal muscle are the mains
supports, and insulates the body (6). organs responsible for the regulation of lipid metabolism. TG
WAT is generally considered a ‘troublesome and excessive biosynthesis and decomposition (lipolysis) in WAT equilibrate
tissue’. Body weight may be lost via intermittent fasting, lipid metabolism. After feeding, glucose and lipids from food are
medication, exercise, or surgery (7). However, it is uncertain absorbed in the intestine in the form of chylomicrons and enter
whether these approaches maintain weight loss or have the bloodstream. The chylomicrons are then hydrolyzed into
unacceptable side effects in the long term. Exercise appears to FFAs by lipoprotein lipase and absorbed and utilized by
be an effective weight loss method, although its efficacy depends adipocytes and liver and muscle tissue. Insulin is secreted by
largely on its duration, frequency, and intensity (8). The b-cells in the pancreas and promotes FFA and glucose uptake,
administration of certain drugs is promising for obesity while insulin inhibits lipolysis via lipase inhibition. Adipocytes
prevention and treatment. Intermittent fasting, drugs, and absorb excess FFA and glucose and produce TG as an energy
exercise decompose TG faster than they are synthesized in the storage form (15). During this process, adipogenesis and
adipocytes. Hence, pharmacological and nutritional lipogenesis increase, while lipolysis, thermogenesis, and
enhancements of this process are potential strategies for browning decrease. De novo lipogenesis involves TG
weight loss and the prevention of obesity-related biosynthesis and occurs in the adipocytes and liver. To
metabolic syndrome. maintain normal blood glucose levels, the liver converts excess
The reservoir effect of WAT protects other tissues against the glucose into glycogen and stores it in liver cells, or hepatocytes,
toxic effects of glycolipids associated with excess energy storage. which can also synthesize TG through the de novo TG synthesis
Adipocytes have limited lipid storage capacity and can hold no pathway. TG subsequently is transported from the liver to
additional TG when their volume expands beyond a critical adipose tissue by very low-density lipid (VLDL) (16). An
point. At this stage, the adipose tissue becomes dysfunctional. important contributor to hepatic fat accumulation is the
This condition is observed in patients with insulin resistance, insufficient hepatic export of TG in the form of VLDL
T2DM, and obesity and is manifested by decreased TG synthesis particles. TG synthesis and metabolism are illustrated
and excess free fatty acid (FFA) release (9). In cases of adipose in Figure 1.
tissue dysfunction, certain compounds improve whole-body During fasting and starvation, TG is decomposed into
energy metabolism by inhibiting lipolysis. glycerol and FFA (17). Adipose triglyceride lipase (ATGL),
Natural products are vital sources of lead compounds and hormone-sensitive lipase (HSL), and monoacylglycerol lipase
are important in drug discovery. Several natural products are (MAGL) hydrolyze TG to FFAs and glycerol. The glycerol is
widely used in obesity treatment (10). Various natural products used to make glucose in gluconeogenesis. FFAs are then released
(11–14), including flavonoids, alkaloids, and terpenoids control into circulation, where they are utilized by the peripheral tissues
obesity by stimulating lipolysis, inhibiting adipogenesis and and/or re-esterified into TG in the adipocytes. Skeletal muscle
lipogenesis, and promoting energy expenditure. However, the and the liver are the most important organs involved in FFA
activities and mechanisms of natural products in modulating metabolism via b-oxidation and subsequent ATP generation.
lipolytic activity have not yet been systematically summarized. In Mitochondrial-rich beige adipose tissue or BAT are the major
the present review, from a lipolysis perspective, we describe the sites responsible for non-shivering thermogenesis in mammals.
biosynthesis and metabolism of TG in adipose tissue and review Cold exposure, b-adrenergic receptor (b-AR) agonists,
the regulatory mechanisms of lipolysis. Furthermore, we peroxisome proliferator-activated receptor-g, and exercise can

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Yang et al. 10.3389/fendo.2022.1000739

FIGURE 1
TG synthesis and metabolism.

