Role of microRNAs in obesity and obesity-related diseases
Iacomino and Siani Genes & Nutrition
Role of microRNAs in obesity and obesity- related diseases
Giuseppe Iacomino 0
0 Institute of Food Sciences, CNR , Via Roma, 64, 83100 Avellino , Italy
In recent years, the link between regulatory microRNAs (miRNAs) and diseases has been the object of intensive research. miRNAs have emerged as key mediators of metabolic processes, playing crucial roles in maintaining/ altering physiological processes, including energy balance and metabolic homeostasis. Altered miRNAs expression has been reported in association with obesity, both in animal and human studies. Dysregulation of miRNAs may affect the status and functions of different tissues and organs, including the adipose tissue, pancreas, liver, and muscle, possibly contributing to metabolic abnormalities associated with obesity and obesity-related diseases. More recently, the discovery of circulating miRNAs easily detectable in plasma and other body fluids has emphasized their potential as both endocrine signaling molecules and disease indicators. In this review, the status of current research on the role of miRNAs in obesity and related metabolic abnormalities is summarized and discussed.
Obesity; Metabolic disease; Disease biomarkers; miRNAs; microRNA
Obesity: a global epidemic
About 10 years ago, the World Health Organization
indicated the increasing prevalence of overweight and/or
obesity worldwide as a challenge for public health, due the
adverse consequences associated with obesity and
]. The trend has been so steep and sudden that
some researchers refer to it as an “epidemic.” Nowadays,
over 60% of the United States (USA) adult population is
considered overweight or obese, but the high prevalence
of obesity is not limited to the USA, being observed in
industrialized as well as in least developed countries. Even
more worrisome is the rapidly increasing prevalence of
obesity among children observed over the last 30 years
. Epidemiological studies have established a firm
association between an elevated BMI and chronic conditions
such as diabetes, dyslipidemia, hypertension, heart disease,
non-alcoholic fatty liver disease, and some types of cancer
]. Dyslipidemia and type 2 diabetes (T2D) have
exhibited a corresponding increase over the same time span
also in children .
The medical costs of obesity, and also the growing
mortality among obese individuals, are likely related to
comorbid conditions rather than obesity per se. A
surplus in energy intake and a limited physical activity are
considered among the driving factors of obesity;
however, the contribution of genetic and epigenetic traits
could not be disregarded. In the last decade, large and
well-powered studies have shown that multiple loci on
the human genome are associated with obesity and
obesity-related phenotypes [
A new layer of control
The individual susceptibility to weight gain and the
associated clinical effects may largely vary due to differences
in the genetic background, lifestyle, and environmental
stimuli. It is well recognized that the “common” obesity
is the result of the interplay of environmental factors
with genetic factors reflecting the additive contribution
of many genes that confer different degrees of
susceptibility (polygenic obesity) [
]. Of note, most of the genes
associated to obesity predisposition are also related to
food intake and regulation of energy balance [
about 20–40% of the variance in energy and
macronutrient intake explained by genetic effects [
studies suggest that as much as 21% of BMI variation can be
explained by common genetic variants [
]. Even though
the genetics of obesity has been extensively explored,
most of the genetic variability in BMI remains
unexplained and, in addition, the confirmation of the effects
of single candidate genes or their combination is still
Genomes contain information that is mandatory to
build and run cells, including the self-coordination
responsible to define complex organs and ultimately to
self-assemble an organism by driving cellular
differentiation and morphogenesis programs. Together, these
processes require contribution of information-dense
and dynamic regulatory systems involving a number
of mechanisms including transcription factors, DNA
methylation, ATP-dependent chromatin remodeling
mechanisms, and post-translational modifications of
histones, as well the dynamic acetylation and
deacetylation of core histones [
]. Virtually, any step of
the gene expression flow is finely controlled, and the
discovery of small non-coding RNAs (ncRNAs) has
added new critical players to the wide range of
existing mechanisms [
In a few years, microRNA (miRNA) research has
proceeded from the discovery of a non-coding RNA in C.
] to thousands of publications describing
their critical connection to a variety of cell processes
and diseases . miRNAs are short ncRNAs, with a
length of 20–24 nucleotides, which are engaged in the
control of gene expression programs [
present, more than 2000 different miRNAs have been
described in humans, and their number is still increasing
in the miRBase database [
]. The release of 21 of the
repository contains 28,645 entries representing hairpin
precursor miRNAs, expressing 35,828 mature miRNA
products, in 223 species. In recent years, miRNA
biogenesis and mechanisms of action have been thoroughly
described as illustrated in Fig. 1 [
]. miRNAs are
essential elements of the cell epigenetic machinery
which post-transcriptionally repress the expression of
target genes, usually by binding to the 3′ UTR of
messenger RNA, contributing to the regulation of many
biological processes [
For base-pairing with a target mRNA, nucleotides in
positions 2–8 of a miRNA are relevant. This sequence
motif is referred to as “seed sequence” and is closely
connected to the recognition of a mRNA target.
However, other regions also contribute in determining the
target specificity [
]. A numeric designation has been
given in sequential order to individual miRNAs
according to the discovery date, and matching miRNAs found
in different organisms have been assigned through the
same numeric code with a species-specific preface.
