Review

Palmitic and Oleic Acid: The Yin and Yang

of Fatty Acids in Type 2 Diabetes Mellitus
Xavier Palomer,1 Javier Pizarro-Delgado,1 Emma Barroso,1 and Manuel Vázquez-Carrera1,*

Increased plasma non-esterified fatty acids (NEFAs) link obesity with insulin Highlights
resistance and type 2 diabetes mellitus (T2DM). However, in contrast to the Substituting SFAs by oleic acid in the
diet improves insulin sensitivity in
saturated FA (SFA) palmitic acid, the monounsaturated FA (MUFA) oleic acid
humans.
elicits beneficial effects on insulin sensitivity, and the dietary palmitic acid:
oleic acid ratio impacts diabetes risk in humans. Here we review recent Preclinical studies have shed light on
the molecular mechanisms by which
mechanistic insights into the beneficial effects of oleic acid compared with oleic acid prevents palmitic acid-
palmitic acid on insulin resistance and T2DM, including its anti-inflammatory induced inflammation and insulin resis-
actions, and its capacity to inhibit endoplasmic reticulum (ER) stress, prevent tance in adipose tissue, liver, skeletal
muscle, and pancreas.
attenuation of the insulin signaling pathway, and improve b cell survival.
Understanding the molecular mechanisms of the antidiabetic effects of oleic The hypothalamus also senses oleic
acid, where it activates a neuronal net-
acid may contribute to understanding the benefits of this FA in the prevention
work that suppresses VLDL-TAG
or delay of T2DM. secretion in liver.

Oleic acid protects against cardiovas-

Increased Plasma NEFAs Link Obesity and Insulin Resistance cular insulin resistance and the ather-
osclerotic process.
Insulin resistance, defined as a defect in the capacity of insulin to drive glucose into its target
tissues, both predicts and precedes the development of T2DM [1]. This condition eventually Some of the effects of oleic acid are
leads to hyperglycemia when pancreatic b cells fail to secrete sufficient insulin to meet the mediated by preventing the reduction
in palmitic acid-mediated AMPK activ-
increased metabolic demand for this hormone. The expansion of adipose tissue in obese
ity, resembling the action of metformin.
individuals releases increased amounts of NEFAs (see Glossary) [also called free FAs (FFAs)],
hormones, proinflammatory cytokines, and other factors that are involved in the development
of insulin resistance. Increased levels of NEFAs provoke insulin resistance and impair b cell
function [2], making them good candidates for a link between obesity and T2DM development.
The link between obesity and T2DM also involves the activation of a chronic low-level
inflammatory process promoted by increased levels of NEFAs, which contributes to insulin
resistance and T2DM [1].
1
Department of Pharmacology,
Plasma NEFA released by adipose tissue reflects fat intake. Oleic acid (C18:1) and palmitic acid Toxicology, and Therapeutic
Chemistry, Faculty of Pharmacy and
(C16:0) are the most abundant dietary and plasma FAs and represent 31% and 27%, Food Sciences, University of
respectively, of total plasma NEFA [3]. However, the SFA (Box 1) palmitic acid and the MUFA Barcelona, Institute of Biomedicine of
oleic acid contribute differently to insulin resistance. Studies of subjects who reduced their SFA the University of Barcelona (IBUB),
Pediatric Research Institute–Hospital
and increased their MUFA intake have shown a significant improvement in insulin sensitivity [4]. Sant Joan de Déu, and Spanish
This beneficial effect of oleic acid on insulin sensitivity can also help to explain the protective Biomedical Research Centre in
effects of the Mediterranean diet against both obesity and T2DM. That diet is characterized by a Diabetes and Associated Metabolic
Diseases (CIBERDEM)–Instituto de
specific FA pattern with a low intake of SFA (7–8% of energy) and a high intake of MUFA (over Salud Carlos III, Avinguda Joan XXIII
20% of total energy), as the primary fat source is olive oil (100 g contains 74 g of oleic acid) [5]. 27-31, E-08028 Barcelona, Spain
Understanding the molecular mechanisms responsible for the beneficial effects of oleic acid
might help to promote its use in the prevention or delay of T2DM. Here we review recent
*Correspondence:
mechanistic insights into the beneficial effects of oleic acid compared with palmitic acid in mvazquezcarrera@ub.edu
insulin resistance and T2DM. (M. Vázquez-Carrera).

