Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 1

Ursolic acid in experimental

models and human subjects:

Potential as an anti-

obesity/overweight treatment?

Saulo J.A. Felizola, MD, PhD

Abbreviated title: Ursolic acid: potential as

anti-obesity treatment?

Key terms: Ursolic acid, obesity, insulin

sensitizer, IGF-I

Abstract

Recently, the world has seen the rise of an

obesity epidemic without historical precedents.

There are several risk factors associated with the

obesity/overweight condition, including insulin

resistance and type II diabetes, cardiovascular

diseases, respiratory and bone-joint

complications, and certain forms of cancer.

Ursolic acid is a pentacyclic triterpenoid

identified in the epicuticular waxes of apples as

early as 1920 and widely found in fruits, herbs

and spices. This substance has been shown to

reduce adipogenesis and body fat percentage

while increasing muscle mass in rodent models

as well as in human volunteers.

A detailed analysis of the current literature

indicates great potential benefits of ursolic acid

as a therapeutic agents in obesity/overweight,

diabetics and metabolic syndrome as a whole.

However, in spite of promising prospects, there

have been no phase-II/III studies about the oral

administration of ursolic acid to human subjects.

Nevertheless, it is hard to ignore that, with

widespread availability of ursolic acid in its

purified and non-purified form, many ursolic

acid consumers have been conducting

experiments among and on themselves. Success

or failure in ursolic acid treatment, however,

certainly depend on several factors that will

remain ignored until wider-ranged scientific

studies and clinical research are actually

conducted.

I. Introduction

In the last few decades, the developed

world has seen the rise of an obesity epidemic

without historical precedents, and this trend is

expected to worsen in the next years (1). There

are several risk factors associated with the

obesity/overweight condition, including

insulin resistance and type II diabetes,

cardiovascular diseases, respiratory and bone-

joint complications, and certain forms of

cancer (1, 2).

For those reasons, in the past years several

research groups have been looking for an

effective and reliable treatment for obesity.

There have been different approaches

proposed, including the blockade of fat

absorption in the gut, or the direct inhibition

of appetite in the central nervous system (3).

The results, however, have been modest at

best while the cost-benefit of undesired effects

is often high.

At the same time, folk medicine and

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 2

supplement makers continued to offer

alternative options, readily available to the

consumer with the promise to effectively treat

or alleviate obesity or its comorbidities. In this

scenario, the crescent demand for new

pharmacological agents and molecules led to

the scientific study of many known molecules

from a variety of natural sources, yielding

sometimes intriguing results.

Ursolic acid (3β-hydroxi-urs-12-en-28-oic

acid, Figure 1) is a pentacyclic triterpenoid

identified in the epicuticular waxes of apples

as early as 1920 and widely found in the peels

of fruits, as well as in herbs and spices like

rosemary and thyme (4, 5). This substance has

been recently shown to reduce adipogenesis

and body fat percentage while increasing

muscle mass in rodent models as well as in

human volunteers (6-11). However, in

addition to the study limitations encountered

so far, the low oral biovailability of this

triterpenoid remains one major downside in its

therapeutic potential. In this review, we

ponder about the potential benefits of ursolic

acid use for the treatment of obesity and

associated diseases, while considering the

limitations of the current knowledge about the

pharmaceutical properties of this molecule.

II. Ursolic acid in experimental models

The effect of ursolic acid on cells in vitro

and non-human mammal models has been

relatively well studied in the past few years.

Some studies present evidence pointing to

anti-inflammatory, anti-oxidant effects of

ursolic acid on inflammatory cells, kidney,

liver and heart of rodents in experimental

models (5, 12-20). A pro-apoptotic or anti-

tumoral effect of ursolic acid has also been

well documented in several human cancer cell

lines, including breast, prostate, lung, bladder,

liver, colorectal, gastric carcinoma and skin

melanoma cells (21-30). Such studies

highlight the possibilities of therapeutic use of

ursolic acid as an inflammatory process

modulator and anti-cancer agent, at least in

animals and in vitro. Nevertheless, ursolic

acid does produce interesting effects on fat

and glucose metabolism, both at the cellular

and systemic levels in experimental models,

which are discussed below.

Figure 1. Molecular structure of ursolic acid.

