polymers

Review
Anti-Obesity Effects of Chitosan and Its Derivatives
Balzhima Shagdarova 1, * , Mariya Konovalova 2 , Valery Varlamov 1 and Elena Svirshchevskaya 2, *

1 Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia;

[email protected]
2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences,
117997 Moscow, Russia; [email protected]
* Correspondence: [email protected] (B.S.); [email protected] (E.S.)

Abstract: The number of obese people in the world is rising, leading to an increase in the prevalence
of type 2 diabetes and other metabolic disorders. The search for medications including natural
compounds for the prevention of obesity is an urgent task. Chitosan polysaccharide obtained through
the deacetylation of chitin, and its derivatives, including short-chain oligosaccharides (COS), have
hypolipidemic, anti-inflammatory, anti-diabetic, and antioxidant properties. Chemical modifications
of chitosan can produce derivatives with increased solubility under neutral conditions, making them
potential therapeutic substances for use in the treatment of metabolic disorders. Multiple studies
both in animals and clinical trials have demonstrated that chitosan improves the gut microbiota,
restores intestinal barrier dysfunction, and regulates thermogenesis and lipid metabolism. However,
the effect of chitosan is rather mild, especially if used for a short periods, and is mostly independent
of chitosan’s physical characteristics. We hypothesized that the major mechanism of chitosan’s
anti-obesity effect is its flocculant properties, enabling it to collect the chyme in the gastrointestinal
tract and facilitating the removal of extra food. This review summarizes the results of the use of COS,
chitosan, and its derivatives in obesity control in terms of pathways of action and structural activity.

Keywords: obesity; chitooligosaccharides; chitosan; chitosan derivatives; anti-obesity

Citation: Shagdarova, B.;

1. Introduction
Konovalova, M.; Varlamov, V.;
Svirshchevskaya, E. Anti-Obesity
Chitosan is a deacetylated derivative of the natural polymer chitin. It is a linear
Effects of Chitosan and Its
polysaccharide consisting of β-(1-4)-linked D-glucosamine and N-acetyl-D-glucosamine
Derivatives. Polymers 2023, 15, 3967. links. Chitosan is biocompatible, biodegradable, and has low toxicity [1]. Due to its
https://doi.org/10.3390/ polycationic nature and the presence of hydroxyl groups in its structure, it can form ionic
polym15193967 and hydrogen bonds. The presence of reactive amino and hydroxyl groups facilitates
chemical modification of the chitosan molecule [2]. Any change in the structure of chitosan
Academic Editor: Luminita Marin
leads to the modification of its physicochemical properties such as solubility, charge,
Received: 4 September 2023 and hydrophobicity/hydrophilicity. This change in biological properties can increase its
Revised: 26 September 2023 antibacterial, antiviral, or antitumor activity [3]. Chitosan nanoparticles are used as drug
Accepted: 28 September 2023 delivery systems; chitosan gels promote accelerated skin wound regeneration; and the
Published: 1 October 2023 powder form acts as a hemostatic and antimicrobial agent [4–6].
Obesity is one of the most serious health problems of our time. The number of people
suffering from obesity is growing every year. The WHO estimates that it affects more than
a billion people worldwide, and by 2025, about 167 million people will be unhealthy due to
Copyright: © 2023 by the authors.
obesity, leading to a range of health problems of the cardiovascular system, liver, kidneys,
Licensee MDPI, Basel, Switzerland.
This article is an open access article
joints, and reproductive system. It also increases the number of people with type 2 diabetes,
distributed under the terms and
as well as cancer and mental illness. During the COVID-19 pandemic, obese people were
conditions of the Creative Commons
three times more likely to be hospitalized [7].
Attribution (CC BY) license (https:// Obesity is a multifactorial disease characterized by increased fat deposition [8]. Few
creativecommons.org/licenses/by/ cases of obesity are due to monogenic causes, and there is an increasing number of cases of
4.0/). obesity due to environmental factors and individual genetic predisposition [9]. Changes

Polymers 2023, 15, 3967. https://doi.org/10.3390/polym15193967 https://www.mdpi.com/journal/polymers