178 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 https://doi.org/10.1016/j.tem.2017.11.009
© 2017 Elsevier Ltd. All rights reserved.
 Box 1. FAs and the Oleic Acid-Derivative OEA
Glossary
It is recommended that dietary fat constitute 20–35% of energy intake [73]. However, the type of FA present in the fat
Atherogenic dyslipidemia: the
ingested is of considerable importance in the development of insulin resistance/T2DM. FAs can be classified according
presence of high levels of
to their chain length as: short-chain FAs, with two to six carbon atoms; medium-chain FAs, with seven to 12 carbon
triglycerides, small-dense low-density
atoms; long-chain FAs, with 13–22 carbon atoms; and very-long-chain FAs, with more than 22 carbon atoms. They are
lipoprotein, and low levels of high-
also divided into: SFAs, with no carbon–carbon double bonds; MUFAs, with a single double bond (alkene) in the FA
density lipoprotein cholesterol. It is
chain; and polyunsaturated FAs (PUFAs), containing several double bonds. PUFAs are subdivided into omega-6 (n-6)
often observed in patients with
and omega-3 (n-3) acids depending on the distance from the first double bond to the methyl end. The ingestion of oleic
metabolic syndrome, obesity, insulin
acid can stimulate the production of OEA in enterocytes [61]. However, excess fat can reduce the synthesis of OEA.
resistance, and T2DM.
OEA belongs to the group of FAs called ethanolamides or N-acylethanolamines, which are a class of naturally occurring
Cytokine: a small protein secreted
bioactive signaling lipids derived from SFAs and unsaturated FAs. OEA controls food intake and promotes fat
by cells that has a specific effect on
catabolism. Fat ingestion results in the release of oleic acid in the small-intestinal lumen, which is internalized by
the interactions and communication
the enterocytes and channeled toward the synthesis of chylomicrons or OEA. The latter can then be hydrolyzed into
between cells.
oleic acid and ethanolamine by FAAH (Figure I).
Endoplasmic reticulum (ER)
stress: the result of any stimulus
that provokes the accumulation of
misfolded proteins in the lumen of
Molecular Mechanisms Involved in Palmitic Acid-Induced Insulin Resistance the ER; triggers the unfolded protein
Three main mechanisms have been reported in palmitic acid-mediated insulin resistance and response (UPR), an adaptive
(defensive) ER stress response that
T2DM (Figure 1): (i) increased synthesis of deleterious complex lipids; (ii) impaired function of involves the activation of a signaling
cellular organelles; and (iii) receptor-mediated inflammation. First, the increase in plasma NEFA pathway to restore folding capacity.
favors the rate of FA delivery to non-adipose tissues such as the liver, muscle, heart, and If ER homeostasis is not restored,
pancreatic islets. Such ectopic lipid deposition promotes metabolically relevant cellular apoptosis is induced.
Glucagon-like peptide-1 (GLP-1):
dysfunction (lipotoxicity) and programmed cell death (lipoapoptosis). In these circumstan- a gut peptide secreted by endocrine
ces increased intracellular levels of palmitic acid exceed its mitochondrial oxidation and it is L cells of the ileum that suppresses
converted into deleterious complex FA-derived lipids such as diacylglycerol (DAG) and glucagon secretion and stimulates
glucose-dependent insulin secretion.
ceramide. By contrast, the accumulation of the relatively inert triacylglycerol (TAG), which is
Lipoapoptosis: when excess lipids
not a signaling lipid, is generally considered to be harmless and could even be protective [6]. are driven into an alternative non-
The increase in the intracellular DAG content caused by the exposure to enhanced levels of oxidative pathway that promotes
palmitic acid activates novel protein kinase C (PKC) isoforms, such as PKCu in skeletal muscle programmed cell death.
Lipotoxicity: when excess lipids in
and PKCe in liver [7], that which ultimately attenuate the insulin signaling pathway by
non-adipose tissues are driven into
phosphorylating serine residues in insulin receptor substrate 1 (IRS-1). The activation of some an alternative non-oxidative pathway
of these PKC isoforms, such as PKCu, can also activate the proinflammatory signaling cascade that promotes metabolically relevant
inhibitor of nuclear factor (NF)-kB (IkB) kinase (IKK)b–IkB–NF-kB [7], a pathway that also cellular dysfunction.
Low-grade inflammatory process:
attenuates insulin action through IKKb-mediated phosphorylation at serine residues of IRS-1 or
obesity-induced inflammation that
by increasing the levels of proinflammatory cytokines. Interestingly, it has been reported that differs from inflammation in classical
only DAG containing SFA in skeletal muscle membranes is related to insulin resistance in immunity through being low grade
humans [8]. Likewise, the coenzyme A (CoA) thioester of palmitic acid is the limiting substrate of and producing much lower levels of
circulating cytokines. It is also
de novo ceramide synthesis. Therefore, the flux through this biosynthetic pathway is increased considered chronic inflammation
because a relatively long duration of
treatment with a high-fat diet is
HO Palmic acid (C16:0) required (>8 weeks in animal
models) before inflammation is
O observed in adipose tissue. Obesity-
induced inflammation is the result of
8 6 4 2 exposure to an excess of nutrients,
HO Oleic acid (C18:1 n-9) resulting in adipocyte hypertrophy,
9 7 5 3 1
O n- ω- Numbering macrophage infiltration and
polarization, and activation of
H inflammatory pathways.
N Oleoylethanolamide (OEA) Macrophage polarization: to fulfill
HO
their functionally distinct roles,
O macrophages are capable of
polarizing toward different
phenotypes, which include classical
(proinflammatory, M1) and alternative
Figure I. Chemical Structures of Palmitic and Oleic acid, and Oleoylethanolamide.

Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 179
 Visceral Adipose ssue lipolysis LPS High-fat diet (anti-inflammatory, M2) activation
obesity states.
Metformin: the first-line drug
Palmic acid prescribed following the diagnosis of
Fetuin A
T2DM in the absence of
(i) Increased levels of contraindications such as severe
deleterious complex lipids TLR4 CD14
FAT/CD36 Insulin renal or hepatic insufficiency; one of
DAG MYD88
(iii) Receptor- the few oral drugs for T2DM that
FATP ceramide Insulin
mediated promotes weight loss rather than
PKC inflammaon receptor
weight gain.
pY pY
Mitochondrial dysfunction: loss of
IRS efficiency in the electron transport
NLRP3 pS pY chain and reductions in the synthesis
of high-energy molecules such as
FAβ-oxidaon Insulin signaling ATP; characteristic of aging, and
CPT-1 pathway essentially of all chronic diseases.
JNK PI3K Non-esterified fatty acid (NEFA):
(ii) Impaired IKKβ FA released from triglycerides by the
funcon of ROS p
action of the enzyme lipase and
cellular
organelles
Akt transported in the blood bound to
Glucose albumin.
IκB
ER stress
NF-κB p50 p65 GLUT4

ER
p50 p65 IL-6, TNF-α, pro-IL-1β, etc.