A. Effects of ursolic acid on

adipocytes in vitro

The differentiation of preadipocytes into

adipocytes is tightly regulated by a sequential

activation of several transcriptional factors,

including CCAAT element binding protein α

(C/EBPα), C/EBPβ, peroxisome proliferator-

activated receptor γ (PPARγ) and sterol

regulatory element binding protein 1c

(SREBP-1c) (31). The work of He et al shows

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 3

that, when 3T3-L1 mouse embryo fibroblasts

are differentiated into preadipocytes and then

induced to further differentiation in the

presence of ursolic acid, there is a significant

decrease in the expression of C/EBPβ with

subsequent inhibition of PPARγ and C/EBPα,

with an anti-adipogenic effect (31). While

there is no effect of ursolic acid over the

proliferation of the 3T3-L1 adipocytes, there

is significant decrease in lipid accumulation as

well as a dose-dependent increase in lipolysis

(31). Similar results were obtained by Kim et

al using isolated rat adipocytes, in which

ursolic acid significantly enhanced lipolytic

activity (32). Ursolic acid does also increase

glucose uptake in 3T3-L1 adipocytes by

activating the PI3K pathway and glucose

transporter 4 (GLUT4) translocation in those

cells (33). A previous work by Jung et al

demonstrates ursolic acid to be an effective

insulin-mimetic agent at doses above 50 μg/ml

and as an insulin-sensitizer at doses as low as

1 μg/ml, by increasing the number of insulin

receptors activated by insulin, potentiating the

tyrosine phosphorylation of the insulin-

receptor β-subunit and the phosphorylation of

Akt and glycogen synthase kinase-3β, and

enhancing the effect of insulin on the

translocation of GLUT4 in 3T3-L1 adipocytes

(34).

B. Ursolic acid and amelioration of

diet-induced obesity, glucose intolerance/

diabetes and metabolic syndrome in vivo

In addition to the lipolytic and insulin-

sensitizing/insulin-mimetic actions in

adipocytes, ursolic acid produces consistent

systemic effects that can facilitate the

successful treatment of obesity and its

associated conditions. Rao et al demonstrate

in their work that ursolic acid has roughly the

same effect as sibutramine on mice fed a high

fat diet (HFD) for 15 weeks (7). In that study,

vehicle-treated HFD mice had an average 24%

increase in body weight, while ursolic acid

and sibutramine treated HFD mice

respectively showed 13.3% and 13.1%

increases in body weight compared to normal

diet fed controls (7). According to the results

of independent studies, ursolic acid does

significantly reduce the increase in basal

levels of blood glucose, cell surface area of

adipocytes and weight of visceral fat in mice

after HFD (7, 11). Sundaresan et al

demonstrate that ursolic acid has an effect

superior to rosiglitazone on body weight,

epididymal fat pad weight, and reserves of

liver glycogen after 5 weeks treatment in mice

on a 15 weeks HFD (11). Ursolic acid

treatment also significantly reduces systolic

and diastolic blood pressure levels in mice

(11), exerting a full spectrum effect on the

clinical signs of HFD induced metabolic

syndrome. Similarly, Kunkel et al also show

significant decreases in body weight,

epididymal and retroperitoneal fat weight, as

well as fasting and post-prandial blood

glucose levels in HFD fed mice (6).

Furthermore, these authors demonstrate a

significant increase in skeletal muscle mass,

grip strength, fast and slow skeletal muscle

fiber size, and weight of interscapular brown

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 4

fat in mice treated with ursolic acid compared

to vehicle-treated controls (6). Skeletal muscle

and brown fat have somewhat high rates of

energy expenditure, and indeed the chronic (6

weeks) treatment with ursolic acid produces

an increase in food intake and energy

expenditure in mice (6, 35).

C. Effects of ursolic acid on skeletal

and cardiac muscle of rodents

Castro et al conducted a study using rats

fed glucose marked with radiocarbon (14C) in

which the amount of glucose uptake was

measured in skeletal muscle fibers (8). These

authors found that doses as low as 0.1mg/kg

of ursolic acid can significantly reduce the

glucose tolerance curve while 1mg/kg ursolic

acid elevates the post-prandial peak of insulin

in glucose fed rats (8). These rats presented

significantly higher muscle glucose uptake 60

min post glucose ingestion, and significantly

higher intramuscular glycogen content 180

min after glucose ingestion (8). The

mechanism by which ursolic acid acts in

skeletal muscle is still unclear, but has been

partially explained by Ogasawara et al, who

demonstrate that ursolic acid can lead to an

extended increase in activation of the

mammalian target of rapamycin complex 1

(mTORC1) after muscular fiber induction by

resistance exercise (36). These authors show

that ursolic acid treated rats maintain elevated

plasma levels of IGF-I as well as higher

intramuscular levels of phosphorylated

PRAS40 and p70S6K compared to vehicle-

treated controls after 6h resistance exercise

(36). In a study evaluating heat-stress

mediated alterations in cardiac myocytes,

Yang et al demonstrate that pre-treatment with

ursolic acid significantly reduces the rate of

apoptosis in heart tissue and subsequently

attenuates the rise in plasma troponin I in mice

subjected to high temperature (41oC) for 2h

(37). These authors postulate that ursolic acid

exerts its protective effect in the heart by

interfering in mitochondrial apoptotic

pathways, as they demonstrate that pre-

treatment with ursolic acid prevents an

elevation in the protein levels of cytochrome

C, cleaved caspase 3, and cleaved caspase 9

evaluated using Western Blot (37).