Polymers 2023, 15, 3967 2 of 15

in the gut microbiome, infectious processes, medication side effects, sleep disturbances,
maternal age at birth, duration of breastfeeding, negative environmental factors, and
epigenetic changes contribute to the development of obesity [10,11].
Over the past two decades, several strategies have been used to identify the genetic
determinants of obesity. These include severe obesity studies, genome-wide linkage studies
(GWLS), genome-wide association studies (GWAS), and candidate gene analyses [12].
Among the GWAS results, the first obesity-prone locus to be identified was the fat mass
obesity-associated (FTO) gene. This gene has by far the largest effect on the risk of obesity
phenotypes. Each FTO risk allele is associated with a 20–30% increased risk of obesity
and a 1–1.5 kg increase in body weight [13]. GWAS studies have identified 127 new loci
associated with common forms of obesity in diverse populations of different ethnicities
and ages [12].
Most cases of obesity in developed countries are a result of an excess and easy access
to unhealthy food [8]. Eating behavior is regulated by the hypothalamic central nervous
system where signaling molecules such as leptin, insulin, neuropeptide Y (NPY), agouti-
related protein, proopiomelanocortin, and adiponectin play important roles. The central
nervous melanocortin system is a key point for nutrient-sensitive neural networks that
control appetite and metabolic responses [14]. This system plays an important role in the
regulation of energy balance and homeostasis processes. An imbalance between energy
intake and energy expenditure leads to obesity [8].
Modern medical treatment of obesity involves the use of FDA-approved drugs that
have different mechanisms of action. Among them, orlistat reduces the absorption of
dietary fats; phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide all
act centrally, suppressing appetite [15,16]. The most popular drug, semaglutide, a glucagon-
like peptide-1 receptor agonist, was developed to treat diabetes [17]. Semaglutide increases
the production of insulin. Severe cases can be corrected via surgical interventions such as
gastric banding with laparoscopy, or biliopancreatic diversion with duodenal switching.
In addition, devices such as an intragastric balloon or endoscopic sleeve gastroplasty can
be used during surgical intervention [18]. Preventive, non-pharmacologic treatments of
obesity include changes in eating habits and an increase in physical activity. It is essential
that everyone is educated in good habits, and has access to and can afford a healthy diet.
Effective steps include imposing taxes on “junk food” such as sugary drinks and providing
greater access to affordable healthy foods. Safe walking, cycling, and recreational spaces
should be created where people live [7].
Clinical and epidemiological studies have shown that metabolic syndrome begins with
central obesity, where adipose tissue plays a special role in the development of the metabolic
syndrome [19]. Adipocytes are sensitive to insulin, which is one of the main regulators of
metabolism. The overdevelopment of adipose tissue as a result of the hyperplasia and/or
hypertrophy of adipocytes leads first to the development of obesity, and then, to insulin
resistance [20]. From an evolutionary point of view, adipose tissue is necessary for the
storage of energetically valuable molecules such as triglycerides. Adipose tissue secretes
hormones called adipokines. The most studied are leptin and adiponectin. Leptin regulates
the synthesis and release of the hunger-mediator peptide NPY, thereby inducing a feeling
of fullness. Adiponectin stimulates the β-oxidation of fatty acids and maintains blood
glucose level [21].

2. Effects of Chitooligosaccharides and Chitosan against Obesity

2.1. Chitooligosaccharides (COS)
Chitosan derivatives with MW < 10 kDa are considered COS, which consist of
β-(1-4)-linked D-glucosamine with a deacetylation degree (DD) greater than 90% and
a polymerization degree less than 20, obtained through the deacetylation and depoly-
merization of chitosan or chitin [22,23]. Compared to chitosan, COS have much higher
solubility and lower viscosity under physiological conditions due to their shorter chain
length and higher DD [23]. COS is readily absorbed through the intestinal epithelium and
Polymers 2023, 15, 3967 3 of 15

is preferentially distributed in the liver, spleen, and kidney. It is mainly excreted with
urine. Interestingly, COS with a degree of polymerization >6 have greater biological activity,
including antimicrobial, antitumor, and immunostimulatory activity, compared to smaller
COS [23]. Chitosan oligomers interact with some proteins in the body, causing anti-obesity
and anti-diabetic effects such as the inhibition of the intestinal enzymes involved in fat
and glucose absorption, the inhibition of PPAR-γ, the stimulation of glucokinase, and the
suppression of phosphoenolpyruvate carboxylase in the liver [22,24].
Multiple in vitro studies have demonstrated that COS (<3 kDa) treatment of the
preadipocyte 3T3-L1 decreases PPAR-γ expression and reduces leptin, adiponectin, and
resistin levels, preventing adipogenic differentiation [25–31] (Table 1). In vivo COS, used
as a food supplement, decreased body weight, the accumulation of subcutaneous and total
fat, and the content of TC, TG, and LDL-C, and improved blood serum HDL-C levels in
rats [32] (Table 1).

Table 1. Anti-obesity effects of COS.

Cells, Doses,
MW, kDa Route Anti-Obesity Effects Ref.
Species Duration
Decreased lipid accumulation, mRNA
1–10 3T3-L1 - 0.5–4 mg/mL expression of C/EBP-α, PPAR-γ, [26]
leptin, adiponectin, and resistin levels
Decreased lipid accumulation, free
glycerol release, expression of
1–10 3T3-L1 - 0.6–4.8 mg/mL [33]
adipogenicity marker genes, and
activation of IL-6 and PTGS2 genes
Suppression of lipid metabolism and
5–10 3T3-L1 - 0.6–4.8 mg/mL lipid accumulation genes; inhibition [25]
of leptin expression
Reduced level of intracellular lipid
3T3-L1 - 0.5–5 mg/mL droplets and TG; decreased level of
1–3 [34]
extracellular glucose
Significant reduction in weight gain
and in TG, TC, LDL-C, glucose, and
FFA levels; significant increase in
HDL-C levels; effective suppression
Sprague–Dawley 600 mg/kg·day, 8
Oral of adipose tissue hypertrophy and
rats, HFD weeks
hyperplasia; and increased
expression of UCP1, PGC1α,
PRMD16, and ATF2 in white adipose
tissue and brown adipose tissue
Reduced body weight; suppressed
300–1200 perirenal, epididymal, subcutaneous,
Sprague–Dawley
≤1 Oral mg/kg·day, 8 and total fat accumulation; reduced [32]
rats, HFD
weeks TC, TG, and LDL-C; and improved
HDL-C levels in blood serum
Mostly weight loss; significant
150–600 decrease in serum total cholesterol
Sprague–Dawley
≤1–3 Oral mg/kg/day, 5 and LDL-C levels; decrease in PPARγ [29]
rats, HFD
weeks and LXRα gene expression in white
adipose tissue
Polymers 2023, 15, 3967 4 of 15

Table 1. Cont.