induce the browning of WAT. FFA produced by regulators (29). The perilipins, including perilipin1, perilipin2,
lipolysis is also absorbed and utilized by beige and perilipin5, as well as the cell death-inducing DNA
adipocytes or BAT through UCP-1-dependent shiver- fragmentation factor alpha (DFFA)-like effector (CIDE) family
independent thermogenesis. proteins, including Cidea, Cideb, and Cidec/Fsp27, have
emerged as key lipolysis regulators (30, 31). Perilipin1 is a
scaffold for organized protein-protein interactions on LD
3 Lipolysis and its mechanisms surfaces. It binds CGI-58 and suppresses HSL translocation to
LD under basal conditions. During stimulatory conditions,
Lipolysis is a finely regulated process mediated by the however, phosphorylation causes perilipin to dissociate from
consecutive actions of ATGL, HSL, and MAGL. ATGL or HSL CGI-58. The free CGI-58 then binds phosphorylated ATGL and
first hydrolyzes TG to diglycerides and FFA. HSL then co-activates TG hydrolysis (32). Perilipin phosphorylation
hydrolyzes diglycerides to monoglycerides and FFA. MAGL recruits HSL from the cytosols to the surfaces of the LDs, and
then hydrolyzes monoglycerides to glycerol and FFA (18). diglycerides are then hydrolyzed (26). FSP27-deficient cells
Lipid droplet autophagy or lipophagy is a complementary exhibite increased basal lipolysis and reduced lipid storage
cellular lipid breakdown pathway (19). Sex, age, physical capacity (33). The mechanisms by which perilipin1 regulates
activity, fat deposit location, and genetic variation regulate lipolysis are generally understood. However, the roles and
basal lipolytic activity in adipocytes (20). The proinflammatory mechanism of perilipin2, perilipin5, and the CIDE family in
cytokines TNF-a (21), IL-6 (22), and IL-1b (23) as well as lipolysis remain to be elucidated.
lipopolysaccharide (LPS) (24) and hypoxia (25) may induce TG
lipolysis. Lipid droplet-associated proteins (LDAPs) (26), cyclic
guanosine monophosphate dependent-protein kinase G (cGMP- 3.2 cAMP-PKA pathway
PKG) (8), mitogen-activated protein kinase (MAPK) (27), and
adenosine 5’-monophosphate (AMP)-activated protein kinase In vivo, dynamic lipolysis processes are mainly regulated by
(AMPK) (28) are also implicated in TG lipolysis. hormones, such as catecholamines, ghrelin, adiponectin, and
insulin. Under conditions of fasting, cold stress, and other
compound treatment, norepinephrine is released from
3.1 LDAPs sympathetic nerve terminals. b-AR agonists, such as
epinephrine, norepinephrine, and dopamine, upregulate cyclic
Lipid droplets (LD) are dynamic lipid storage organelles AMP (cAMP) by linking various AR subtypes to the G-protein
surrounded by single layers of polar and amphipathic receptor complex that controls adenylate cyclase in the cell
phospholipids and structural proteins. They are now membrane. Thereafter, protein kinase A (PKA) is activated by
considered major fat storage, lipid secretion, and lipolysis cAMP (34). PKA phosphorylates both HSLs at Ser563, Ser659,

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Yang et al. 10.3389/fendo.2022.1000739

and Ser660, thereby activating them and promoting their decomposition (44). However, the roles of AMPK in
translocation from the cytoplasm to the surfaces of LDs (35). regulating TG lipolysis in adipocytes are controversial. AMPK
cAMP degradation is mediated by phosphodiesterase (PDE). may phosphorylate HSL at Ser565 to inhibit phosphorylation at
Insulin inhibits lipolysis mainly by activating the HSL Ser660 and Ser563. In this manner, it reduces HSL activity
phosphoinositide 3-kinase/protein kinase B/PDE 3B (PDE3B) and suppresses lipolysis (45). AMPK is implicated in chaperone-
pathway, which leads to p-HSL and p-perilipin mediated autophagy which selectively degrades perilipins and
dephosphorylation (36). In addition, ligands of Gi protein- initiates lipolysis (46). Therefore, proteins and signaling
coupled receptors, such as succinic acid, nicotinic acid, beta- pathways that modulate AMPK expression and activity, such
hydroxybutyric acid, and neuropeptide Y, inhibit the formation as SIRT (47) and SIRT3 (48), mobilize TG in adipocytes.
of cAMP by binding to their receptors, thereby exerting an anti- Protein kinase C (49), Ca2+ (50), inositol hexakisphosphate
lipolytic effect. kinase-1 (51), transient receptor potential vanilloid channels (38,
52), and endoplasmic reticulum (ER) stress (53) regulate
lipolysis in adipocytes either alone or by interacting with the
3.3 cGMP-PKG aforementioned signaling pathways (Figure 2).

Cyclic guanosine 3’5’-monophosphate (cGMP) is an

important intracellular secondary messenger of hormone- 4 Natural products involved in
induced lipolysis. Atrial and b-type natriuretic peptides are
nitric oxide (NO) donors that stimulate lipolysis in adipocytes
lipolysis
via the cGMP/PKG pathway (8). PKG phosphorylates proteins
The structural diversity of natural products determines their
associated with lipolysis, including HSL and perilipin, thereby
wide range of pharmacological activity. Natural products may be
promoting TG breakdown (37). The cGMP is also involved in
used to treat obesity and its associated metabolic diseases.
TNF-a (iNOS/NO/GC/cGMP-dependent pathway)- and
Traditional and complementary medicines including various
endothelin-1 (GC/cGMP/Ca 2+ /ERK/CaMKIII signaling
herbs and extracts have been widely used to prevent and treat
pathway)-induced lipolysis in adipocytes (38–40). Few studies
metabolic disorders (54, 55). Flavonoids (56), alkaloids (57),
have reported on the involvement of cGMP/PKG in lipolysis
terpenoids (58), and polyphenols (59) stimulate lipolysis in
regulation. Moreover, the roles of cGMP/PKG in lipolytic
adipocytes, thereby causing weight loss and improving
enzymes regulation and LDAPs remain to be clarified.
metabolic status. Their modes of action involve the PKA-HSL,
PKC, AMPK, MAPK, and other signaling pathways.
3.4 Mitogen-activated protein kinase