D. Effects of ursolic acid in the liver

Several studies concur that ursolic acid

suppresses oxidative stress and promotes liver

regeneration, improving hepatic functions in

rodents (6, 13, 38-42). The actions of ursolic

acid in the liver appear to be intrinsically

related to its activitity in other systemic tissues,

while also playing a more direct role in liver

cells. Li et al demonstrate that HFD-induced

obese rats treated with 0.125%, 0.25% and

0.5% ursolic acid in chow for 6 weeks have a

dose-dependent reversal of advanced non-

alcoholic fatty liver disease (NAFLD), with a

return of total liver weight, serum aspartate

aminotransferase (AST) and alanine

aminotransferase (ALT) to near basal levels in

the 0.5% group (39). The histological

assessment of hepatic tissues also show a dose

dependent regeneration of the liver cell

morphology and organization, with near

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 5

absence of steatosis in the 0.5% ursolic acid-

treated group (39). Kunkel et al found similar

results in HFD-induced obese mice, with

significant reductions in liver weight, hepatic

tryglicerides and plasma levels of AST and

ALT after 6 weeks treatment with 0.14%

ursolic acid in chow versus vehicle-treated

controls (6). Sundaresan et al show in their

work that, when added to chow for 5 weeks,

ursolic acid (5mg/Kg) is superior to

rosiglitazone (4mg/Kg) in reducing the

plasma concentrations of AST and ALT, free

fat acids (FFA), tryglicerides (TG) and total

cholesterol (TC) in HFD-induced obese mice

(41). In a work about carbon tetrachloride

(CCl4) induced hepatic injury, Ma et al

demonstrate that ursolic acid inhibited

oxidative stress, apoptosis and fibrosis caused

by CCl4 in the mouse liver in a dose-

dependent manner (13).

III. Ursolic acid in human subjects

Because it of its ubiquity in nature and

widespread availability, the commercial-

ization and use of ursolic acid has been free of

strict regulation in many if not all countries.

However, to this date there have been few

studies on human subjects, and the data

available have been obtained from healthy,

non-obese, non-diabetic individuals (9, 43).

Nevertheless, despite a lack of solid

scientific validation, ursolic acid has been

known for its recent popularity among sport

practitioners, especially resistance training

athletes. The currently most up-to-date

information on the use of ursolic acid by

human subjects is discussed below.

A. Pharmacokinetics

Using ultra performance liquid

chromatography tandem mass spectrometry,

Xia et al have conducted a pharmacokinetic

Figure 2. Graphic representation of the mean plasma concentrations of ursolic acid adapted from the work of Xia et al

(44): Plasma concentrations of ursolic acid in 8 healthy volunteers treated with intravenous infusion of ursolic acid

nano-lipossomes at a dose of 98mg/m2. Blood samples were collected before dosing (0h) and 0.5, 1, 2, 4h during the

4h-continuous infusion and 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12h after the end of infusion.

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 6

study of ursolic acid in the plasma of human

subjects (44). Quantitation was performed in

the plasma of 8 healthy volunteers who were

treated with intravenous infusion of ursolic

acid nano-lipossomes at a dose of 98mg/m2,

with about 4ml blood samples being collected

before dosing (0h) and 0.5, 1, 2, 4h during the

4h-continuous infusion and 0.083, 0.25, 0.5, 1,

2, 3, 4, 6, 8, 12h after the end of infusion (44).

Stability tests conducted by those authors

showed ursolic acid is stable in human plasma

at room temperature for 6h, at 10oC for 24h,

and after storing at -20oC for 90 days and

through freeze-thaw cycles (44). The graphic

representation of the mean plasma

concentrations of ursolic acid from the work

of Xia et al has been adapted in Figure 2. The

main pharmacokinetic parameters of ursolic

acid after intravenous infusion were: Cmax

3404.6±748.8 SD (ng/ml), Tmax 4.0±0.0 SD

(h), AUC0-t 9644.1±1193.2 SD (ng h/ml),

AUC0-∞ 9918.4±1215.2 SD (ng h/ml), t1/2

3.9±2.1 SD (h), CL 10.0±1.2 SD (L/h/m2) (44).