Cells, Doses,
MW, kDa Route Anti-Obesity Effects Ref.
Species Duration
Inhibition of body weight gain;
reduction in adipocyte hypertrophy
and fat accumulation; reduction in
hepatic steatosis; significant
150–600
Sprague–Dawley reduction in leptin; increase in LepRb
≤1 Oral mg/kg·day, 8 [35]
rats, HFD expression and JAK2-STAT3
weeks
phosphorylation levels; inhibition of
lipid synthesis in the liver; regulation
of SREBP-1c, FAS, ACC, HMGCR,
and adiponectin gene expression
HFD, high-fat diet; C/EBP-α, CCAAT/enhancer-binding protein-α; PPAR-γ, peroxisome proliferator-activated
receptor protein γ; PG-endoperoxide synthase 2 (PTGS2); TG, triglyceride; LDL-C, low-density lipoprotein
cholesterol; FFA, free fatty acids; HDL-C, high-density lipoprotein cholesterol; UCP1, uncoupling protein 1;
PGC1α, PPARγ coactivator-1α; PRMD16, PR/SET Domain 16; ATF2, activating transcription factor 2; LXRα,
Liver X receptor alpha; LepRb, long-form leptin receptor-b; JAK2-STAT3, Janus kinase-2-signal transducer and
activators of transcription-3; SREBP-1c, sterol regulatory element-binding protein 1; FAS, fatty acid synthase;
ACC, acetyl-CoA carboxylase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase.

COS can improve dyslipidemia and prevent weight gain by inhibiting adipocyte
differentiation in obese rats. Bahar et al. studied the effect of COS with MW < 1, 1–3, 3–5,
and 5–10 kDa on the differentiation of 3T3-L1 cells and determined their antiadipogenic
potential. The inhibition of lipid accumulation, free glycerol release, and the expression
of adipose-related genes was observed under the action of COS. The listed indicators
varied depending on the concentration and MW, with COS 5–10 kDa showing the greatest
effect. The inhibition of adipogenesis at all studied COS concentrations was associated
with IL-6 and prostaglandin-endoperoxide synthase 2 gene expression. At the same time,
IL-6 probably induces the breakdown of lipid molecules and prevents lipid accumulation
during adipogenesis [33]. It was also found that COS with MM 5–10 kDa suppressed
lipid metabolism gene expression and lipid accumulation during adipocyte differentiation.
COS also inhibited the expression of the leptin gene during adipogenesis [25]. The inhi-
bition of leptin is important because leptin is turned on by epigenetic modulation when
preadipocytes are stimulated to initiate the process of adipogenesis [36].
Obesity models using experimental animals play an important role in the study of
the pathogenesis and therapy of this metabolic disorder. The commonly used model is the
high-fat diet (HFD). It is important to use HFDs with a defined macro- and micronutrient
composition and a clear description of the diet. The development of obesity in animals
using HFD is pathophysiologically very similar to the human disease, allowing for the
study and intervention of obesity in the experimental studies [37].
Deng et al. found that high doses of COS (1200 mg/kg) with MW ≤ 1kDa, used for
8 weeks in HFD-induced obese rats, reduced body weight and lessened the accumulation
of perirenal, epididymal, subcutaneous, and total fat. The ratio of fat to body weight
decreased by 19%, serum TC levels by 37%, and TG levels by 50% in the COS group
compared to the HFD one. Serum LDL-C levels were significantly reduced and serum
HDL-C levels were improved in COS-fed rats [32]. COS used as a food supplement were
more effective in weight loss compared to the commercial drug orlistat. Serum total
cholesterol and LDL-C levels were significantly reduced in all treatment groups compared
with the control HFD one. Various doses of COS reduced the mRNA expression levels of
PPAR-γ and liver X receptor alpha mRNA in white adipose tissue [29]. COS significantly
enhanced the thermogenic ability of HFD-induced obese rats and increased the expression
of brown adipose tissue genes and proteins such as uncoupling protein 1 (UCP1), PPAR
coactivator-1α, PR/SET domain 16 (PRMD16), and activating transcription factor 2 (ATF2),
in white adipose tissue (WAT) and brown adipose tissue (BAT). By studying the function
Polymers 2023, 15, 3967 5 of 15