The mitogen-activated protein kinase (MAPK) family, 4.1 Natural products promote lipolysis
which including extracellular signal-regulated kinases (ERKs),
jun aminoterminal kinase (JNK), and p38 mitogen-activated 4.1.1 Flavonoids
protein kinases (p38) plays vital roles in adipogenesis and Flavonoids comprise a large family of natural substances
lipolysis. (b−AR) stimulation by catecholamine activates sharing a molecular structure characterized by at least one
ERK1/2, which is sufficient to induce lipolysis by direct HSL phenolic ring. Flavonoids are reputed for their health benefits.
phosphorylation at Ser600. JNK regulates lipolysis. JNK1/2 Epigallocatechin-3-gallate (EGCG) is a polyphenolic catechin in
deficiency accelerates basal lipolysis in mouse adipocytes (41). green tea that improves the lipid prolife and reduces body weight
The MEK1/2-ERK1/2 pathway controls TNF-a-stimulated (60). EGCG inhibits adipogenesis and adipocyte differentiation,
lipolysis in human adipocytes (42). reduces energy intake, and increases energy expenditure and
lipolysis (61, 62). EGCG-stimulated lipolysis is mediated by
activating HSL (63), ERK1/2 (64), and p-AMPK (65).
3.5 AMPK pathway Lipophagy is also associated with EGCG-induced lipolysis.
Rab7 knockdown attenuates EGCG-dependent lipid reduction
AMPK is a Ser/Thr protein and an important regulatory (65). However, a clinical trial demonstrated no effect of EGCG
sensor of cellular energy metabolism. Activated AMPK inhibits on obesity reduction, lipolysis, or white adipocyte browning in
sterol regulatory element binding protein-1, CCAAT/enhancer humans (66).
binding protein alpha, peroxisome proliferator activated Kaempferol (67), apigenin (68), genistein (69), morusin (70),
receptor gamma, and acetyl-CoA carboxylase (ACC). Hence, medicarpin (71), and myricetin (72) commonly occur in fruits,
AMPK suppresses adipocyte differentiation (43). AMPK also vegetables, and tea. These flavonoids have anti-obesity and pro-
phosphorylates ATGL Ser406, which promotes TG lipolysis efficacy. Elevated lipolysis upregulates thermogenic

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FIGURE 2
Signaling pathways regulating lipolysis in adipocytes.

genes and increases mitochondrial biogenesis by supplying FFAs (65) inhibit adipogenesis, stimulate adipocyte lipolysis, and may
for mitochondrial b-oxidation. Apigenin activates lipolysis via act as browning or beiging agents because they upregulate the
the ATGL/FOXO1/SIRT1 pathway and increases FFA thermogenic protein UCP1 (Table 1).
consumption by upregulating fatty acid oxidation (FAO)
(AMPK/ACC), thermogenesis, and browning (UCP-1, PGC- 4.1.2 Alkaloids
1a) (68). Lipolysis is also associated with activated BAT or Consumption of coffee, ephedrine, or capsaicin increases
beiging which is regarded as an alternative strategy against diet- lipolytic responses, raise metabolic rates, and increase energy
induced obesity. Xanthohumol (73), apigenin (68), and EGCG expenditure and weight loss (74, 75). Caffeine is the main

TABLE 1 Lipolytic effects and modes of action of flavonoids.

Compound Model Concentration Effect Mechanism Reference

EGCG 3T3-L1 adipocytes; 10 µM Adipogenesis inhibition Increasing p-AMPK Kim et al. (65)
C3H10T1/2 cells Lipophagy activation and adipocyte Lipophagy mediates EGCG-induced
browning lipolysis
3T3-L1 adipocytes 10 µM Lipolysis promotion Increasing HSL Lee et al. (63)
Rat primary adipocytes 2.79 µM Lipolysis promotion Increasing p-ERK1/2 Ogasawara et al.
(64)
Kaempferol 3T3-L1 adipocytes 60 mM Lipolysis promotion Increasing ATGL and HSL Torres-Villarreal
Adipogenesis inhibition et al. (67)
Apigenin HFD-Fed mice 0.04% Increasing lipolysis, thermogenesis, Increasing ATGL, SIRT1, and p- Sun et al. (68)
and browning AMPK
Myricetin 3T3-L1 adipocytes 50 and 100 mM Increasing lipolysis Decreasing perilipin1 Wang et al. (72)
Increasing p-p38 and p-JNK
Genistein Primary rat adipocytes 0.1 and 1 mM Increasing lipolysis PKA-mediates, genistein-induced Szkudelska et al.
lipolysis (69)
Morusin 3T3-L1 and primary 5, 10 and 20 mM Lipolysis promotion Increasing HSL, ATGL, and p- Lee et al. (70)
adipocytes Adipogenesis inhibition perilipin expression
Medicarpin BAT cells (10 mM) Lipolysis promotion PKA-mediates, medicarpin-induced Imran et al. (71)
lipolysis
Xanthohumol 3T3-L1 and primary human 25 mM Adipogenesis suppression AMPK signaling pathway mediates Samuels et al. (73)
adipocytes. Increasing lipolysis and white lipolysis
adipocyte beiging