Cytokines Insulin
Nucleus
resistance

Figure 1. Palmitic Acid Attenuates the Insulin Signaling Pathway through Various Mechanisms Leading to
Insulin Resistance. As visceral obesity develops, it results in greater release of non-esterified fatty acids (NEFAs) since
visceral adipocytes are more sensitive to lipolytic stimuli. In addition, insulin resistance leads to the failure of lipolysis
inhibition by this hormone and further augments the increase in plasma NEFA levels. The increase in plasma NEFA, mainly
the saturated palmitic acid, results in inflammation and insulin resistance via three main mechanisms. (i) Increased
internalization of palmitic acid results in lipotoxicity when this FA exceeds oxidative needs and spills over into deleterious
non-oxidative metabolic pathways, increasing the levels of diacylglycerol (DAG) and ceramide. DAG activates protein
kinase C (PKC), which in turn attenuates the insulin signaling pathway by phosphorylating insulin receptor substrate (IRS)-1
at serine residues and also activates the inhibitor of nuclear factor (NF)-kB (IkB) kinase (IKK)b–NF-kB pathway, further
exacerbating the impairment of insulin signaling and provoking inflammation. The increase in ceramide activates the nod-
like receptor containing a pyrin domain (NLRP3) inflammasome-mediated release of interleukin (IL)-1b and also leads to the
activation of protein phosphatase 2A (PP2A) and PKC, which both attenuate the insulin signaling pathway. (ii) The excess
of palmitic acid impairs the function of the endoplasmic reticulum (ER) and mitochondria. Impairment of ER homeostasis
results in ER stress, which promotes inflammation [the NF-kB, c-Jun N-terminal kinase (JNK), and NLRP3 inflammasome
pathways are activated] and apoptosis (e.g., b cells). The impairment of mitochondrial function may reduce FA oxidation
and can increase reactive oxygen species (ROS) generation. (iii) Palmitic acid can activate Toll-like receptor (TLR)-4
through fetuin A and high-fat diets increase the levels of lipopolysaccharide (LPS), an activator of this receptor, leading to
an increase in the activity of the IKKb–NF-kB pathway. Abbreviations: Akt, mammalian homolog of retroviral oncogene v or
protein kinase B; FAT, FA translocase; FATP, FA transporter protein; PI3K, phosphatidylinositol 3-kinase; pS, phos-
phorylated serine; pY, phosphorylated tyrosine; p50/p65, NF-kB subunits; TAG, triacylglycerol.

following enhanced availability of palmitic acid [9]. Increased ceramide synthesis leads to insulin
resistance through several mechanisms, including inhibition of Akt via PKCz and protein
phosphatase 2A (PP2A), which promotes the dephosphorylation and inactivation of Akt [9].
In addition, ceramide also induces ER stress, inhibits mitochondrial b-oxidation of FA and
activates the nod-like receptor containing a pyrin domain (NLRP3) inflammasome [9], a major
instigator of inflammation.

180 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
Second, the mechanisms underlying the detrimental effects of excess NEFA on T2DM also
include impairment of the function of cellular organelles. Enhanced NEFA levels perturb ER
homeostasis by causing lipid dysregulation in the ER that affects the lipid composition of the
membranes of this organelle. This results in a process known as ER stress (Figure 1), which
affects calcium signaling, can cause cell death, and attenuates protein translation [10]. In
addition, palmitic acid-induced ER stress intersects with the inflammatory process by activating
several proinflammatory pathways, such as NF-kB, c-Jun N-terminal kinase (JNK), double-
stranded RNA (dsRNA)-dependent protein kinase (PKR), and the NLRP3 inflammasome [10].
Ultimately, all of these changes contribute to metabolic dysregulation and T2DM [10].

Mitochondrial dysfunction has also been associated with muscle insulin resistance in several
studies [11]. T2DM is characterized by the presence of disturbances in FA metabolism, and
mitochondrial dysfunction can result in reduced oxidative capacity promoting the intracellular
accumulation of complex lipids that activate pathways that interfere with the insulin signaling
pathway. In addition, it has been proposed that increased lipid oversupply into the mitochondria
because of increased NEFA levels leads to incomplete FA oxidation provoking increased
generation of reactive oxygen species (ROS), with concomitant mitochondrial stress, which
ultimately leads to cellular damage and insulin resistance [12]. Moreover, FA translocase, or
CD36, is a scavenger receptor that recognizes long-chain FAs and is involved in their trafficking;
it also plays an important role in T2DM. Palmitic acid is a potent inducer of ROS in several cell
types, including b cells, and CD36 appears to be required for FA-induced ROS production [13].