and mechanism of thermogenesis, it has been shown that COS can increase brown WAT
and BAT thermogenesis to suppress obesity [34].
The anti-obesity properties of COS were also investigated in ob/ob mice. An increase
in body weight (12%) and a decrease in food intake (13%) and in lipid levels (29%) were
observed with COS supplementation. An improvement in plasma adiponectin and resistin
levels and the suppression of adipose tissue-specific TNF-α and IL-6 gene expression was
shown. The expression of PPAR-g genes confirmed enhanced adipokine production [30].
In addition, the anti-obesity effect of COS capsules (MN ≤ 1000 g/mol; DD 95.6%) was
investigated in rats suffering from HFD-induced obesity. The administration of COS for
8 weeks resulted in the activation of the JAK2-STAT3 signaling pathway to attenuate
leptin resistance. COS can not only decrease body weight gain, but can also correct serum
alanine aminotransferase and aspartate aminotransferase levels. Therefore, COS may be a
potentially valuable natural product for the prevention and treatment of obesity [35].
However, a toxic effect of COS was reported by Chiu et al. [38]. Diets supplemented
with 5% COS caused liver damage in animals on the HFD. Liu et al. studied COS toxicity
(0.7kDa, DD 100%) using non-obese rats. The results showed that the addition of 5% COS to
the diet of mice for 12 weeks did not cause lipid metabolism disturbance and hepatotoxicity
in normal rats [39]. To avoid side effects, it is necessary to study chitosan toxicity in more
detail.

2.2. Chitosan
The biological properties of chitosan with MW > 10 kDa and its derivatives are highly
dependent on the MW and DD of the polymer [22]. Depending on the aim, chitosan
preparations with different properties should be selected. Multiple data discussed above
demonstrated that COS are effective both in vitro and in vivo. At the same time, the
international market has a number of dietary supplements with chitosan designed for
the treatment of obesity, hypercholesterolemia, and hypertension [40,41]. Commercial
supplements rarely describe the MW of chitosan. Still, it is shown that any MW chitosan
used as a food supplement reduces the absorption of fat and cholesterol [42]. Chitosan
diets generally reduce plasma lipid levels and increase the excretion of fat and cholesterol
in the feces [31].
Sumiyoshi and Kimura investigated the effects of chitosans with MW 21, 46, and
130 kDa in mice by using HFD for 20 weeks (Table 2). Chitosan with MW 46 kDa was
the most effective; its lipid-lowering effect was probably due to an increase in the fecal
excretion of fat and/or bile acids as a result of bile acid binding, and a decrease in the
absorption of dietary lipids (triacylglycerol and cholesterol) from the small intestine as
a result of inhibition of pancreatic lipase activity. MW 46 kDa chitosan did not cause
liver or renal damage [43]. Supplementation with chitosan MW 80 kDa, DD 84%, at a
concentration of 0.5% to rats receiving HFD for 10 weeks, showed that it resulted in body
weight loss and liver and adipose tissue fat decreases in the rat model. It also corrected the
imbalance of lipid profiles in the plasma, liver, and feces, as well as the activity of intestinal
disaccharidases in the HFD rat model. A significant decrease in the activity of mucinase
and β-glucuronidase in the fecal microflora was also observed [44].
Polymers 2023, 15, 3967 6 of 15

Table 2. Anti-obesity effects of 20–740 kDa chitosan.

MW, Doses,
Species Route Anti-Obesity Effects Ref.
kDa Duration
Suppression of weight gain;
improved balance of plasma,
liver, and feces lipids and
Sprague–
80 Food supplement 5%, 10 weeks intestinal disaccharidase [44]
Dawley rats, HFD
activity. Reduced mucinase and
β-glucuronidase activities in
fecal microflora.
Effective improvement of
hypercholesterolemia and
Sprague– cholesterol homeostasis through
80, 740 Food supplement 5%, 8 weeks [38]
Dawley rats, HFD activation and inhibition of
hepatic AMPKα, PPARα, and
intestinal ACAT2.
Significantly reduced weight
gain, TG, TC, and LDL-C levels,
and glucose and FFA levels.
Promotion of energy release;
Sprague– 600 mg/kg·day, 8 increase in HDL-C levels;
- Oral [34]
Dawley rats, HFD weeks suppression of adipose tissue
hypertrophy and hyperplasia;
and increased UCP1, PGC1α,
PRMD16, and ATF2 in white
and brown adipose tissue.
Suppression of body weight
and adipose tissue gain;
100 and 300 induction of lipid-lowering
C57BL/6J mice,
21, 46, 130 Oral mg/kg·day, 10 effects; increase in fecal [43]
HFD
weeks excretion of fat and/or bile
acids; decreased absorption of
triacylglycerol and cholesterol.
Body weight reduction;
epididymal fat pad and
60 mg/kg·day, 5
300 ICR mice Oral intra-abdominal fat thickness [31]
weeks
reduction; decrease in TC, TG,
and LDL-C plasma levels.
Decreased crude fat digestibility,
daily food intake, and final
300–1200 ppm, 1 body weight; increased leptin
- Pigs, basal diet Food supplement [45]
week concentration; and decreased
serum C-reactive protein
concentration.
HFD, high-fat diet; AMPKα, AMP-activated protein kinase α; PPARα, peroxisome proliferator-activated receptor
protein γ; ACAT2, acetyl-coenzyme A acetyltransferase 2; TG, triglyceride; TC, total cholesterol; LDL-C, low-density
lipoprotein cholesterol; FFA, free fatty acids; HDL-C, high-density lipoprotein cholesterol; UCP1, uncoupling protein 1;
PGC1α, PPARγ coactivator-1α; PRMD16, PR/SET Domain 16; ATF2, activating transcription factor 2.