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Yang et al. 10.3389/fendo.2022.1000739

alkaloid in tea, coffee, and cacao. It decreases body fat, improves 4.1.3 Terpenoids
glucose tolerance and insulin sensitivity (76), and increases Terpenoids comprise five-carbon isoprene units and have
lipolysis by raising cAMP levels and upregulating lipolytic diverse effects on obesity and its associated metabolic diseases.
enzymes (77). Ephedrine is an a- and b-adrenergic receptor Triterpenoids include 18b-glycyrrhetinic acid (18b-GA) (88),
agonist with efficacy as a bronchodilator. It also activates the b- ursolic acid (89), acetyl-keto-b-boswellic acid (AKBA) (90),
adrenergic receptors, contributing to lipolysis (78). Capsaicin alisol A 24-acetate (AA-24-a) (91), celastrol (92), and betulinic
analogs significantly increase cAMP levels and PKA activity in acid (93). All of these reduce neutral lipids in the cytosol and
BAT (79). While ephedrine, caffeine, capsaicin, and synephrine increase FFA release. Madecassoside (94), tanshinone 1 (95),
strongly induce lipolysis, they are also associated with various triptolide (58), crocin (96), guggulsterone (97), bilobalide
cardiovascular and gastrointestinal side effects when they are (98), a-cubebenoate (99, 100), betulinic acid (93),
administered for weight loss (80). Therefore, novel lipolytic fucoxanthinol (101), widdrol (102), ginkgolide C (103), and
compounds with m inimal adverse r e a c ti o n s m eri t illudins C2 and C3 (104) could all potentially treat obesity
further investigation. either by inhibiting adipocyte differentiation and lipogenesis or
Berberine (BBR) is an isoquinoline alkaloid derived from the by increasing lipolysis. The LDAP (88–90), PKA (89, 90),
Chinese herb Coptis chinensis. It has anti-obesity, anti-diabetic, AMPK (96, 98), and PKC-MEK-ERK (102) pathways are
and anti-hyperlipidemic efficacy. BBR stimulates basal lipolysis involved in the lipolytic mechanisms induced by these
in 3T3−L1 adipocytes by upregulating ATGL via the AMPK compounds (Table 3).
pathway (81, 82). However, Zhou et al. found that BBR Celastrol and triptolide are the main bioactive constituents
attenuates isoprenaline-stimulated lipolysis in 3T3−L1 in the root of Tripterygium wilfordii. The administration of
adipocytes by reducing phosphodiesterase-3B and -4 celastrol and triptolide reduces body and fat weight, suppresses
inhibition, thereby decreasing cAMP production and lipogenesis (58, 92), increases heat production in BAT, and
inhibiting HSL activation (83). Trigonelline (N-methylnicotinic enhances lipolysis (58). Celastrol rapidly lowers body weight by
acid) is a pyridine derivative that increases brown and beige fat- covalently inhibiting GRP78 chaperone activity and
specific markers as well as mitochondrial biogenesis in 3T3-L1 disconnecting ER stress signal transduction (92). Elevated
adipocytes (57). Trigonelline as well as cordycepin from lipolysis induced by triptolide is mediated by p53 which
Cordyceps militaris promotes white adipocytes beiging and directly binds and promotes the transcription of the ATGL
browning and increases lipolysis by various mechanisms (57, promoter (58). Although triptolide and celastrol have good
84) (Table 2). anti-obesity efficacy, their potential toxicity must be established.

TABLE 2 Lipolytic effects and modes of action of alkaloids.

Compound Animal or cell model Concentration Effect Mechanism Reference

BBR Differentiated porcine adipocytes 10-40 mM Lipolysis and FFA oxidation Increasing p-ATGL Yang et al.
promotion Decreasing perilipin (82)
AMPK mediates BBR-induced
lipolysis
Trigonelline 3T3-L1 cells 75 mM Promoting lipolysis, browning, and b3-AR/PKA activation Choi et al.
FFA oxidation PDE4 inactivation (57)
Decreasing adipogenesis and
lipogenesis
Capsaicin 3T3-L1 cells 10 mM Promoting lipolysis Increasing HSL and UCP2 Lee, et al. (85)
HFD-Fed transient receptor potential Animal: chow plus Promoting lipolysis TRPV1 mediates capsaicin-induced Chen, et al.
vanilloid 1 deficient (TRPV1-/-) mice 0.01% capsaicin lipolysis (86)
3T3-L1 cells Cell: 1 mmol/L
Caffeine SD rats 5 mg/kg Promoting lipolysis N.A. Kobayashi-
Hattori et al.
(87)
Cordycepin Animal: S-D rats Animal: 12.5, 25, White adipocyte beiging and Decreasing Fsp27, perilipin 3, Xu et al. (84)
Cell: 3T3-L1 cells and 50 mg/kg browning perilipin 2, Rab5, Rab11, CGI-58 and
Cell: 1.563-25 mg/ Blocking lipid droplet formation perilipin 1
mL and promoting lipid droplet Increasing ATGL
degradation

HFD, high-fat diet; N.A., not available.

