Chingshu - Molecular Mechanism
Chingshu - Molecular Mechanism
Chingshu - Molecular Mechanism
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The prevalence of obesity has increased rapidly, resulting in a the most responsible for the development of obesity
huge impact on human health worldwide. Obesity is also [1,3]. Currently, obesity is not only regarded as a simple
associated with an increased risk of various metabolic disease but is also highly associated with development of
diseases. Despite understanding the pathological mechanisms metabolic diseases, cardiovascular disease and cancer.
in development of obesity, pharmacotherapy remains of limited In addition to TGs storage, adipose tissue is a major
effectiveness for the management of this disease. Over the past endocrine and metabolic organ that secretes adipocyto-
few decades, research in the bioactive compounds of kines, cytokines, growth factors and hormones involved in
functional foods has provided a new strategy for anti-obesity. energy homeostasis, systemic insulin sensitivity, host
These dietary bioactives act to regulate food intake, adipocyte immunity and other pathological processes [4]. In fact,
lifecycle and function, and the lipid metabolism through genetic the pathogenesis of obesity is complicated and multi-
and epigenetic mechanisms to prevent and improve obesity. factorial, involving the dysfunction of different hormones,
Although the efficacy of these bioactives in humans requires peptides and neuron signals from the brain, stomach,
further investigation, they hold great promise for improving pancreas and adipose tissue. The signals from these
population obesity and metabolic health. organs and tissues generally regulate the food intake
Addresses and energy expenditure that maintain the energetic
1
Institute of Food Science and Technology, National Taiwan University, homeostasis in our bodies [5]. Their functions and
Taipei 10617, Taiwan interactions also become newly attractive targets for
2
Department of Medical Research, China Medical University Hospital,
the development of pharmacological drugs for anti-
China Medical University, Taichung 40402, Taiwan
obesity, including appetite suppressants, lipase inhibi-
Corresponding author: Pan, Min-Hsiung ([email protected], tors, hormone receptor agonists and inhibitors of TGs
[email protected]) synthesis, among others [6].
Current Opinion in Food Science 2015, 2:9–13 It is widely accepted that dietary control and physical
This review comes from a themed issue on Functional foods and
exercise are effective for the prevention and treatment of
nutrition obesity, but many people find it difficult to achieve these
Edited by Chi-Tang Ho
goals, in particular changing their dietary behaviors
alone. Moreover, although many drugs are mechanisti-
cally designed to treat obesity, they usually fail due to
limited efficacy, lesser success in long-term treatment,
doi:10.1016/j.cofs.2014.11.008 and concerns of side effects and safety [6,7]. In recent
S2214-7993/# 2014 Elsevier Ltd. All right reserved. years, novel pharmacological agents have been devel-
oped by targeting the modulation of the energy homeo-
stasis pathways; still, their efficacy and long-term safety
require further investigation [6,7]. In the meantime,
the identification of natural products with anti-obesity
properties that can be obtained from the diet is increas-
Introduction ingly desirable. Dietary foods not only provide essential
Obesity is recognized as a serious health problem and a nutrition for the human body but also act as a source of
highly prevalent condition in the world. In 1988, WHO functional ingredients, including various phytochem-
defined obesity as a phenotypic manifestation of abnor- icals, sterols, fatty acids and fibers. Crucially, they have
mal or excessive fat accumulation that alters health and fewer detrimental effects than many pharmacological
increases mortality. Due to an imbalance between energy agents. A large body of literature has shown that bioactive
intake and expenditure, the body’s adipocytes store compounds from foods are used to prevent and manage
excessive energy in the form of triglycerides (TGs), obesity by targeting different mechanisms [8,9,10].
resulting in enhanced adipogenesis, increased adipose Some bioactives exert anti-obesity effects through
tissue mass, and consequent obesity [1]. The risk factors multiple targeted molecules or enhance their efficacy
for obesity include genetic and non-genetic factors alike, through synergistic interactions. The aim of this review is
such as age, physiological condition, dietary behaviors and to summarize some of the recent potential proposed
lifestyle [1,2]. Many epidemiological researchers have bioactives from functional foods and their mechanisms
agreed that high caloric diets and inactive lifestyles are of actions in obesity.
Figure 1
Functional Food
Bioactives
EGCG Phytochemical
Chitosan Sterol
Resveratrol Fatty acid
Fiber
Adipose Adi
tissue pog
ene
sis
Leptin
n-3 PUFA
Genetic or Epigenetic Obesity
Food Intake
Regulation (Adipogenesis)
Current Opinion in Food Science
Schematic represents of anti-obesity activity of functional food bioactivies through modulation of appetite, differentiation and function of
adipocytes, lipid metabolism and adipokine secretion by genetic and epigenetic mechanisms. GLP-1, glucagon-like peptide-1; CCK, ghrelin and
cholecystokinin; MBP-2, methyl-binding protein 2.
for the intake of EGCG [14]. Chitosan is a natural poly- mechanisms for these bioactives act through the suppres-
saccharide derived from chitin that has multiple functions, sion of preadipocyte proliferation and mitogenesis, the
especially for the treatment of obesity [15]. Diabetic male inhibition of adipocyte differentiation and adipogenesis,
rats fed chitosan for 10 weeks demonstrated elevated the stimulation of lipolysis and fatty acid b-oxidation, the
plasma glucose and reduced insulin resistance. Chitosan induction of mature adipocyte apoptosis and the
supplementation also up-regulated adiponectin (an adipo- reduction of inflammatory adipokines, all of which have
cyte-specific adipokine) and increased the lipolysis of the been believed to be promising approaches to anti-obesity.