Third, palmitic acid can activate proinflammatory pathways through membrane receptors such
as Toll-like receptor 4 (TLR4), a pattern recognition receptor that recognizes bacterial com-
ponents including lipopolysaccharide (LPS). SFA can also activate TLR4 through fetuin A, an
adaptor protein that mediates the interaction between SFA and TLR4. Once activated, TLR4
subsequently promotes the activation of proinflammatory transcription factors such as NF-kB
[14]. Moreover, SFA can modify gut microbiota leading to an increase in the levels of LPS after
high fat intake, enhancing this natural TLR4 ligand [15]. In addition to TLR4, another molecule
that integrates immune and nutritional signaling with inflammation and insulin action is PKR,
which is activated by viral dsRNA as part of the mammalian immune response. It has been
suggested that small nucleolar RNAs (snoRNAs), which accumulate in the cytosol and act as
critical mediators of lipotoxicity, interact and activate PKR in a palmitic acid-dependent manner
[16,17].

As mentioned above, substituting palmitic acid by oleic acid, together with additional lifestyle
changes, offers an opportunity to reverse or delay the deleterious metabolic effects of this SFA.
Increased consumption of olive oil, which is high in oleic acid and contains antioxidant
compounds, was associated with a reduction in the risk of T2DM in US women [18]. Likewise,
it has been reported that the dietary palmitic acid:oleic acid ratio impacts diabetes risk in
women [19]. Overall, these and other reports suggest that oleic acid has a protective effect
against insulin resistance and T2DM. In the following sections, we describe the molecular
mechanisms by which oleic acid prevents palmitic acid-induced insulin resistance and T2DM.

Oleic Acid-Activated Mechanisms That Attenuate the Increase in the

Synthesis of Deleterious Complex Lipids Caused by Palmitic Acid
Skeletal muscle is a key tissue that affects the metabolic state of the whole organism since it
accounts for about 80% of insulin-stimulated glucose disposal and is the main organ for NEFA
utilization [20]. Accumulation of deleterious complex lipids (DAG and ceramide) in muscle fibers
is considered a key factor in the development of insulin resistance [1] and may occur because of

Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 181
 Palmic acid

FAT/CD36
Oleic acid FATP Insulin
Insulin
receptor
pY pY

PKCθ IRS
+
AMPK pS pY
DAG
Insulin signaling
DGAT2
pathway
TAG IKKβ PI3K
PP2A
Ceramide p
+
CPT-1 IκB Akt
NF-κB p50 p65 Glucose
FA oxidaon
GLUT4

PGC-1α PGC-1α
PPAR IL-6, TNF-α Insulin
RXR p50 p65
Sirt1 + CPT-1 resistance
PGC-1α PGC-1α…
Ac
Nucleus
Cytokines