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TABLE 3 Lipolytic effects and modes of action of terpenoids.

Compound Animal or cell model Concentration Effect Mechanism Reference

18b-GA 3T3-L1 cells 40 mM Inhibiting adipogenic Increasing HSL, ATGL, perilipin and Moon et al.
differentiation p-HSL expression (88)
Increasing lipolysis
Ursolic acid Primary rat adipocytes 25 and 50 mM Increasing lipolysis Increasing HSL translocation and Li et al. (89).
ATGL expression
Decreasing perilipin1
PKA participates in lipolytic action of
UA
AKBA 3T3-L1 adipocytes 30 mM Increasing lipolysis Increasing ATGL and HSL Liu et al.
Decreasing perilipin (90)
Betulinic acid Rat adipocytes 10 and 25 mM Increasing lipolysis Decreasing PDE activity Kim et al.
(93)
AA-24-a 3 T3-L1 cells 30, 40 and 50 mM Increasing lipolysis PKA- and ERK- mediated AA-24-A- Lou et al.
promote lipolysis (91)
Celastrol C57BL/6N mice fed HFD 7.5 mg/kg/d for 21 d Inhibiting lipogenesis Inhibiting endoplasmic reticulum (ER) Luo et al.
Increasing lipolysis and stress (92)
thermogenesis
3T3-L1 adipocytes 400 nM Inhibiting adipocyte N.A. Choi et al.
differentiation and (105)
adipogenesis
Tanshinone 1 Immortalized brown adipocytes (iBAs) 15 mM Reducing HFD-induced Increasing HSL and p-AMPK Jung et al.
and differentiated C3H10T1/2 cells obesity (95)
Activating brown adipocytes
Increasing lipolysis and
browning
Cis-Guggul- 3T3-L1 adipocytes 25 and 50 mM Inhibiting lipid content Increasing p-ERK1/2 Yang et al.
sterone Increasing lipolysis (97)
Madecas- KKay/TaJcl obese diabetic mice 40 mg/kg/d Inhibiting lipogenesis. Increasing p-HSL, p-AMPK Sun et al.
soside Promoting lipolysis and (94)
thermogenesis
Triptolide Cell: 3T3-L1 and porcine adipocytes Cell: 10 nM Animal: Reducing fat tissue P53-mediated ATGL transcription Wang et al.
Animal: C57BL/6J fed HFD 0.2 mg/kg for 7 wks accumulation responsible for triptolide-induced (58)
Increasing heat production lipolysis
Increasing lipolysis
Crocin Cell: 3T3-L1 adipocytes Animal: db/db Cell: 20 mM Increasing lipolysis AMPK mediates crocin-trigged Gu et al.
mice Animal: 20 mg/kg/d Inhibiting preadipocyte lipolysis (96)
differentiation and
adipogenesis
Bilobalide 3T3-L1 adipocytes 25 and 100 mM Inhibiting preadipocyte Increasing ATGL, pHSL, pACC1/ Bu et al.
differentiation and ACC1, and pAMPK/AMPK (98)
adipogenesis
Increasing lipolysis
a-Cubebe- Primary adipocytes and 3T3-L1 10, 20, and 30 mg/mL Inhibiting adipogenesis and Increasing pHSL, ATGL, and p- Bae et al.
noate adipocytes lipogenesis perilipin (99)
Increasing lipolysis
a-Cubebenol 3T3-L1 adipocytes 7.5, 15, and 30 mg/mL Inhibiting adipogenesis Increasing cAMP, ATGL, p-perilipin, Lee et al.
Increasing lipolysis and p-HSL (100)
Decreasing perilipins and PDE4
Illudins C2 3T3-L1 adipocytes 5 and 10 mM Suppressing adipogenesis PKA and ERK mediate illudins C2 and Kim et al.
and C3 Increasing lipolysis C3-stimulated lipolysis (104)
Fuco- 3T3-L1 adipocytes 5 and 10 mM Decreasing TG content Increasing ATGL, pHSL, pACC1/ Yoshikawa
xanthinol Increasing lipolysis ACC1, and pAMPK/AMPK et al. (101)
Decreasing CGI-58, ATGL, p-HSL, and
perilipin
Widdrol 3T3-L1 adipocytes 10-25 mg/mL Increasing lipolysis PKC and MEK/ERK pathway mediated Jeong et al.
Widdrol-induced lipolysis (102)
Ginkgolide C 3T3-L1 adipocytes 10, 30 and 100 mM Suppressing adipogenesis and Increasing ATGL, p-HSL, and p- Liou et al.
promoting lipolysis AMPK (103)

N.A., not available.