The analysis of chitosan with MW 300 kDa, DD 72%, in vitro using 3T3-L1 fibroblasts
demonstrated increased platelet-derived growth factor-induced mitochondria fragmenta-
tion, and enhanced cell proliferation and migration [46]. Another work showed that the
oral administration of chitosan MW 300 kDa, DD 97%, to mice for 5 weeks resulted in a
9.3% weight loss. Chitosan reduced epididymal fat pad and intra-abdominal fat thickness
by 10%, plasma TC levels by 26%, TG by 40%, and LDL-C by 38%, with no significant
effect on plasma HDL-C levels [31]. Chiu et al. studied the change in cholesterol levels
in rats treated with HFD when chitosans with different molecular masses of 740, 80, and
Polymers 2023, 15, 3967 7 of 15

0.7 kDa were supplemented for 8 weeks. Chitosan 80 and 740 kDa significantly decreased
liver total cholesterol levels, increased TC levels in feces, suppressed the expression of
the PPARα gene, and effectively reversed the HFD-inhibited/induced expression of low-
density lipoprotein receptor (LDLR) and cholesterol-7α-hydroxylase (CYP7A1) genes. Both
low- and high-molecular-weight chitosan effectively reduced hypercholesterolemia and
regulated cholesterol homeostasis [38]. Furthermore, chitosan accelerated brown fat forma-
tion and thermogenesis by increasing the expression of UCP1, PRDM16, and PGC-1α genes,
thereby accelerating energy metabolism and increasing fat consumption in HFD-induced
obese rats. Therefore, chitosan with MW > 10 kDa also can potentially be used for obesity
prevention and treatment [34].
Taken collectively, chitosans with different MWs (10–700 kDa) all have close activity,
mediated mostly by binding lipids in food stimulating their excretion with feces.

3. Effect of Chitosan Derivatives on Obesity

The chemical modification of chitosan is possibly due to the presence of reactive amino
groups at the C-2 atom and primary and secondary hydroxyl groups at the C-3 and C-6
atoms in the chitosan molecule. This approach makes it possible to change the chemical
properties and enhance or add biological activity depending on the nature of the introduced
groups, while preserving the natural backbone of chitosan [47]. To improve water solubility,
pH sensitivity, and the targeting of chitosan derivatives, chitosan is often modified via
acylation, carboxylation, alkylation, and quaternization [48]. Modified chitosans are most
commonly used in the field of biomedicine, such as drug delivery, antitumor agents, the
development of wound dressings, and promoting bone and tissue regeneration [49].
The results of chitosan derivatives’ anti-obesity activity are shown in Table 3. Phos-
phorylated glucosamine (glucosamine-6-phosphate, PGlc) decreased lipid accumulation
and suppressed PPAR-γ, sterol regulatory element-binding protein 1 (SREBP1), and protein
C/EBP-α expression in 3T3-L1 cells. In addition, PGlc induced a significant increase in
preadipocyte factor 1 expression and the suppression of gene promoters such as adipocyte
fatty acid-binding protein, fatty acid synthase lipoprotein lipase, and leptin [27].

Table 3. Anti-obesity effects of chitosan derivatives.

MW, Cells, Doses,

Objects Routes Anti-Obesity Effects Ref.
DD/DS Species Duration
Reduced lipid and triglyceride
accumulation; facilitated lipolysis
(N,O)-sulfatedchitosan <1kDa 3T3-L1 - 0.1–4 mg/mL and mRNA expression; and [28]
reduced PPAR-γ receptor and
C/EBP-α protein levels
Reduction in lipid accumulation;
dose-dependent suppression of
PPAR-γ receptor and C/EBP-α
Phosphorylated protein activity; induction of
- 3T3-L1 - 0.2 mg/mL [27]
glucosamine(PG1c) preadipocyte factor 1 mRNA
activation; suppression of fatty
acid synthase, lipoprotein lipase,
and leptin
Suppression of leptin and resistin
O-carboxymethyl chitosan 50 kDa, DD mRNA expression; increased
(O-CMCs), 85%; 3T3-L1 - 0.1 mg/mL
adiponectin and PPAR-γ mRNA
N-[(2-hydroxy-3-N,N- O-CMCs expression
dimethylhexadecyl DS 72% [50]
ammonium)propyl] chitosan N-CQCs Reduction in plasma leptin,
Clean Wistar 100 mg/kg·day,
chloride (N-CQCs) DS 21% Oral glucose, insulin, and total
rats, HFD 6 weeks
cholesterol levels
C57BL/6 250 mg/kg day, 8 Significant reduction in weight
Chitosan –thioglycolic acid - Oral [51]
mice, HFD weeks gain and fat distribution
HFD, high-fat diet; PPAR-γ, peroxisome proliferator-activated receptor protein γ; C/EBP-α, CCAAT/enhancer-
binding proteins-α.
Polymers 2023, 15, 3967 8 of 15