Figure 2. Oleic Acid Prevents the Palmitic Acid-Induced Increase in the Synthesis of Deleterious Complex
Lipids. Oleic acid prevents the deleterious effects of palmitic acid by increasing the mitochondrial oxidation of saturated
fatty acids (SFAs) and by promoting their accumulation in the form of triacylglycerol (TAG), thereby reducing the synthesis
of diacylglycerol (DAG) and ceramide. The increase in FA oxidation caused by oleic acid is mediated by the restoration of
AMP-activated protein kinase (AMPK) activity and the increase in the expression of Cpt-1 and Pgc-1a. In addition, oleic
acid increases the activity of peroxisome proliferator-activated receptor (PPAR)g coactivator 1a (PGC-1a) through the
activation of Sirt1 and the subsequent reduction of the acetylated (inactive) form of this protein. Oleic acid prevents the
reduction in AMPK activity caused by palmitic acid and ultimately inhibits endoplasmic reticulum (ER) stress and
inflammation as well as the activation of the mammalian target of rapamycin complex (mTORC1)–S6K1 pathway. Blue
arrows show the potential effects of oleic acid. Abbreviations: Ac, acetylated; Akt, mammalian homolog of retroviral
oncogene v or protein kinase B; CPT-1, carnitine palmitoyl transferase 1; DAGT2, DAG acyltransferase 2; FAT, FA
translocase; FATP, FA transporter protein; IkB, inhibitor of nuclear factor (NF)-kB; IKKb, IkB kinase subunit b; IL,
interleukin; IRS, insulin receptor substrate; p50/p65, NF-kB subunits; PI3K, phosphatidylinositol 3-kinase; PKC, protein
kinase C; pS, phosphorylated serine; PP2A, protein phosphatase 2A; pY, phosphorylated tyrosine; ROS, reactive oxygen
species; RXR, retinoid X receptor.

increased FA uptake due to excess plasma NEFA and/or because of a reduced rate of
mitochondrial FA oxidation [21]. We previously reported that exposure of myotubes to palmitic
acid leads to enhanced DAG levels and the subsequent activation of the proinflammatory
pathway PKCu–NF-kB. This causes both phosphorylation of IRS-1 at serine residues and
inhibition of insulin-stimulated Akt phosphorylation, thereby attenuating insulin signaling [22]
(Figure 2). However, exposure to oleic acid does not cause these changes and co-incubation of
palmitic acid-exposed cells with a lower concentration of oleic acid reverses the effects of the
latter. When we examined the incorporation of these FAs into TAG and DAG, we observed that
palmitic acid was mainly incorporated into DAG whereas oleic acid was mainly incorporated
into TAG. Furthermore, cells incubated with both palmitic and oleic acid showed greater
incorporation of FA into TAG than cells exposed only to palmitic acid. These findings have
been confirmed in additional studies [23]. The increased channeling of palmitic acid into DAG

182 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
was associated with a reduction in the expression levels of DAG acyltransferase-2 (Dgat2),
which is the enzyme that catalyzes the conversion of DAG into TAG, whereas no changes were
observed in cells incubated with either oleic acid or palmitic plus oleic acid. These differences
might explain why palmitic acid increases the level of DAG and activates the PKCu–NF-kB
pathway, whereas the addition of oleic acid favors the synthesis of TAG, protecting the cells
from inflammation and attenuation of the insulin signaling pathway. Moreover, palmitic acid and
oleic acid have different effects on the expression of genes involved in mitochondrial FA
oxidation. The expression of these genes is regulated at the transcriptional level by several
nuclear receptors, including peroxisome proliferator-activated receptor (PPAR)a and PPARb/
d, whose potency as transcription factors largely depends on the assembly of transcriptional
coactivators such as PPARg coactivator (PGC)-1a, which also controls mitochondrial biogen-
esis [24]. Palmitic acid reduces the expression of Pgc-1a in myotubes whereas oleic acid does
not, and co-incubation of palmitic acid-exposed cells with lower concentrations of oleic acid
prevents the reduction in its expression. The capacity of oleic acid to prevent the down-
regulation of the expression of Pgc-1a was dependent on PPARa and protein kinase A (PKA)
[22]. PGC-1a activity is also controlled through reversible acetylation. PGC-1a is deacetylated
and activated by sirtuin 1 (Sirt1) and acetylated and inhibited by general control of amino acid
synthesis 5-like 2 (GCN5). Interestingly, Sirt1 deacetylase activity is induced by various
signaling pathways, including AMP-activated protein kinase (AMPK) and cAMP/PKA, ultimately
enhancing mitochondrial FA oxidation [25]. Importantly, myotubes exposed to oleic acid, but
not to palmitic acid, display an increase in levels of cAMP, which activates PKA. This results in
SIRT1 phosphorylation at serine 434, which increases its deacetylase activity, eventually
leading to enhanced activity of PGC-1a and the expression of genes involved in mitochondrial
FA oxidation, as well as the subsequent higher rate of FA oxidation [26]. Oleic acid also
increases levels of carnitine palmitoyltransferase 1 (CPT-1) [22,27], which enables the transport
of FA into mitochondria for b-oxidation. This effect of oleic acid results in a reduction of
ceramide and DAG levels in palmitic acid-exposed cells [27]. Further, co-incubation with oleic
acid increases mitochondrial b-oxidation of the FA through a second mechanism: activation of
AMPK, which in turn inhibits acetyl-CoA carboxylase (ACC) and consequently its product
malonyl-CoA, a CPT-1 inhibitor [26]. Similarly, oleic acid abolishes palmitic acid-induced
ceramide synthesis in myotubes by preventing the upregulation of dihydroceramide desaturase
1, the enzyme responsible for generating ceramide from its precursor. This effect of oleic acid
protects cells from attenuation of the insulin signaling pathway caused by the SFA [28].

