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Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease
Course
BIOL MISC
Institution
BIOL MISC
Abstract: Accumulating evidence indicates that obesity is closely associated with an
increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia
and nonalcoholic fatty liver disease. Obesity results from an imbalance between food
intake and energy expenditure, ...
obesity and its metabolic complications the role of adipokines and the relationship between obesity
dyslipidemia and nonalcoholic fatty liver disease
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Int. J. Mol. Sci. 2014, 15, 6184-6223; doi:10.3390/ijms15046184
OPEN ACCESS
International Journal of
Molecular Sciences
ISSN 1422-0067
www.mdpi.com/journal/ijms
Review
Obesity and Its Metabolic Complications:
The Role of Adipokines and the Relationship between Obesity,
Inflammation, Insulin Resistance, Dyslipidemia and
Nonalcoholic Fatty Liver Disease
Un Ju Jung and Myung-Sook Choi *
Center for Food and Nutritional Genomics Research, Kyungpook National University,
1370 Sankyuk Dong Puk-ku, Daegu 702-701, Korea; E-Mail: jungunju@naver.com
* Author to whom correspondence should be addressed; E-Mail: mschoi@knu.ac.kr;
Tel.: +82-53-950-7936; Fax: +82-53-958-1230.
Received: 4 February 2014; in revised form: 27 March 2014 / Accepted: 1 April 2014 /
Published: 11 April 2014
Abstract: Accumulating evidence indicates that obesity is closely associated with an
increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia
and nonalcoholic fatty liver disease. Obesity results from an imbalance between food
intake and energy expenditure, which leads to an excessive accumulation of adipose tissue.
Adipose tissue is now recognized not only as a main site of storage of excess energy
derived from food intake but also as an endocrine organ. The expansion of adipose tissue
produces a number of bioactive substances, known as adipocytokines or adipokines, which
trigger chronic low-grade inflammation and interact with a range of processes in many
different organs. Although the precise mechanisms are still unclear, dysregulated production
or secretion of these adipokines caused by excess adipose tissue and adipose tissue
dysfunction can contribute to the development of obesity-related metabolic diseases. In this
review, we focus on the role of several adipokines associated with obesity and the potential
impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable
insights into the roles of adipokines in the development of obesity and its metabolic
complications. Further research is still required to fully understand the mechanisms
underlying the metabolic actions of a few newly identified adipokines.
The worldwide prevalence of obesity and its metabolic complications have increased substantially
in recent decades. According to the World Health Organization, the global prevalence of obesity has
nearly doubled between 1980 and 2008, and more than 10% of the adults aged 20 and over is obese in
2008 [1]. Projections based on the current obesity trends estimate that there will be 65 million more
obese adults in the USA and 11 million more obese adults in the UK by 2030, consequently accruing
an additional 6–8.5 million cases of diabetes, 5.7–7.3 million cases of heart disease and stroke for
USA and UK combined [2]. The increased prevalence in obesity is also associated with increasing
prevalence of nonalcoholic fatty liver disease (NAFLD). Among the Americas, the prevalence of
NAFLD is highest in the USA, Belize and Barbados and Mexico, which have a high prevalence of
obesity [3]. Obesity, especially abdominal obesity, is one of the predominant underlying risk factors
for metabolic syndrome [4]. Obesity increases the risk of developing a variety of pathological
conditions, including insulin resistance, type 2 diabetes, dyslipidemia, hypertension and NAFLD
(Figure 1). Accumulating evidence suggests that chronic inflammation in adipose tissue may play a
critical role in the development of obesity-related metabolic dysfunction [5–7].
Figure 1. Concept of metabolic syndrome.
Adipose tissue has been recognized as an active endocrine organ and a main energy store of the
body [8]. Excess adiposity and adipocyte dysfunction result in dysregulation of a wide range of
adipose tissue-derived secretory factors, referred to as adipokines, which may contribute to the
development of various metabolic diseases via altered glucose and lipid homeostasis as well as
inflammatory responses [9,10]. In addition, excess fat accumulation promotes the release of free fatty
acids into the circulation from adipocytes, which may be a critical factor in modulating insulin
sensitivity [11,12]. However, plasma free fatty acid levels do not increase in proportion to the amount
,Int. J. Mol. Sci. 2014, 15 6186
of body fat, since their basal adipose tissue lipolysis per kilogram of fat is lower in obese subjects than
in lean subjects [13]. This finding has been supported by other studies of adipocytes from obese
subjects [14,15] and it was associated with down-regulation of hormone sensitive lipase and adipose
triglyceride lipase, key enzymes involved in intracellular degradation of triglycerides [14,16–18].
Thus, Karpe et al. [19] have recently suggested that the link between circulating free fatty acid levels
and insulin sensitivity in vivo is needed to further elucidate this complicated relationship.
In this review, we will first discuss the critical role of adipose tissue for health and as a repository
of free fatty acids. We will also review how the dysregulation of free fatty acids and inflammatory
factors released by enlarged adipose tissue is associated with the pathogenesis of metabolic syndrome
(insulin resistance, dyslipidemia and NAFLD). In particular, we will focus on the imbalance of
pro-inflammatory and anti-inflammatory molecules secreted by adipose tissue which contribute to
metabolic dysfunction.