The sulfation of chitosan is primarily necessary to impart anticoagulative proper-

ties upon the polymer, but in addition, such derivatives are characterized by antioxidant,
antibacterial, and antiviral properties [47]. (N,O)-sulfated chitosan was also effective in re-
ducing lipid accumulation and triglyceride levels, and facilitated lipolysis in differentiating
3T3-L1 preadipocyte cells. In addition, the gene expression and protein levels ofPPAR-γ
and C/EBP-α were significantly reduced [28].
O-Carboxymethyl chitosan (O-CMC) and quaternized chitosan (N-[(2-hydroxy-3-
N,N-dimethylhexadecylammonium)propyl]chitosan chloride, N-CQC) are some important
chitosan derivatives that have different charges and, consequently, different properties [52].
Both O-CMC and N-CQC demonstrated anti-obesity effects not only in vitro in 3T3-L1 cells
but also in vivo in a rat HFD model. O-CMCs and N-CQCs decreased plasma leptin, glu-
cose, insulin, and total cholesterol levels, suppressed leptin and resistin mRNA expression,
and increased adiponectin and PPAR-γ mRNA expression [50].
Li et al. synthesized chitosan derivatives containing coumarins to enhance the antioxi-
dant activity of chitosan. No cytotoxicity was observed in 3T3-L1 cells when incubated with
chitosan and its derivatives at all studied concentrations from 1 to 1000 µM. Meanwhile,
the synthesized chitosan derivatives stimulated the growth of 3T3-L1 cells, which could
be attributed to their high antioxidant activity [53]; however, this could be a result of the
anti-differentiation effect.
Thus COS, high-MW chitosans, and their derivatives all demonstrate close properties
and can be used as anti-obesity agents. Due to the high variability in chitosan samples it is
difficult to conclude which preparation demonstrates the highest anti-obesity effects. Our
hypothesis is that the major anti-obesity mechanisms of chitosan are due to its flocculant
effect in the gut. Chitosan, due to its charge and independently of its weight, DD, or
modification, absorbs and increases the chyme volume, stimulating its movement in the
intestine.

4. Regulation of Gut Flora by Chitosan and COS

Chitosan and COS may find uses as dietary supplements that can regulate intestinal
flora. The human gut microbiota consists of 1013 –1014 microorganisms [54]. The commen-
sals can be affected by numerous factors such as different environmental conditions, diet,
antibiotics, or physical activity [55]. The gut microbiota directly affects nutrient absorption
as well as fat accumulation in the human intestine [56]. Disturbances in the gut microbiota
are closely related to the pathogenesis of obesity and related metabolic syndromes [57].
The prolonged use of chitosan can affect the gut microbiome. A chitosan-supplemented
diet decreased the number of the obesity-related species Coprobacillus cateniformis and
Clostridium leptum. Their numbers correlate with increased serum leptin levels. Contrary to
this, Clostridium lactatifermentans and Clostridium cocleatum, the numbers of which positively
correlate with the serum lipid levels, were significantly reduced [58]. He et al. used LMW-
COS-H and LMW-COS-L, with MWs of 0.9 kDa and 0.36 kDa, respectively. Compared
with LMW-COS-L, LMW-COS-H was more effective in improving metabolic disturbances
induced by HFD. The addition of LMW-COS to the diet induced overall changes in the gut
microbiota, which were significantly associated with metabolic parameters. LMW-COS
both significantly increased the abundance of beneficial gut bacteria such as Akkermansia
and Gammaproteobacteria and decreased the relative abundance of inflammatory bacteria
such as Erysipelatoclostridium and Alistipes. Thus, it is possible that LMW-COS act as a
prebiotic that regulates dysfunctional gut microbiota, alleviate low-grade inflammation,
and maintain the intestinal epithelial barrier [57].
Elebeedy et al. used chitosan as a prebiotic alone or in combination with a probiotic
for 45 days in rats. The rat kidneys showed a normal histologic structure of renal tubules
when treated with probiotics, chitosan, and their mixture. A decrease in total body weight
was observed when these approaches were combined [59].
In addition, chitosan can be used to deliver probiotics. Probiotic bacteria must first be
protected from ingestion in the stomach. Microencapsulation is one of the most utilized
Polymers 2023, 15, 3967 9 of 15

methods. In a digestion test, chitosan preserved the required amount of viable probiotic
bacteria [60]. The coating of microcapsules with chitosan or a combination of chitosan
and alginate contributes to the survival of many probiotic bacteria (Bifidobacterium and
Lactobacillus spp., L. bulgaricus, L. casei, L. plantarum, L. rhamnosus, L. helveticus, L. gasseri,
B. bifidum, etc.), which opens promising avenues in the food industry [61]. Of note, the
protection of these bacteria by chitosan could be one of the anti-obesity mechanisms.