Moreover, miRNAs have been clustered into families
constructed on seed region similarity, which is
accountable for the corresponding ability to target common
groups of gene transcripts [
]. Although some miRNAs
exhibit a tissue-specific localization, most miRNAs show
a broader tissue distribution [
]. Each miRNA can
simultaneously regulate large cohorts of transcripts, and
individual mRNA may include multiple binding sites for
different miRNAs originating an intricate regulatory
]. Even though miRNAs usually act as
slight modulators, defining only a weak inhibitory effect
on a single target, more often, they coordinately affect
multiple transcripts in a signaling pathway or nodes
correlated in complex regulatory networks, exercising
significant cumulative effects. A notable example is given
by the members of the miR-200 family, acting at
multiple levels as enforcers of the epithelial phenotype.
Actually, they target both cytoskeletal effectors,
regulating actin filament organization, and pathways that locally
coordinate the cytoskeleton organization to preserve cell
morphology and prevent cell migration [
Computational and experimental analyses support the
view that endogenous miRNAs may comprehensively
influence the expression of up to 60% of mouse and
human genes [
] and that a huge number of miRNAs
are under the control of relevant signal transduction
cascades. Therefore, miRNAs have been reported to be
involved in a countless cellular processes, including
proliferation, differentiation, DNA repair, apoptosis, and
]. Additionally, increasing evidence
indicates that miRNA dysregulation is causative and/or
indicative of several diseases, including cancer [
Substantial progress has been made in interpreting the
role of individual miRNAs in a number of biological
settings. As an example, members of the highly conserved
miR-34 family act as tumor suppressor. Dysregulation or
loss of the host gene from which this miRNA is derived
is associated with cancer progression in numerous cell
miRNA profiling is a key step which requires sensitive
and reproducible detection methods. A number of
different techniques have been developed to determine
miRNAs in biological samples, such as NGS (RNAseq),
reverse transcription quantitative PCR, and microarray,
each method having its own strengths and weaknesses
]. In general, miRNA characterization, as compared
to mRNA profiling techniques, is more difficult to
perform because procedures should be able to discriminate
miRNAs differing by as little as a single nucleotide, also
taking into account differences between mature miRNAs
and their precursors (which also encompass the
sequence of the mature miRNA species).
Furthermore, precise measurement of circulating
miRNAs can be challenging, due to their relatively low
concentration, to the presence of undesired inhibitors
potentially interfering in the downstream quantification
procedures and, finally, to confounding sources of
intracellular miRNAs that may contaminate the extraction
process. Indeed, the inconsistencies and dissimilar
results reported among different studies could be partially
explained by differences in both detection procedures
and experimental setup. The source of miRNAs, the
extraction procedures, the quantities used in profiling
analysis workflow, and the methods of data analysis all
together possibly contribute to the uncertainty still
observed in the literature, highlighting the need for
reproducible and well-standardized methods [
miRNAs in obesity and metabolic diseases
At the time of our search, 61,363 published papers
concerning miRNAs were found on PubMed. Most of them
deal with human diseases/disorders and a growing
number of reports about miRNAs as useful clinical tools
], in particular with regard to the identification of
“circulating” miRNAs (see the “Circulating miRNAs”
section) as cancer biomarkers [
]. Omics studies
have indeed demonstrated that changes in miRNA
profiles of various tissues (e.g., pancreas, adipose tissue, and
liver) correlate with obesity  and several metabolic
]. There are intriguing reports suggesting
that miRNAs may be regulated by diet and lifestyle
factors  and could be responsive to various nutritional
For the purpose of the present review, we thoroughly
explored PubMed using different combinations of the
subsequent keywords: “microRNA,” “circulating
miRNAs,” “adipose tissue,” “adipogenesis,” “obesity,”
“diabetes,” and “metabolic diseases.” Obviously, a complete
and comprehensive scrutiny of the available literature
was outside our scope. Actually, the most cited research
papers as well as the most recent and complete reviews
on this research area were included.
miRNAs in the adipose tissue
The obesity–diabetes connection has been long time
established, having its roots in interdependent
alterations of glucose and lipid metabolism. Adipose tissue,
the storage site of triglycerides, is the key machinery
where energy homeostasis is regulated, to the extent that
adipose tissue is now considered an endocrine organ
(see Table 1) [
]. In this context, it is not surprising
that miRNAs may contribute to the regulation of energy
balance and metabolic homeostasis, by controlling a
wide range of metabolic pathways .