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4.1.4 Other compounds rodents and humans necessitates the re-evaluation of RSV as a
Resveratrol (RSV) (106), 2,4,5-trimethoxybenzaldehyde putative anti-obesity drug.
( 2 , 4 , 5 - T MB A ) ( 1 1 ) , r a s p b e r r y k e t on e ( R K ) ( 1 0 7 ) , RK has a structure resembling those of capsaicin and
cinnamaldehyde (108), lipoic acid (109), syringic acid (110), synephrine and can prevent HFD-induced obesity (117). 3T3-
6’-O-acetyl mangiferin (111), ferulic acid (112), and magnolol L1 adipocytes treated with 10 µM RK presented with elevated
(113) have all demonstrated potential prophylactic and FAO and inhibition of lipid accumulation (118). Magnolol is the
therapeutic efficacy against obesity. RSV directly affectes main bioactive compound in Magnolia officinalis. Its lipolytic
isoprenaline-stimulated lipolysis in vitro in fac cells from effect is mediated by the calcium/calmodulin-dependent protein
overweight humans (114). It also increases FFA and glycerol kinase (CaMK)/ERK1/2 signaling pathway and not by PKA
content in high-fat diet (HFD)-fed mice or 3T3-L1 adipocytes (119). Magnolol may cause browning in white adipocytes and
(106). Arrate et al. showed ATGL-mediated, RSV-induced augment thermogenesis (113) (Table 4). Further research in the
lipolysis in vivo (115). However, a randomized, double-blind, form of animal models is required to validate the lipolytic
crossover study revealed that RSV improved adipose tissue potential and clinical value of the foregoing compounds.
lipolysis and decreased plasma FFA and glycerol levels (116). The lipolytic effects of the compounds above have already
This apparent contradiction in the anti-obesity effects of RSV in been established in in vivo or in vitro experiments. For

TABLE 4 Lipolytic effects and modes of action of other compounds.

Compound Animal or cell model Concentration Effect Mechanism Reference

2,4,5-TMBA 3T3-L1 adipocytes 100 mg/mL Suppressing differentiation and Reducing perilipin Wu et al. (11)
adipogenesis Increasing HSL
Increasing lipolysis
Raspberry Animal: ICR mice +HFD Animal: 1) HFD Preventing obesity Increasing HSL protein Morimoto (117).
ketone Cell: Primary adipocytes including 0.5, 1, or 2% Increasing norepinephrine-induced translocation
RK lipolysis
2) HFD containing 1%
RK
Cell: 10−3 mM and 10-4
mM
3T3-L1 adipocytes 10 mM Increasing FAO and lipolysis N.A. Park et al. (118)
Suppressing lipid accumulation
3T3-L1 adipocytes 10, 20, and 50 mM Inhibiting adipogenic and lipogenesis Increasing ATGL and HSL Park et al. (120)
Increasing lipolysis
RSV Human adipocytes 100 mM Increasing isoprenaline-induced lipolysis N.A. Gomez-Zorita
Impairing insulin-mediated anti-lipolysis et al. (114)
Animal: C57BL/6J mice +HFD Animal: 15 mg/kg Promoting lipolysis N.A. Gong et al.
Cell: 3T3-L1 adipocytes Cell: 20 mM Improving metabolic abnormalities (106)
Cell: 3T3-L1 adipocytes, human 100 mM Increasing basal-, isoproterenol-, and ATGL mediates RVS- Lasa et al. (115)
SGBS adipocytes isoproterenol-stimulated lipolysis induced lipolysis
Tissue: fat pads from wild-type,
ATGL-/- and HSL-/- mice
Lipoic acid 3T3-L1 adipocytes 250 mM Increasing lipolysis cAMP-PKA mediates LA- Ferná ndez-
induced lipolysis Galilea et al.
(109)
Cinnamal- Animal: Swiss albino mice fed Animal: 10 mg/kg/d for Inhibiting preadipocyte differentiation and Increasing HSL Khare et al.
dehyde HFD. 14 wks lipid accumulation in adipocytes Decreasing Plin1 (108)
Cell: 3T3-L1 adipocytes Cells: 20 mM and 40 mM Increasing lipolysis and browning
Magnolol Sterol ester (SE)-loaded 3T3-L1 5-60 mM Promoting lipolysis CaMK/ERK mediate Huang et al.
preadipocytes magnolol-induced lipolysis (119)
3T3-L1 adipocytes Promoting lipolysis, browning, and Increasing p-HSL, PKA, p- Parray, et al.
thermogenesis AMPK, Plin1 (113)
Syringic acid 3T3-L1 adipocytes 1000 mmol/mL Promoting lipolysis N.A. John et al. (110)
6’-O-acetyl 3T3-L1 adipocytes 12.5, 25, and 50 mM Promoting lipolysis Increasing p-HSL, ATGL, Sim et al. (111)
mangiferin and p-AMPK
Ferulic acid 3T3-L1 adipocytes 10 mM Inhibiting lipogenesis and promoting Increasing p-perilipin, p- Kuppusamy
lipolysis HSL et al. (112)

N.A., not available.

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TABLE 5 Anti-lipolytic effects and mechanisms of various compounds.