5. Treatment of Obesity with Chitosan-Based Delivery Systems

Oral administration is the preferred and easiest route of drug administration for
the long-term therapy of diseases and complications. However, the oral delivery of many
therapeutic peptides and proteins is still an unsolved problem due to the size, hydrophilicity,
and instability of these molecules [62]. Therefore, recent studies have focused on obtaining
carriers for efficient drug administration in obese and diabetic patients. Due to the presence
of amino groups, chitosan has a positive surface charge at slightly acidic pH. This charge
can easily interact with the anionic mucin present in the mucosal layer. The mucoadhesive
properties of chitosan promote its uptake by intestinal and nasal cells, and have become a
promising basis for drug delivery. Chitosan can be used in various forms, and depending on
the method of preparation, these can be nanoparticles, microspheres, capsules, hydrogels,
conjugates, etc. The possibilities of chemical modification expand the applications of
chitosan. Chitosan-based delivery systems have been shown to be biodegradable and have
low toxicity in both in vitro and in vivo studies [63,64].
Chitosan was used as a matrix for pterostilbene (PS) drug delivery. PS was used in
conjunction with hydroxypropyl β-cyclodextrin (HPβCD) to enhance its solubility. This
complex was incorporated into chitosan nanoparticles (PS/HPβCD-NP). PS/HPβCD-NPs
showed improved bioavailability compared to free PS. The nanoparticles were non-toxic,
had an improved effect on obesity, reduced cholesterol levels, and helped to convert
white fat (which stores fat) into brown fat (which burns calories). PS/HPβCD-NP was
administrated orally to obese rats on an HFD diet. A significant anti-obesity effect was
demonstrated, as evidenced by the histological examination, lipid profile, UCP1 gene
expression, and protein levels of SIRT1, COX2, IL-6, and leptin [65].
Liang et al. delivered silymarin incorporated into hybrid nanoparticles (CS-LPN)
of a lipid polymer containing chitosan (DD 75–85%, MW 50–190 kDa) to the livers of
adiponutrin/patatin-like phospholipase-3 transgenic I148M mice, a model of non-alcoholic
fatty liver disease (NAFLD). NAFLD is associated with insulin resistance and metabolic
syndrome with excess lipid accumulation in liver tissue. Silymarin requires a delivery
system as it has low bioavailability when taken orally due to poor aqueous solubility.
HepG2 and Caco-2 cells had stronger uptake of CS-LPN nanocarriers treated with fat
emulsion CS-LPN. In vivo experiments confirmed that CS-LPNs enhanced the efficacy of
silymarin and suppressed lipid accumulation in the livers of mice. CS-LPNs effectively
reduced blood lipid levels and decreased lipid accumulation. These results suggest that
this delivery system may be used for the treatment of NAFLD [66].
Another drug, hesperidin, a flavanone glycosite, was delivered using chitosan cross-
linked with thioglycolic acid (CT-TGA). CT-TGA acted as a physical barrier in the gas-
trointestinal tract and prevented the absorption of nutrients. No cytotoxicity or adverse
immunological reactions in vivo were detected for CT and CT-TGA. Encapsulated hes-
peridin reduced the body weight of C57BL/6 mice by 41% compared to the group receiving
HFD, and limited fat accumulation by inhibiting its absorption [51].
N-trimethylated chitosan (TMC) was used as a coating polymer to deliver celastrol
(Cel), a bioactive component derived from Tripterygium wilfordii [67]. It is known that drug
delivery using TMC coating has shown enhanced oral bioavailability [68]. Due to the
protection provided by the TMC coating, Cel was stable in the gastrointestinal tract. In vivo
tests showed that Cel-TMC significantly reduced body weight and blood lipid regulation,
and suppressed fatty inflammation, WAT anti-angiogenesis, and WA T reduction [67].
 Polymers 2023, 15, 3967 10 of 15

Animal experiments show significant effects of chitosan supplementation; however,

humans’ and rodents’ gastrointestinal tracts differ significantly as rodents are mostly herbi-
vores, while humans are carnivores. Two recent meta-analyses collected clinical data up to
the year 2019 on chitosan supplementation [69,70], which included more than 1500 persons.
Both meta-analyses found statistically, but not clinically, significant differences in weight
and body mass index (BMI) in the chitosan group versus the placebo. All studies included
overweight persons with BMI>30. Two more recent clinical trials included 30 and 74 obese
patients. Fatahi et al. demonstrated that chitosan supplementation significantly improved
indicators of obesity (body weight: −3.6 kg, lipid triglycerides: −5.7, total cholesterol: −14,
insulin: −5.5, adiponectin: 1.7 ng/dL, leptin −19.4, and neuropeptide Y–42 ng/dL). Valero-
Pérez et al. used the chitosan preparation LipiGO, containing β-glucan and chitin–chitosan,
a patented mix of natural polysaccharides from the Saccharomyces cerevisiae yeast cell wall.
The subjects with obesity type 1 from the treated group experienced significantly reduced
body weight (−5.3 kg) and BMI (−2) compared with those in the placebo group [71,72].
Early studies used chitosan capsules for a month as a supplement to the normal diet,
which resulted in the absence of an effect [73]. Later on, increasing the chitosan dose and
duration to 2 mo resulted in a change of −1 kg in the chitosan group versus the placebo [74].
Another study, which tried chitosan treatment for 3 mo, already resulted in a change of
−3 kg [75]. Finally, using a 1-year protocol supplemented with caloric restriction resulted
in −10 kg of weight loss [76]. Taking these results collectively, it becomes clear that chitosan
is not a magic anti-obesity drug per se; however, it presents an opportunity to lose some
Polymers 2023, 15, x FOR PEER REVIEW
weight when it is used for longer, at a relatively high dose, in conjunction with a caloric
10 of 15
restriction, and with increased physical activity (Figure 1). Currently, on the market, there
are many different formulations of chitosan with anti-obesity activity and many more could
appear (Table 4).

Figure 1. Loss of body weight during one year in kg.

Figure 1. Loss of body weight during one year in kg.

Table 4. Patents of chitosan-based applications to combat obesity.

Patent № Patent Title Description Ref.