The first evidence suggesting a role of miRNAs in fat
cells regulation was in Drosophila, showing that miR-14
exerts a suppressive effect on fat metabolism by
targeting p38 and MAPK [
]. Subsequentely, a wide array of
miRNAs involved in the regulation of glucose and lipid
metabolism was identified, with particular focus on
adipocyte differentiation, control of β-cell mass, and insulin
signaling pathway in both physiological and pathological
]. However, the information regarding
the possible mechanisms is still limited . As an
example, the miRNAs reported in Table 2 have been
White adipose tissue achieves metabolic functions through the release of signaling molecules, such as adipokines, and hundreds of diverse factors,
including classical hormones such as leptin, growth factors such as IGF-1 and PDGF, and cytokines such as IL-6, IL-8, or TNF-α acting as inflammatory
], comprehensively linked to appetite regulation and insulin sensitivity. Growing evidence supports the notion that chronic low-grade
inflammation is a basic characteristic of obesity contributing to the establishment of insulin resistance into the target organs, including the adipose
tissue, liver, and muscle, and the vascular system [
]. Excess of nutrients, such as lipids and glucose, may simultaneously trigger inflammatory
responses, which further disrupt metabolic function, enhancing stress and inflammation. Accordingly, the nutrition–immunity theory suggests that in
the adipose tissue, overnutrition-induced obesity triggers low-level inflammatory processes [
]. Anomalous fat accumulation has been shown to
increase pathogenic risks since adipose tissue remains in a state of subclinical chronic inflammation [
]. This condition is strictly related to a massive
recruitment of macrophages and to an increased immune cell proliferation activation–infiltration connected to adipocyte hypertrophy and an
impaired adipogenesis [
]. The latter process is tightly controlled by a mixture of regulatory signals including endocellular transcription factors,
extracellular circulating hormones [
], and additional post-transcriptional regulators of gene expression [
Adipogenesis is the process during which fibroblast-like pre-adipocytes differentiate into mature adipocytes, a complex mechanism involving cell
commitment, clonal expansion, and terminal differentiation [
]. More in detail, differentiation from pre-adipocytes into mature adipocytes is a key
step orchestrated by several transcription factors such as the peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding
proteins (C/EBPs) that coordinately control expression of genes required for adipocyte phenotypes. C/EBPβ and C/EBPδ are induced by adipogenic
stimuli and represent primary regulators of adipogenesis. Targets of C/EBPβ and C/EBPδ are the promoters of the genes encoding critical adipogenic
factors such as C/EBPα and PPARγ, as well as the sterol regulatory element-binding protein (SREBP1), the key regulator of lipogenic genes. The protein
encoded by the C/EBPα intronless gene is a leucine zipper transcription factor which can bind to specific promoters and enhancers as a homodimer
or it can form heterodimers with the related proteins C/EBPβ and C/EBPγ. The C/EBPα protein has been shown to bind to the promoter and to also
modify the expression of the leptin gene, playing a central role in body weight homeostasis. C/EBPα is sufficient to trigger differentiation of
preadipocytes into mature adipocytes [
]. Peculiarly, PPARγ directly triggers endogenous C/EBPα transcription. In turn, C/EBPα activates the PPARγ
gene through a positive feedback loop, thereby promoting adipogenesis [
]. Together, PPARγ and C/EBPα promote the expression of genes
involved in insulin sensitivity, in lipogenesis and lipolysis, and, ultimately, in the terminal differentiation and mature functions of adipocytes. The
complex series of events governing adipose cell commitment and differentiation also includes anti-adipogenic signaling cascade controlled by Wnt,
BMPs, TGF-β, and hedgehog [
]. As expected, an increase in size (hypertrophy) and number (hyperplasia) of adipocytes causes higher level of fat
mass and energy storage in the adipose tissue, possibly ending in increased obesity risk.
shown to possibly promote adipogenesis through
different mechanisms, while other species (Table 3) have been
reported to interfere with adipocyte differentiation [
miR-143 and miR-130 are the best studied among the
miRNAs linked to adipogenesis. miR-143 and miR-145
are often investigated together, since they are closely
located and can be co-transcribed. miR-143 has been
identified as a positive regulator of human adipocyte
differentiation acting via ERK5 signaling. Expression of
miR-143 and miR-145 is upregulated in the liver of
mouse models of obesity, and the iperexpression of
miR143 impairs insulin-stimulated AKT activation and
glucose homeostasis. On the contrary, mice lacking for the
miR-143–145 cluster did not develop the
obesityassociated insulin resistance [
]. Another notable
example is given by miR-27a and miR-130a that inhibit
adipocyte differentiation through PPARγ downregulation
]. The overexpression of miR-27a and miR-130a
clearly suppresses adipocyte differentiation along with
PPARγ expression. Lower expression levels of miR-130a
and miR-130b have been reported in the abdominal
subcutaneous adipose tissue and in the plasma of obese
women compared with those of lean subjects . In
contrast, circulating miR-130b has been found to be
higher in obese children [
]. An interesting study from
Wang et al. identified miR-130b as a potential biomarker
for overweight, hypertriacylglycerolemia, and metabolic
syndrome, suggesting a mechanism linking obesity and
obesity-related metabolic diseases, through an adipose–
muscle crosstalk mediated by circulating miRNAs [
They have also found that the addition of TGF-β in
matured 3T3-L1 adipocytes dramatically elevated the level
of miR-130b in the culture medium, while slightly
decreasing intracellular level of miR-130b, thus confirming
that this miRNA is released from differentiating
adipocytes during adipogenesis. Other miRNAs affect lineage
determination. As an example, miR-124 has a
proadipogenic effect by targeting Dlx5, a pro-osteogenic
transcription factor that determines cell fate in human
bone marrow-derived mesenchymal stem cells [
miRNAs can be expressed from separate transcripts or
from a primary transcript structured in co-transcribed
clusters encoding more than one miRNA (polycistronic)
]. The best-characterized polycistronic miRNA cluster
is represented by miR-17-92, encoding for miR-17,
miR18a, miR-19a, miR-20a, miR-19b-1, and miR-92a [
This cluster is overexpressed during adipocyte clonal
expansion and acts by directly repressing the RB family
Rb2/p130, so controlling the RB-E2F-mediated
checkpoint. In the same pathway, miR-363 inhibits adipocyte
differentiation by targeting E2F and concomitantly
downregulating C/EBPα and PPARγ [
Let-7 was the first human miRNA discovered. This
miRNA is included in a well-conserved family counting
11 members associated with many critical cell functions
(e.g., apoptosis, proliferation, and cell cycle checkpoints).