Compound Animal or cell model Concentration Effect Mechanism Reference

RA 3T3-L1 adipocytes 50 mM Inhibiting adipogenesis and Decreasing p-HSL-ser660 and p-perilipin A Rui et al.
lipolysis (136)
AS-IV Animal: ICR mice fed HFD Animal: 50 and Inhibiting lipolysis and hepatic Decreasing cAMP Du et al.
100 mg/kg lipid deposition Increasing PDE3B, AMP, and Akt (126)
Improving glucose tolerance
3T3-L1 adipocytes 50, 100, and 200 Inhibiting TNF-a-induced Increasing perilipin Jiang et al.
mM lipolysis and improving IR Decreasing p-ERK1/2 (131)
Curcumin Adipose tissue 0.1, 1, and 10 mM Inhibiting lipolysis Decreasing cAMP, p-HSL and ER stress Wang et al.
Cells: 3T3-L1 adipocytes Reducing lipid deposition and Increasing AMP and PDE3B (125)
IR in liver
3T3-L1 adipocytes 20 mM Inhibiting TNF-a or Decreasing p-ERK1/2, p-perilipin, and HSL Xie et al.
catecholamine-induced lipolysis translocation (132)
Ilexgenin A Adipose tissue 20 or 50 mg/kg Inhibiting lipolysis and hepatic Decreasing cAMP, pSer-660-HSL and ER Li et al. (127)
IR stress
Increasing AMP, PDE3B, pSer-565-HSL,
and p-AMPK
BBR 3T3-L1 adipocytes 10 mM BBR-decreased isoprenaline- Reducing PDE inhibition Zhou et al.
and noradrenaline-induced (83)
lipolysis
RSV Obese human 150 mg/d for 30 d Inhibiting lipolysis N.A. Timmers
Increasing muscle and et al. (116)
decreasing hepatic lipid content
Piceatannol 3T3-L1 adipocytes, brown 25 and 50 mM Inhibiting basal and Autophagy mediated ATGL, CGI-58, and Kwon et al.
adipocyte, and WAT isoprenaline-stimulated lipolysis perilipin1 downregulation induced by (140)
piceatannol
EPA Primary rat adipocytes, 3T3-L1 100 and 200 mM Inhibiting IL-6- and TNF-a- Increasing pSer565 HSL Lorente-
adipocytes, and rat adipose tissue induced lipolysis Decreasing ATGL Cebriá n et al.
(134)
C3G 3T3-L1 adipocytes 50 mM Inhibiting high glucose-induced Increasing AMPK activity Guo et al.
lipolysis Decreasing FoxO1-mediated ATGL (138)
transcription
Emodin 3T3-L1 adipocytes 50 mM Increasing glucose metabolism Decreasing p-perilipin and p-ERK1/2 Zhang et al.
Decreasing TNF-a-induced (133)
lipolysis
DDE 3T3-L1 adipocytes or human 1 and 10 mM Inhibiting basal- and TNF-a- N.A. Nehrenheim
subcutaneous adipocytes induced lipolysis et al. (139)
Phillyrin 3T3-L1 adipocytes 20, 40, 80 mM Increase in glucose uptake and Decreasing p-ERK1/2 Kong et al.
decrease in TNF-a-induced Increasing perilipin (135)
lipolysis
Rg5 Animal: ICR mice fed HFD Animal: 50 mg/kg Inhibiting lipolysis in adipocytes Decreasing cAMP and p-PKA Xiao et al.
Cells: 3T3-L1 adipocytes Cells: 0.1, 1, 10 and IR in muscle Increasing PDE3B and AMP (128)
mM
Carnosic acid Human multipotent, adipose- 10 mM Inhibiting isoprenaline-induced N.A. Colson et al.
derived stem cells lipolysis (137)

N.A., not available.

compounds with pro-lipolytic activity tested only in vivo, 4.2 Natural products that inhibit lipolysis
preclinical pharmacodynamics and safety evaluations are
required. In pharmacodynamics experiments, primary Adipose tissue dysfunction increases circulating FFA levels.
outcome measures, such as change in body weight, food Elevated FFAs are often observed in patients with IR and T2DM
intake, resting metabolic rate, blood lipids, and biochemistry, (9). Impaired lipogenic capacity driven by insulin signaling and
need to be tested. In addition to general and specific toxicities of re-esterification of FFA with adipocytes results in impaired
drugs, the safety evaluation should pay special attention to liver buffering capacity for FFA and high concentrations of
and kidney toxicity caused by long-term use of lipolysis agonists, circulating FFA (26). Long-term over-activation of lipolysis
as well as pancreatic damage, insulin resistance, and may promote lipid ‘overflow’ into the muscle, liver,
cardiovascular events that may be caused by elevated FFA. endothelium, heart, and b-cells, thereby causing muscular/

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Yang et al. 10.3389/fendo.2022.1000739

FIGURE 3
Network analysis of natural products and lipolytic pathways.