adipose tissues and of the plasma GLP-1 [16]. An in vitro Some of these bioactives target multiple signaling mol-
study supported the effect of chitosan on GLP-1 secretion. ecules, transcription factors and enzymes that affect
Human intestinal cells (NCI-H716) treated with chitosan different stages of the adipocyte life cycle (Figure 1).
increased their GLP-1 secretion through a transcriptional We have previously shown that the hydroxylated poly-
mechanism [17]. methoxyflavones, particularly in citrus peels, derived
from the auto-hydrolysis of their permethoxylated
CCK is another gut hormone secreted from the enteroen- counterparts during storage were able to suppress adipo-
docrine cells of the small intestine with the physiological cyte differentiation and lipid accumulation by interfering
functions of controlling appetite, promoting intestinal with adipocyte-specific transcriptional regulators and
motility and delaying gastric emptying [18]. After food multiple signaling pathways, in addition to attenuating
intake, CCK is quickly released and circulated to act on the mitotic clonal expansion in 3T3-L1 adipocytes [27]. A
CCK receptor that is widely distributed in the brainstem combination of various bioactives was able to target
and hypothalamus. The citrus peel is a rich source of different mechanisms in adipocyte differentiation as a
flavonoids and has been used in traditional medicine novel strategy for anti-obesity, but these effects have
in Asian countries for relieving stomach indigestion, skin been subject to only limited investigation in recent years.
inflammation and muscle pain. Hesperetin and naringenin Baicalin is a flavone present in the medicinal plant
are both flavanones that are abundantly present in citrus Scutellaria baicalensis Georgi and has been found to
fruits and peels and function to regulate lipid metabolism enhance berberine (an alkaloid derived from a variety
[19]. In vitro studies showed that these two flavanones of herbs)-induced glucose uptake in 3T3-L1 adipocytes
stimulated CCK release in enteroendocrine cells, contri- [28]. Further epidemiological data have shown that the
buting to changes in the intracellular Ca2+ influx and the intake of EGCG combined with resveratrol increased
activation of transient receptor potential channels. These energy expenditure among overweight subjects, in com-
studies concluded that hesperetin and naringenin might parison to those who consumed EGCG or resveratrol
be useful for appetite suppression through their induction alone [29]. Although these studies suggest an enhanced
of CCK secretion [20,21]. anti-obesity effect for a combination of different bioac-
tives and although their individual mechanisms have
Targeting the adipocytes been widely investigated in vitro and in vivo, the mol-
Adipocytes are main cellular components of adipose tissue. ecular mechanisms behind the efficacy of combined
As caloric intake increases, adipocytes undergo differen- treatment are still unclear.
tiation from fibroblast-like preadipocytes to mature adipo-
cytes, increasing their size via adipogenesis or their The induction of programmed cell death in adipocytes is
numbers via the proliferation of preadipocytes, the latter considered a pivotal therapeutic strategy for obesity that
of which is known as the adipocyte life cycle and is a directly reduces adipose mass [30]. Autophagy is a mech-
consequence of increased adipose tissue mass [22]. This anism of programmed cell death but plays a different role in
process is also significantly associated with a chronic low- adipocyte differentiation than in apoptosis. Several studies
grade inflammation in the adipose tissue as a result of have indicated that autophagy is required for adipocyte
dysfunction in the adipose tissue, contributing to abnormal differentiation via its implication in the removal of intra-
inflammatory cytokine and hormone production in adipo- cellular components and proteins following lipid accumu-
cytes; this process has been suggested to be involved in lation during adipogenesis [31,32]. Although the research
metabolic syndromes [23]. These effects reflect the relating autophagy and adipocyte differentiation is still in
importance of adipocyte function to energy metabolism the beginning stages, further investigation could provide
and as a principal target for the prevention and treatment new insight into potential interventions for obesity via
of obesity. dietary bioactives. For example, a-lipoic acid is a potent
antioxidant present in many foods and has been found to
Increasingly, the literature has shown that many bioac- suppress adipogenesis in 3T3-L1 preadipocytes through
tives and natural products from functional foods and the inhibition of autophagy [31].
edible plants have been reported to modulate the adipo-
cyte life cycle or its functions; for instance, curcumin, Targeting the epigenetics
resveratrol, EGCG and genistein have been discussed in Epigenetics are heritable and reversible regulations of
several excellent reviews [11,24,25,26]. The potential genetic expression without changing the DNA sequence
and include DNA methylation, histone modification and expanding in recent years. Scientific data suggest the anti-
microRNA. Epigenetic modifications play a crucial role in obesity activity of dietary bioactives through modulation
various biological process for development and cellular of appetite, differentiation and function of adipocytes,
function, whereas aberrant epigenetic functionality con- lipid metabolism and adipokine secretion by genetic and
tributes to disease [33]. Aberrant epigenetic regulation epigenetic mechanisms. Although consumption bioac-
has been linked to the pathogenesis of obesity via the tives in functional foods are beneficial to the management
overexpression or silencing of gene expression of adipo- of obesity, many issues require further investigation,
genic factors that affect adipocyte differentiation and including the dosage, bioavailability and effectiveness
adipokine secretion, such as peroxisome proliferator- in clinical studies, as well as the synergistic actions
activated receptor (PPAR) g, leptin and adiponectin between different bioactives and possible combinations
[34–36]. Growing evidence supports that epigenetic pro- with anti-obesity drugs.
cesses can be influenced and reversed by bioactive com-
ponents in the diet and medical sources [33]. Leptin is an Acknowledgement
adipokine from the adipose tissue and plays an important
This study was supported by the National Science Council NSC 101-2628-
role in the regulation of glucose and lipid metabolism, B-022-001-MY4, 102-2628-B-002-053-MY3, and NTU-103R7777
energy expenditure and caloric intake by binding to its
receptor in the brain, thereby maintaining the energetic
balance [37]. However, leptin expression is often changed References
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