This miRNA family directly regulates oncogenes such as
RAS and HMGA2 and plays a significant role in
developmental processes. Moreover, miRNAs of this family
regulate glucose metabolism and peripheral insulin
resistance by targeting IGF1R, insulin receptor (INSR),
and insulin receptor substrate-2. Let-7 negatively
controls adipogenesis by regulating the expression of
highmobility group AT-hook2. Let-7 is upregulated in the
model of 3T3-L1 adipogenesis. The ectopic introduction
of let-7 in 3T3-L1 and 3T3-F442A cells decreased the
clonal expansion as well as the terminal differentiation
]. Overall, there is an indication that let-7 acts as an
anti-adipogenic factor controlling the transition from
clonal expansion to terminal differentiation. Moreover,
let-7 has been shown to be directly involved in glucose
metabolism and insulin resistance acting on targets
associated with the insulin/IGF-1R pathway in mice [
let-7 knockout mice, animals with a reduced expression
of let-7 did not develop insulin resistance despite
dietinduced obesity, suggesting that let-7 may represent an
interesting therapeutic target for diabetes [
Various miRNAs affect adipocyte differentiation by
targeting C/EBPs and insulin signaling. miR-375 has been
shown to promote 3T3-L1 adipocyte differentiation by
increasing mRNA levels of C/EBPα and PPARγ2 and by
inducting adipocyte fatty acid-binding protein (aP2) and
triglyceride accumulation. Conversely, miR-375 suppresses
phosphorylation levels of ERK1/2 in 3T3-L1 cells [
There is evidence that miR-206 plays a key role in the
growth and development of the skeletal muscle,
promoting the myogenic differentiation and has been related to
the pathogenesis of numerous diseases, including heart
failure, chronic obstructive pulmonary disease,
Alzheimer’s disease, and some cancers [
]. In most of these
diseases, miR-206 is downregulated, suggesting this
miRNA as a “disease-avoiding” molecule [
Interestingly, miR-206 expression is abundant in brown
adipocytes in mice but missing in white adipocytes [
Moreover, miR-206 suppresses liver X receptor α
(LXRα), a gene target of PPAR, thus inhibiting
lipogenesis and controlling lipid metabolism in HepG2 cells
]. Another miRNA involved in the regulation of
adipogenic differentiation is miR-26b [
of miR-26b in 3T3-L1 cells significantly accelerated the
mRNA expression of adipogenic markers, PPARγ, fatty
acid synthase (FAS), C/EBPα, and lipoprotein lipase, and
increased lipid accumulation, by inhibiting the PTEN
expression. In contrast, inhibition of miR-26b expression
decreased cell differentiation [
Current findings indicate that miR-146b expression in
3T3-L1 is evidently increased during adipogenesis [
Sirtuin 1 (SIRT1) is negatively regulated by miR-146b.
SIRT1 promotes gene transcription by deacetylating
various transcription factors, including the forkhead box
O1 (FOXO1). The role of SIRT1 as a regulator of
metabolic homeostasis has been extensively investigated.
SIRT1 level is decreased during adipogenesis. SIRT1, by
interacting with the PPARγ co-repressors N-CoR and
SMRT, inhibits PPARγ and prevents adipogenesis.
Accordingly, differentiation of 3T3-L1 cells is induced by
overexpression of miR-146b, and on the contrary,
inhibition of miR-146b reduces adipocyte differentiation in
The highly conserved miR-8/miR-200 family consists
of a single ortholog in the fruit fly (miR-8) and of five
members in the vertebrates (miR-200a, miR-200b,
miR200c, miR-141, and miR-429) [
]. miR-8/miR-200 have
been reported as repressors of the evolutionarily
conserved Wnt/wingless pathway in the Drosophila eye and
in mouse mesenchymal stem cells, controlling the eye
size and the differentiation of the mesenchymal stem
cells into adipocytes, respectively [
]. Drosophila miR-8
and human miR-200 family also prevent the expression
of an inhibitor of the insulin/phosphoinositide-3 kinase
(PI3K) signaling in fat body and liver cells, thus
controlling fat body/liver cell growth and proliferation [
particular, overexpression of members of this miRNA
family increases adipogenesis, the level of fatty
acidbinding protein 4 (FABP4), and lipid accumulation.
Liang et al. showed that the expression of miR-210
was highly increased during 3T3-L1 adipogenesis.