hepatic IR, CVD, and impaired insulin secretion (121). For and piceatannol (140) may also inhibit lipolysis. The effects
example, adipocyte-derived FFA is involved in regulating and mechanisms of these compounds are summarized
hepatic energy metabolism (122). FFA impairs the insulin in Table 5.
signaling pathway by forming diacylglycerol and ceramides
and increases gluconeogenesis via the hepatic acetyl-CoA
pathway in liver during diseased states (26, 123), which leads 5 Conclusions and perspectives
to TG accumulation in the liver. In patients with adipose tissue
dysfunction, then, the inhibition of lipolysis may ameliorate IR- In the present review, we summarized the effect and modes
and obesity-associated metabolic diseases. Thiazolidinedione of action of a wide range of natural products on lipolysis.
antidiabetic drugs improve insulin sensitivity and reduce Overall, these compounds individually or synergistically affect
circulating FFA levels by attenuating lipolysis and FFA lipolytic enzymes, LDAPs, ER stress, and the cAMP-PKA,
release (124). MAPK, AMPK, and PKC signaling pathways (Figure 3). The
Curcumin (125), astragaloside IV (AS-IV) (126), and ilexgenin lipolytic effects of certain compounds have already been
A (127) attenuate lipolysis by modulating the cAMP/PKA/HSL established. Nevertheless, their influences and mechanisms in
pathway. The inhibition of lipolysis in adipose tissue may improve fat synthesis and metabolism, their toxicity, and their effects on
hepatic insulin sensitivity (125, 126). Ginsenoside Rg5 (Rg5) whole-body phenotypes, appetite, energy expenditure, and
suppresses lipolysis and inhibited IR in muscle (128). The thermogenesis remain to be determined. About half the
foregoing findings suggest that a decrease in adipose tissue compounds evaluated herein affect lipolytic enzyme
lipolysis mediated by natural bioactive components is a expression. However, in vitro enzyme activity assay and
potentially efficacious therapy for hepatic IR and related disorders. compound-enzyme interaction data were lacking for them.
TNF-a is a proinflammatory cytokine expressed in adipose These experiments may help identify novel lipolysis inhibitors
tissue that might link obesity and IR (129) and increases plasma and agonists.
FFA levels in obesity and T2DM (130). AS-IV (131), curcumin Our understanding of adipocyte lipolysis has progressed
(132), emodin (133), eicosapentaenoic acid (EPA) (134), and from basic knowledge of its associated enzymatic processes to
phillyrin (135) attenuates TNF-a-induced lipolysis by elucidtation of the dynamic and complex regulatory
suppressing p-ERK1/2 and reversing perilipin or p-perilipin mechanisms involved. Lipolysis interacts with other related
downregulation. Rosmarinic acid (RA) (136, 137), RSV (116), processes, including thermogenesis, adipocyte browning, and
B BR (8 3 ) , c y a n id i n - 3 - O- b - g l u c o s i d e ( C 3 G ) (1 3 8 ) , lipogenesis. Clarification of the mechanisms of lipolysis and the
dihydrodehydrodiisoeugenol (DDE) (139), carnosic acid (137), changes it causes in whole-body energy metabolism has positive

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Yang et al. 10.3389/fendo.2022.1000739

clinical value and socioeconomic benefits in that it may help Author contributions
develop modalities to prevent and treat obesity and its associated
metabolic disorders. Lipolysis regulates TG metabolism and X-DY and Y-YY wrote the manuscript. X-CG and S-YJ
weight loss. Certain compounds with lipolytic activity, such collected and checked the data. Y-YY contributions to design of
as celastrol (141), apigenin (142), cordycepin (84), and BBR the work and revised the work. All authors contributed to the
(143), have demonstrated anti-obesity efficacy. Theoretically, article and approved the submitted version.
activating lipolysis may be a rational therapeutic approach
for obesity. Thus far, however, no anti-obesity drugs
targeting lipolytic enzymes or its related targets have Funding
been marketed.
The pathologies of obesity and its related metabolic This study was supported by the National Natural Science
conditions are highly complex. Simply targeting lipolysis can Foundation (No. 81603171) and the Natural Science Foundation
achieve weight loss. From the perspective of energy metabolism, of Hunan Province (2022JJ30860 and 2022JJ30862).
however, weight loss is the result of multiple factors, including
dietary restrictions and increases in lipolysis and energy
utilization. It remains to be established whether lipolysis Conflict of interest
triggered by lipolytic agonists may damage certain cells,
tissues, and organs or cause complications. The ideal anti- The authors declare that the research was conducted in the
obesity drug should safely suppress appetite, increase lipolysis, absence of any commercial or financial relationships that could
and activate energy expenditure. Finally, the physiological be construed as a potential conflict of interest.
functions of adipocytes should be rationally exploited, and
their roles during metabolic disease should be identified. For
patients with adipose dysfunction, the dynamic regulation of Publisher’s note
lipolysis and the amelioration of adipocyte dysfunction could
improve obesity-associated metabolic conditions. For All claims expressed in this article are solely those of the
example, AS-IV and curcumin inhibit adipose lipolysis and authors and do not necessarily represent those of their affiliated
thus prevent hepatic IR, which demonstrates their potential organizations, or those of the publisher, the editors and the
as treatments for metabolic-associated fatty liver disease reviewers. Any product that may be evaluated in this article, or
through the regulation of lipolysis in adipose tissue during claim that may be made by its manufacturer, is not guaranteed
diseased states. or endorsed by the publisher.

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