2. Function of Adipose Tissue
Adipose tissue is the major site for storage of excess energy in the form of triglycerides, and it
contains multiple cell types, including mostly adipocytes, preadipocytes, endothelial cells and immune
cells. During positive energy balance, adipose tissue stores excess energy as triglycerides in the lipid
droplets of adipocytes through an increase in the number of adipocyte (hyperplasia) or an enlargement
in the size of adipocytes (hypertrophy) [20]. The number of adipocytes is mainly determined in
childhood and adolescence and remains constant during adulthood in both lean and obese subjects,
even after marked weight loss [21]. Hence, an increase in fat mass in adulthood can primarily be
attributed to hypertrophy. However, recent study has reported that normal-weight adults can expand
lower-body subcutaneous fat, but not upper-body subcutaneous fat, via hyperplasia in response to
overfeeding [22], suggesting hyperplasia of adipocytes can also occur in adulthood. Although overall
obesity is associated with metabolic diseases, adipose tissue dysfunction caused by hypertrophy has
been suggested to play an important role in the development of metabolic diseases such as insulin
resistance [23–25]. In contrast to positive energy balance states, when energy is needed between meals
or during physical exercise, triglycerides stored in adipocytes can be mobilized through lipolysis to
release free fatty acids into circulation and the resulting free fatty acids are transported to other tissues
to be used as an energy source. It is generally accepted that free fatty acids, a product of lipolysis, play
a critical role in the development of obesity-related metabolic disturbances, especially insulin
resistance. In obesity, free fatty acids can directly enter the liver via the portal circulation, and
increased levels of hepatic free fatty acids induce increased lipid synthesis and gluconeogenesis as well
as insulin resistance in the liver [26]. High levels of circulating free fatty acids can also cause
peripheral insulin resistance in both animals and humans [26,27]. Moreover, free fatty acids serve as
ligands for the toll-like receptor 4 (TLR4) complex [28] and stimulate cytokine production of
macrophages [29], thereby modulating inflammation of adipose tissue which contributes to
obesity-associated metabolic complications. However, circulating free fatty acid concentrations do not
increase in proportion to fat mass and do not predict the development of metabolic syndrome [30–33],
although many studies suggest a relationship between the release of free fatty acids from adipose tissue
and obesity-related metabolic disorders.
, Int. J. Mol. Sci. 2014, 15 6187
Adipose tissue also has a major endocrine function secreting multiple adipokines (including
chemokines, cytokines and hormones) (Figure 2). Many of the adipokines are involved in energy
homeostasis and inflammation, including chemokines and cytokines. In the obese state, the adipocyte
is integral to the development of obesity-induced inflammation by increasing secretion of various
pro-inflammatory chemokines and cytokines [34,35]. Many of them, including monocyte chemotactic
protein (MCP)-1, tumor necrosis factor (TNF)-α, interlukin (IL)-1, IL-6 and IL-8, have been reported
to promote insulin resistance [36–39]. Moreover, the macrophage content of adipose tissue is
positively correlated with both adipocyte size and body mass, and expression of pro-inflammatory
cytokines, such as TNF-α, is mostly derived from macrophages rather than adipocytes [40]. Along
with the increased number of macrophages in adipose tissue, obesity induces a phenotypic switch in
these cells from an anti-inflammatory M2 polarization state to a pro-inflammatory M1 polarization
state [41]. The accumulation of M1 macrophages in adipose tissue has been shown to result in
secretion of a variety of pro-inflammatory cytokines and chemokines that potentially contribute to
obesity-related insulin resistance [5,42]. In contrast, M2-polarized macrophages participate in
remodeling of adipose tissue, including clearance of dead or dying adipocytes and recruitment
and differentiation of adipocyte progenitors [43]. Decreased adipose macrophage infiltration or
macrophage ablation reduces expression of inflammatory cytokines in adipose tissue and improves
insulin sensitivity in diet-induced obese mice [44–47]. Furthermore, weight loss decreases macrophage
infiltration and pro-inflammatory gene expression in adipose tissue in obese subjects [48,49]. In
addition to M1 macrophages, levels of multiple pro-inflammatory immune cells, such as interferon
(IFN)-γ+ T helper type 1 cells and CD8+ T cells, are increased in adipose tissue in obesity [50]. In
contrast, secretion of insulin-sensitizing adiponectin is reduced in obese subjects [51].
3. Obesity and Insulin Resistance
Insulin resistance is an integral feature of metabolic syndrome and is a major predictor of the
development of type 2 diabetes [52]. It has long been recognized that obesity is associated with type 2
diabetes, and the major basis for this link is the ability of obesity to induce insulin resistance. Insulin
resistance is defined as the decreased ability of tissues to respond to insulin action. Adipose tissue is
one of the insulin-responsive tissues, and insulin stimulates storage of triglycerides in adipose tissue
by multiple mechanisms, including promoting the differentiation of preadipocytes to adipocytes,
increasing the uptake of glucose and fatty acids derived from circulating lipoproteins and lipogenesis
in mature adipocytes, and inhibiting lipolysis [53]. The metabolic effects of insulin are mediated by
a complex insulin-signaling network (Figure 3). Insulin signaling is initiated when insulin binds to
its receptor on the cell membrane, leading to phosphorylation/activation of insulin receptor
substrate (IRS) proteins that are associated with the activation of two main signaling pathways:
the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) pathway and the
Ras-mitogen-activated protein kinase (MAPK) pathway. The PI3K-AKT/PKB pathway is important
for most metabolic actions of insulin. IRS-1, which is phosphorylated by the insulin receptor, activates
PI3K by binding to its SH2 domain. PI3K generates phosphatidylinositol-(3,4,5)-triphosphate,
a lipid second messenger, which activates several phosphatidylinositol-(3,4,5)-triphosphate-dependent
serine/threonine kinases, including AKT/PKB. Ultimately, these signalling events result in the
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