Transfection of miR-210 mimics into 3T3-L1 cells promoted
the expression of adipogenic markers and adipocyte
differentiation by targeting SHIP1, a negative regulator of
the PI3K/Akt pathway. Additionally, ectopic inhibition
of the endogenous miR-210 during adipogenesis possibly
blocks adipocyte differentiation [
Likewise, miR-21 in 3T3-L1 cells significantly
promotes adipocyte differentiation and increases
adiponectin expression, while decreasing AP-1 protein level.
miR21 may enhance differentiation of human
adiposederived stem cells by direct inhibition of the TGF-β
receptor 2 expression [
Current evidence indicates that inflammation induces
a specific miRNA response in adipocytes with effects on
the physiopathology of obesity-induced inflammation of
adipose tissue [
]. As an additional example, a research
in mice identified a pro-inflammatory loop mediated by
NF-κB and miR-155 that could participate in the
amplification of inflammatory status in adipocytes [
An interesting paper from Thomou et al. has recently
defined a new role for adipose tissue and its potential
implications in the mechanism of cell crosstalk [
authors have established the role of adipose tissue as a
major source of circulating miRNAs, which can regulate
gene expression in distant tissues so acting as regulators
of metabolism. Mice with an adipose tissue-specific
knockout of Dicer miRNA-processing enzyme, as well as
humans with lipodystrophy, display an extensive decline
in the levels of circulating miRNAs. Transplantation of
both white and brown adipose tissues reestablishes the
level of many circulating miRNAs associated with an
improvement in glucose tolerance and a reduction in
hepatic fibroblast growth factor 21 (FGF21) mRNA and
circulating protein. FGF21 plays a critical role in
metabolism, stimulating the fatty acid oxidation in the liver
and glucose uptake in fat. Of note, levels of FGF21 are
significantly increased in patients with T2D and
nonalcoholic fatty liver disease and positively correlate with
BMI in humans, indicating obesity as a possible
FGF21resistant state [
miRNAs in the pancreas
The endocrine pancreas plays a major role in regulating
glucose homeostasis through the secretion of insulin and
glucagon. Alterations of pancreatic hormone production
and activity are causally linked to diabetes. T2D is a
complex disease characterized by pancreatic islet
dysfunction and insulin resistance in peripheral tissues.
Declined insulin levels in T2D have been attributed to a
decrease in β-cell function/mass [
]. Identity and
dedifferentiation of β-cells may also contribute to the insulin
production decay. The first suggestion for a role of
miRNAs in hormone secretion in vertebrates came from a
cloning approach of small RNAs from the β-cell-derived
line MIN6 [
]. Comparing islet–cell miRNA profiles
with those of 15 other human tissues, a panel of 40
miRNAs predominantly expressed in the islets have been
recently identified [
]. Numerous miRNAs have been
reported to be involved in pancreatic development, with
some of them playing positive roles, while others
exhibiting negative effects [
]. One of the most relevant
is miR-375, which is the most abundant in pancreatic
islets and is essential in maintaining normal pancreatic
βcell mass . An increase in miR-375 expression is
observed during pancreatic islet cell development, whereas
β-cell functioning is linked to its decrease [
Numerous genes associated with cellular growth are controlled
by this miRNA during human pancreas development
]. Moreover, miR-375 targets a number of
transcription factors, such as PDX1, HNF6, and INSM1, engaged
in pancreatic islet functioning [
]. Interestingly, the
transcription factor neurogenin3 (Ngn3), considered as
an early marker of pancreatic islet cells with a prominent
role during the development of the endocrine lineages in
], also interferes with miR-375 expression.
Additional miRNAs, such as miR-15a, miR-15b, miR-16,
and miRNA-195, also target Ngn3. Remarkably, miR-375
has been reported to be involved in the modulation of
insulin secretion in stimulated cell line MIN6 [
in detail, miR-375 leads to a reduced glucose-stimulated
insulin secretion by downregulating myotrophin mRNA
(encoding a key protein involved in cell membrane
fusion with insulin granules) and therefore inhibiting
exocytosis. Furthermore, it has been shown that miR-375
concurrently downregulates expression of insulin by
targeting the phosphoinositide-dependent kinase-1 in
INS1-E cells [
]. Other miRNAs such as miR-7 and
miR-124 have been recognized to be engaged in
regulation of β-cell differentiation and establishment of
pancreatic islets [
]. High levels of miR-7 are detectable in
the pancreatic cells, both in the developing and adult
]. Overexpression of miR-7 in pancreatic
progenitors has been shown to impair the differentiation
of both α- and β-cells and is associated with a repression
of Pax6 expression. The knockdown of miR-7 during
early embryonic life determines an overall
downregulation of insulin production, a decrease in the number of
β-cells, and the onset of glucose intolerance in the
postnatal period. Furthermore, an in vitro inhibition of
miR7 promotes death of β-cell in explanted pancreatic buds.