Application of chitosan in This invention relates to the use of chitosan in the preparation of food
CN110477398 preparation of anti-obesityproducts against obesity. In a food product with a high fat content, chi- [77]
food tosan is added in an amount of 3–10% of the weight of the product.
Compositions for oral administration are proposed that contain chi-
Body weight control prepara-
tosan, capable of binding fatty acids and cellulose, and capable of
EP3225239 tion based on chitosan and [78]
forming a gel. These compositions are intended to combat obesity and
cellulose
overweight.
Chitosan mixture containing A chitosan mixture containing added vitamin C and organic acid is
Polymers 2023, 15, 3967 11 of 15

Table 4. Patents of chitosan-based applications to combat obesity.

Patent № Patent Title Description Ref.

This invention relates to the use of
chitosan in the preparation of food
Application of chitosan in
products against obesity. In a food
CN110477398 preparation of anti-obesity [77]
product with a high fat content,
food
chitosan is added in an amount of
3–10% of the weight of the product.
Compositions for oral administration
are proposed that contain chitosan,
Body weight control
capable of binding fatty acids and
EP3225239 preparation based on chitosan [78]
cellulose, and capable of forming a
and cellulose
gel. These compositions are intended
to combat obesity and overweight.
A chitosan mixture containing added
Chitosan mixture containing vitamin C and organic acid is
KR1020110010018 complex additives for presented, designed to suppress fat [79]
antioxidation accumulation and enhance the fight
against obesity.
An anti-obesity composition is
presented, containing chitosan
Anti-obesity composition
oligosaccharides and deep-sea water
containing chitosan
KR1020090119319 with chlorine, sulfate, and [80]
oligosaccharide and deep-sea
magnesium. Designed to inhibit fat
water with fewer side effects
accumulation and for use as an
additive in functional foods.
Anti-obesity biomaterials consisting
Functional anti-obesity of low-molecular-weight chitosan are
biohealth material containing proposed, which improve
KR1020060082351 low-molecular-weight physiological metabolism in obesity [81]
chitosan as effective by reducing cell mass and abdominal
ingredient fat size and improving serum lipid
levels.
A dietary preparation containing
Dietary agent comprising chitosan microparticles is proposed,
chitosan microparticles useful which can be used as a therapeutic
KR1020050055643 [82]
in health-promoting food for food for the treatment of obesity
treating obesity without causing the so-called “yo-yo”
phenomenon.
A composition is presented that
contains as the main components a
Composition containing
mixture of Lentinus edodes
mycelium of Lentinus edodes
mycelium, Agaricus blazei Murill
KR1020030056753 and Agaricus blazei Murill [83]
mycelium, and water-soluble
and water-soluble chitosan for
chitosan. This composition is used as
controlling obesity
a healthy food product to combat
obesity and prevent cancer.
It is proposed to add an anorectic
agent containing
JP2002104975 Anorectic agent low-molecular-weight chitosan or its [84]
derivative to healthy foods and
drinks to prevent obesity.

Chitosan can induce side effects at high doses, such as constipation and bloating,
which can be resolved with increased water intake; however, people with gastrointestinal
problems should be careful.
Polymers 2023, 15, 3967 12 of 15

6. Conclusions and Future Directions

Obesity is a manifestation of metabolic syndrome, which has become a serious public
health problem worldwide. Nowadays, there is a search for substances that could reduce
the risk and manifestations of metabolic syndrome. Chitosan, a natural, biocompatible,
biodegradable, and low-toxicity polymer may be suitable for this purpose. Summarizing the
results, it can be concluded that all studied chitosan preparations (COS, medium- and high-
MW chitosan, and their various derivatives and conjugates) are able to affect adipogenesis.
To this end, average- to high-MW chitosans are cheaper than COS in preparation. Without
not much difference in their activity, there is no need to produce more expensive COS.
Empirically found commercial chitosan preparations have demonstrated good efficacy. We
hypothesize that chitosan mostly acts as a flocculant, collecting charged molecules in the
gut and promoting the chyme to move quicker in different parts of the digestive tract. The
removal of extra chyme improves gut microbiota and intestinal barrier dysfunction and
explains why all chitosan derivatives demonstrate comparable activity. This also explains
why a prolonged diet is more effective than short courses. However, more studies are still
needed to support or reject this hypothesis and further reveal the molecular mechanism of
chitosan.
Multiple data show that chitosan supplements not only prevent obesity and dys-
lipidemia but also regulate BAT thermogenesis and hepatic lipid metabolism, protect
pancreatic β cells, decrease insulin resistance, stimulate glucose uptake by muscle cells,
improve the gut microbiota, and restore intestinal barrier dysfunction. This looks promising
as chitosan supplements could affect/protect major tissues such as the pancreatic, adipose,
intestinal, liver, and muscle tissues. To maximize the multi-targeted effects of chitosan
preparations, oral application is recommended as the most effective pathway for its activity.
Thus, chitosan, a cheap and safe natural biopolymer, can be used as a safe food
supplement that can help to prevent obesity and improve multiple body characteristics
when used in a combination with a healthy diet and lifestyle.

Author Contributions: Conceptualization, B.S., M.K. and E.S.; software, B.S. and M.K.; writing—
original draft preparation, B.S. and M.K.; writing—review and editing, B.S., M.K. and V.V. and E.S.;
supervision, V.V. and E.S.; project administration, B.S. and E.S.; funding acquisition, B.S. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was supported by the Russian Science Foundation, grant No. 23-24-10070,
https://rscf.ru/project/23-24-10070/.
Institutional Review Board Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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