B. Bioavailability

By the time of writing of this review,

there were no accurate or reliable data

available regarding the oral biovailability of

ursolic acid in humans. However, studies in

rodents suggest it to be relatively low. Yin et

al show that mice (n=10) on a diet containing

0.5% ursolic acid in chow for 8 weeks

presented with plasma concentrations of

0.55±0.08 SD (µg/ml) (45). Ursolic acid

concentration in organs was detected as

follows: brain 1.7±0.2 SD (µg/g), heart

4.2±0.8 SD (µg/g), liver 10.3±1.4 SD (µg/g),

kidney 5.5±0.5 SD (µg/g), colon 6.0±1.0 SD

(µg/g), and bladder 3.7±0.4 SD (µg/g) (45).

These data show an accumulation of ursolic

acid in organs and tissues, which can also be

expected in humans.

C. Reduction of body fat percentage

and increase in skeletal muscle strength

and mass

Only two studies addressing the oral use

of ursolic acid by human subjects were

available on worldwide scientific databases, to

the best of our knowledge. One of these

studies, conducted by Bang et al, evaluated the

ursolic acid-induced elevation of serum irisin

and its correlation to muscle strength during

resistance exercise in men (9). In this study, 16

Korean male volunteers with over three years

of resistance training experience performed a

resistance training program for 8 weeks using

free weights and machines under supervision,

while receiving 3 capsules daily containing

450mg of ursolic acid or placebo after meals,

and blood samples were collected before and

after the 8 week intervention (9). These

authors found that, although there were no

significant differences in body weight, after 8

weeks individuals in the ursolic acid treatment

group (n=9) showed significantly lower body

fat percentage than their control group

counterparts (n=7) (8.7%±2.51 SD vs

12.78%±3.36 SD respectively; P<0.001) (9).

There were no significant changes in blood

glucose or insulin levels in those individuals,

but ursolic acid treated subjects had

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 7

significantly higher plasmatic levels of IGF-I

and irisin compared to placebo treated

volunteers (9). Maximal muscle strength of

participants was significantly higher in the

ursolic acid group when evaluated on a

Human/Norm Testing and Rehabilitation

System (Computer Sports Medicine Inc., MA,

USA) (9). In another study, Church et al

randomized 9 healthy, resistance-trained male

volunteers between 18-30yo, who performed

three separate testing sessions of lower-body

resistance exercise involving 4 sets of 8-10

repetitions angled leg press and knee

extension exercises (43). Immediately after

each resistance exercise session, participants

ingested 3 grams (0.043 g/kg equivalent) of

placebo, L-leucine, or ursolic acid, and a

blood sample was obtained before, and 0.5, 2,

and 6h post-exercise, while a vastus lateralis

muscle biopsy obtained before and 2 and 6h

post-exercise (43). These authors found no

significant differences among the three

treatment modalities in serum IGF-I, nor in

skeletal muscle phosphoproteins IGF-IR, Akt,

and p70S6K (43).

IV. Discussion

When looking at the data from cell lines

and animal models, the potential benefits of

ursolic acid as a therapeutic agents in

obesity/overweight, diabetics and metabolic

syndrome as a whole appear obvious. In spite

of promising prospects, however, it was not

possible to find any phase-II/III studies

involving the oral administration of ursolic

acid in human subjects. As ursolic acid is

expected to yield low oral bioavailability

based on rodent model studies and theoretical

predictions, one might wonder whether low

levels can be enough to shift a few

physiopathological parameters, as the pauper

present literature on human subjects indicates

(9). Apparent contradictions (9, 43) in the

currently available information from human

studies and the low number of

patients/volunteers enlisted are also reason for

skepticism about any possible benefits of the

oral administration of ursolic acid in humans.

Despite the widespread availability of

ursolic acid in its purified and non-purified

form in the market, the lack of information

about its use in humans is blatant in the

scientific literature. It is, however, true and

difficult to ignore that, as easy as it is to

exchange and publish information nowadays,

many ursolic acid consumers have been

conducting experiments among and on

themselves, sometimes confirming the

findings in experimental model studies,

sometimes generating no more than self-

frustration. The reason for success and failure

in ursolic acid treatment does certainly depend

on several currently ignored factors that will

remain unknown until further and wider-

ranged scientific studies and clinical research

are in fact conducted.

Acknowledgements

The present scientific review is an

independent work and the author has no

conflicts of interest to declare.

Ursolic acid: potential as anti-obesity treatment? Felizola S.J.A. 2015

doi: 10.13140/RG.2.1.4502.4804 8

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