In summary, data suggest that dysregulation of miR-7
signaling network in response to metabolic stress or
cellular insults contribute to the loss of β-cell identity and
establishment of T2D [
Other miRNAs, like miR-146a and miR-34a, seem
overexpressed only during the differentiation processes
and have been shown to contribute, at least partially, to
cytokine-mediated β-cell dysfunction occurring during
the initial phases of type 1 diabetes in non-obese
diabetic (NOD) mice [
]. Further, miRNAs expressed in
pancreatic islets, such as miR-143 and let-7, have been
connected to glucose homeostasis by targeting key
insulin signaling components [
Other pancreatic functions can be modulated by
miRNAs. For instance, miR-29, in addition to its ability to
regulate β-cell proliferation, has also been shown to
negatively regulate insulin secretion by directly targeting
Stx-1a involved in insulin exocytosis [
miR-124a, miR-9, and miR-96 can regulate insulin
release by β-cells [
]. During the late pancreas
development, miR-124a is upregulated [
]. This miRNA
targets mRNA of both cAMP-responsive
elementbinding protein 1 (Creb1) and forkhead box protein A2
(Foxa2). Notably, Foxa2 modulates the expression of the
insulin gene in multiple pathways responsible for the
secretion of this hormone, mainly through an upstream
regulation of pancreatic and duodenal homeobox 1
(Pdx1). Pdx1 is critical for glucose balance and pancreas
development and together with Ngn3 is required for
βcell differentiation. Moreover, miR124a increases the
levels of SNAP25, Rab3A, and synapsin-1A and
decreases those of Rab27A and Noc2, targets involved in
the exocytotic mechanisms for insulin release [
Overexpression of miR-9 in insulin-secreting INS-1E
cells results in a reduction of insulin exocytosis. mir-9
acts by downregulating the expression of the
transcription factor Onecut-2 and, in turn, by increasing the level
of Granuphilin/Slp4, a Rab GTPase effector associated
with β-cell secretory granules [
Finally, miR-29 also controls insulin secretion by
regulating the monocarboxylate transporter 1 (Mct1)
miRNAs in the muscle
The skeletal muscle represents the major user of glucose
in human body, accounting for about 75% of
insulinmediated glucose uptake. Several miRNAs, referred to as
myomiR family, are preferentially detectable in muscle
tissue and act as modulators of skeletal and cardiac
muscle myogenesis, proliferation, and metabolism, as
well as hypertrophy. The myomiRs include miR-1,
miR133a, miR-133b, miR-206, miR-208a, miR-208b,
miR486, and miR-499 [
]. miR-206 is specifically
expressed in the skeletal muscle, whereas miR-208a is
cardio-specific; nevertheless, most of these miRNAs are
co-expressed in the heart and skeletal muscles [
MyomiRs have been proven to directly target pathways
regulating skeletal muscle homeostasis; their
deregulation is observed across cardiac and muscular
]. As an example, a reduced expression of
miR-133 is observed in mouse and human models of
cardiac hypertrophy, with several studies connecting this
miRNA to the pathogenesis of heart diseases [
Interestingly, it has been proven that acute exercise
determines an increase in the levels of miR-1, miR-133a,
and miR-206 [
], important molecules possibly driving
cell-to-cell communication. A recent paper from Zhou
et al. has demonstrated the involvement of miR-29a in
the induction of insulin resistance by targeting PPARδ in
rats’ skeletal muscle cells. Overexpression of miR-29a in
the cell line C2C12 suppresses the expression of PPARδ,
finally affecting the expression of its coactivator
PGC1α. PPARδ/PGC-1α-dependent signaling determines a
decrease in levels of glucose transporter 4, the principal
glucose transporter in the skeletal muscle, which
partially induces a decrease in insulin-dependent glucose
uptake and adenosine triphosphate (ATP) availability
]. Similarly, another study found that miR-29a levels
are elevated in the diabetic (db/db) mouse liver and its
overexpression prevents insulin-mediated inhibition of
hepatic phosphoenolpyruvate carboxykinase (PEPCK)
gene expression, which is normally implicated in
inhibition of gluconeogenesis and suppressed in diabetes
]. Other studies have shown that high-fat diet
significantly increases the expression of miR-29a in
myocytes, impairing insulin signaling and glucose uptake
through an extensive decrease in insulin receptor
substrate 1 (IRS-1). Possibly, the upregulation of miR-29a
by saturated fatty acids (SFA) is causally related to the
development of insulin resistance in the muscle [
miR-106b, highly expressed in the muscle of diabetic
subjects, has been associated to skeletal muscle insulin
resistance and T2D. Overexpression of miR-106b
determines mitochondrial dysfunction and insulin resistance
in C2C12 myotubes by targeting mitofusin-2. Notably,
expression of this miRNA is improved following
TNF-α treatment, suggesting that its enhanced
production under chronic low-grade inflammation may
represent a valuable link between mitochondrial
alteration and T2D [
A fascinating research topic is the pleiotropic
regulatory network exerted by miR-208a, a heart-specific
miRNA that also controls glucose metabolism and
energy homeostasis. The heart contributes to regulate
systemic energy homeostasis via MED13 [
], a subunit of
the Mediator complex, which governs the transcription
by the thyroid hormone (that enhances energy
expenditure and regulates body weight) and other nuclear
hormone receptors [
]. MED13 is negatively controlled
by miR-208a. Remarkably, anti-miR-208 oligonucleotides
confer resistance to diet-induced obesity and improve
glucose tolerance in mice [
miRNAs in the liver
miRNAs control various functions in the liver, and
cumulative evidence suggests that they have a relevant
role in this organ pathology [
]. miR-122 is a
dominant hepatocyte-specific miRNA accounting for about
75% of total miRNA expression in human hepatocytes
with approximately 135,000 copies, making it one of
the highly expressed in the human body. Levels of
miR-122 are controlled by liver-enriched transcription
factors (LETFs), including hepatocyte nuclear factor
(HNF) 6 and 4a. Interestingly, miR-122 regulatory
network has been implicated in numerous liver
functions, ranging from cholesterol metabolism, stress
responses, viral infection, cancer, and circadian
regulation of hepatic genes [
]. The role of this
miRNA is also emerging in the metabolic syndrome
and other liver diseases, such as liver inflammation
related to alcohol use, autoimmune processes, and the
development of liver fibrosis both in human and
animal models. Pathological suppression of miR-122 has
miR-23a, miR-27a, miR-130, miR-195, miR-197, miR-320a, and miR-509-5p
↑miR-1, miR-21, miR-133a, and miR-208
↑miR-130a and miR-195
been described in hepatocellular carcinoma [
non-alcoholic steatohepatitis [
], and liver cirrhosis
]. This miRNA is intensely investigated because
of its role in cholesterol metabolism. Antisense
inhibition of miR-122 in normal mice results in lower
levels of serum cholesterol, LDL, and serum
triglyceride and increased hepatic fatty acid oxidation. These
effects on lipid metabolism have been associated with
the expression of key genes involved in fatty acid
metabolism and cholesterol biosynthesis, including the
]. Similarly, antisense inhibition of this
miRNA in chimpanzee provokes a plasma cholesterol
reduction supporting its key role in maintaining liver
]. Since miR-122 can be detected in
blood, it has been proposed as a circulating
biomarker of liver injury in chronic hepatitis B and C,
non-alcoholic fatty liver disease, and drug-induced
liver disease [
Other miRNAs, such as miR-27b, miR-33, miR-34,
miR-103, miR-104, 223, and miR-370, also control the
fatty acid metabolism and cholesterol biosynthesis in the
liver. As an example, miR-27b could exert regulatory
effects in the lipid metabolism and is altered in
dyslipidemia, theoretically affecting both liver and heart
functions in mouse [
]. Moreover, miR-34a targets
hepatic SIRT1. The upregulation of miR-34a, with a
concomitant decrease in SIRT1 levels, has been described in
fatty livers of mice with diet-induced obesity [
Additionally, the mitochondrial enzyme carnitine palmitoyl
transferase, involved in the transport of long-chain fatty
acids across the membrane, is targeted by miR-370 that
concurrently affects lipid metabolism [
MiR-33-3p regulates cholesterol and lipid metabolism
as well as fatty acid oxidation [
]. This miRNA
downregulates several genes encoding key enzymes involved
in fatty acid metabolism, cholesterol efflux, such as
ATP-binding cassette A1 (ABCA1), and insulin
signaling. This miRNA in vitro targets IRS2 and SIRT6 genes
involved in insulin signaling. Inhibition of miR-33 in
non-human primates resulted in elevated plasma HDL
and protective effects against atherosclerosis. However,
recent studies suggest that miR-33 inhibition may
have adverse effects on lipid and insulin metabolism
in mice [
Hepatic miR-223 has been shown to reduce
cholesterol biosynthesis in mice by targeting the
3-hydroxy-3methylglutaryl-CoA synthase 1 and the
sterol-C4methyloxidase-like protein. Moreover, this miRNA
inhibits the HDL-C uptake by targeting the scavenger
receptor class B member 1 and promotes cholesterol
efflux by positively regulating the expression of ABCA1.
Notably, miR-223 level is controlled by the cholesterol
miR-26a additionally regulates insulin signaling as well
as metabolism of glucose and lipids in mice and humans
]. Overweight compared with lean subjects exhibit a
decreased liver expression of miR-26a. Overexpression
of this miRNA in mice fed a high-fat diet enhanced
insulin sensitivity and reduced hepatic glucose and fatty acid
synthesis, so preventing obesity-induced metabolic
Remarkably, a number of hepatic miRNAs have been
reported to be dysregulated in obese patients with
NAFLD and NASH [
124, 135, 136
Although miRNAs were first identified inside cells, more
recently, an increasing number of miRNAs have been
found, in surprisingly high concentrations, in plasma
and other body fluids such as serum, urine, and saliva
]. The concept that miRNAs could be stable in
blood and body fluids [
], in spite of the ubiquity of
nucleases, was originally met with skepticism by the
scientific community. However, this characteristic
generated high interest for the possibility that variations in
cell-free miRNA expression could be used as
noninvasive biomarkers for several diseases and, possibly, as
early diagnostic tools. [
]. Due to their accessibility,
the most common miRNA sources investigated are
whole blood, serum, and plasma [
Circulating miRNAs (cmiRNAs), as expected, are not
naked molecules, and two major mechanisms have been
identified to shield them from nuclease activity. The first
one consists in the formation of complexes of specific
binding proteins, such as Argonaute 2 (AGO-2) [
protein involved in the RNA silencing complex, with
high-density lipoproteins [
], or nucleophosmin-1
(NPM-1), a nucleolar RNA-binding protein implicated
in the nuclear export of the ribosome [
]. The second
proposed mechanism stems from the discovery of
cmiRNAs enclosed within circulating microvesicles or
] deriving either from the endosomal
compartments or from the cell plasma membrane [
Although an established mechanism for the release of
miRNAs from cells remains largely unknown, growing
evidence supports the indication that extracellular
miRNAs, arranged either into exosomes or protein
complexes, may be delivered to the receiver cells, where they
can be engaged in the control of target gene translation
]. However, the physiological role of circulating
miRNAs is still uncertain.
Differential cmiRNA profiles have been reported in
individuals with obesity and T2D [
]. In Table 4, the
behavior of specific cmiRNAs in different metabolic
disorders is summarized. For instance, miR-126 is
reduced in T2D [
] and has been proposed as a
biomarker of endothelial dysfunction caused by
uncontrolled glycemia in T2D [
]; miR-1, miR-21, miR-133a,
and miR-208 are enriched in the plasma after myocardial
]; miR-122 is enhanced in hepatic injury
and steatosis [
], as well as let-7e in hypertension
]. Additionally, circulating miR-130a and miR-195
have been connected with high blood pressure [
Alterations in circulating miR-23a, miR-27a, miR-130,
miR-195, miR-197, miR-320a, and miR-509-5p have
been associated to metabolic syndrome [
Moreover, cmiRNA profiles exhibited a sex-specific
association with metabolic syndrome . Circulating
let7b, miR-143, and 221 have been proposed to regulate
atherogenic and adipogenic processes [
Furthermore, the expression of circulating miR-17-5p and
miR132 was decreased in obesity, mirroring the expression
pattern of miRNAs in omental fat from the same group
of obese subjects [
]. Different cmRNA profiles have
also been described in pre-gestational and gestational
Ortega et al. have reported that morbidly obese
patients exhibit a marked increase of circulating
miR-1405p, miR-142-3p, and miR-222 and a decrease of
miR532-5p, miR-125b, miR-130b, miR-221, miR-15a,
miR423-5p, and miR-520c-3p. In the same study, a
surgeryinduced weight loss caused a significant decrease of
circulating miR-140-5p, miR-122, miR-193a-5p, and
miR16-1 and an increase of miR-221 and miR-199a-3p [
Furthermore, various studies have shown a differential
cmiRNA signature in overweight/obese as compared in
normal weight children and adolescents [
thus suggesting that these molecules could have a
promising role in the early identification of children at risk of
excess body fat accumulation and related metabolic
Since their first detection in 1993, miRNAs have attracted
growing interest among the scientific community.
Considerable progress has been achieved in the research of
contributory crosstalk between regulatory miRNAs and diseases.
miRNAs have emerged as key regulators of lipid and glucose
metabolism and play pivotal roles in the onset of obesity
and obesity-related diseases by affecting status and functions
of the adipose tissue, pancreas, liver, and muscle (Fig. 2).
However, information about the mechanisms of action
remains nearly limited, due to the miRNAs’ ability to
simultaneously affect multiple pathways/gene networks and to
the technical limitations of in vivo profiling [
A comprehensive understanding of the role of
miRNAs in tissue metabolism and energy homeostasis may
in perspective open the road to therapeutics strategies.
Two main approaches are currently considered: the
inhibition strategy, which uses anti-miR sequences able to
target a specific miRNA and block its function, and the
replacement therapy employing miRNA mimics [
The exciting emergence of circulating miRNAs as
stable and accessible molecules opened a promising
research avenue for the detection of non-invasive
biomarkers potentially useful to the early identification of
subjects at risk of excess body fat accumulation and
related metabolic abnormalities.
For the etiological characterization, prospectively
designed studies are strongly needed. A number of miRNA
candidate signatures have been defined, and clinical
trials are ongoing to validate their significance.
ABCA1: ATP-binding cassette A1; AGO: Argonaute; BMI: Body mass index; C/
EBPs: CCAAT/enhancer-binding proteins; cmiRNAs: circulating miRNAs;
Creb1: cAMP-responsive element-binding protein 1; ERK: Extracellular
signalregulated kinases; FABP4: Fatty acid-binding protein 4; FAS: Fatty acid
synthase; FGF21: Fibroblast growth factor 21; Foxa2: Forkhead box protein
A2; FOXO1: Forkhead box O1; HNF: Hepatocyte nuclear factor; INSR: Insulin
receptor; IRS-1: Insulin receptor substrate 1; LETFs: Liver-enriched
transcription factors; LXRα: Liver X receptor α; Mct1: Monocarboxylate
transporter; miRNAs: microRNAs; NAFLD: Non-alcoholic fatty liver disease;
NASH: Non-alcoholic steatohepatitis; N-CoR: Nuclear receptor corepressor;
ncRNAs: Small non-coding RNAs; Ngn3: neurogenin3; NGS: Next-generation
sequencing; NOD: Non-obese diabetic mice; NPM-1: Nucleophosmin-1;
Pdx1: Pancreatic and duodenal homeobox 1; PEPCK: Phosphoenolpyruvate
carboxykinase; PI3K: Insulin/phosphoinositide-3 kinase; PPARγ:
Proliferatoractivated receptor-γ; RB: Retinoblastoma susceptibility protein; RISCs:
RNAinduced silencing complexes; RNAseq: RNA sequencing; SFA: Saturated fatty
acids; SHIP1: SH2 (Src homology 2)-containing inositol phosphatase-1;
SIRT1: Sirtuin 1; SMRT: Silencing mediator for retinoid and thyroid hormone
receptors; SREBP1: Sterol regulatory element-binding protein; T2D: Type 2
The authors are grateful to Dr. Paola Russo for hepful discussion and comments.
Availability of data and materials
We systematically explored PubMed using different combinations of key
words. Articles published until July 2017 were selected. Whenever possible,
the most recent and complete reviews on the topic were selected.
All authors confirmed they have contributed to the intellectual content of
this review. GI and AS acquired the data, drafted the paper, revised the
manuscript, and made substantial contributions to its final content and
design. GI and AS read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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