In the liver an excess of SFA, such as palmitic acid, induces lipotoxicity, leading to the
development of nonalcoholic fatty liver disease (NAFLD), a process associated with insulin
resistance. Moreover, the severity of NAFLD correlates with the presence of lipoapoptosis. In
cultured hepatocytes, palmitic acid, but not oleic acid, impairs the insulin signaling pathway
[29]. Likewise, co-incubation with both FAs increases the extent of steatosis, but oleic acid
reduces apoptosis and the impairment of insulin signaling caused by palmitic acid. Moreover,
palmitic acid-induced apoptosis suppresses autophagy by inducing caspase-dependent
beclin 1 cleavage. By contrast, it was suggested that oleic acid protects hepatocytes against
apoptosis by inducing the formation of TAG-enriched lipid droplets and the induction of
autophagy [30].

Chronic exposure of rodent and human islet b cells to FA impairs glucose-stimulated insulin
secretion (GSIS) and induces apoptosis through the activation of several pathways, including
increased synthesis of ceramide, mitochondrial dysfunction, ER stress, and activation of long-
chain FFA receptor (FFAR)1 or G protein-coupled receptor (GPR)40 [2,31]. As for other cell types,
oleic acid protects palmitic acid-exposed b cells, modifying the metabolism of the SFA by

Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 183
increasing its oxidation or promoting its incorporation into TAG, thereby reducing the levels of
ceramide and DAG, or by preventing ER stress [32–34]. The increase in palmitic acid-induced
mitochondrial oxidation caused by oleic acid is mediated through PPARb/d activation [35].

Oleic Acid-Activated Mechanisms That Prevent Impaired Function of Cellular

Organelles Caused by Palmitic Acid
ER stress is a potentially new mechanism involved in the association between saturated NEFA-
induced inflammation and insulin resistance [10]. We [36] and others [23] have reported that
palmitic acid increases ER stress and inflammation and attenuates the insulin signaling pathway
in mouse and human myotubes and in vivo. Oleic acid, by contrast, does not, and co-
incubation of palmitic acid-exposed cells with oleic acid at a lower concentration than the
palmitic acid prevents these changes (Figure 3). This beneficial effect of oleic acid on palmitic
acid-exposed cells is dependent on the AMP-mediated activation of AMPK [36], a metabolic
sensor that also modulates inflammation and is recognized as a therapeutic target for diabetes
[37]. The reduction in the levels of phosphorylated AMPK caused by palmitic acid in myotubes

Oleic acid

Palmic acid

FAT/CD36
Insulin
FATP
Raptor Insulin
AMPK mTOR receptor
pY pY
S6K1
ER stress IRS
pS pY
Insulin signaling
pathway
PI3K
CPT-1 IKKβ
p
Akt Akt
ROS IκB TRB3
Glucose
NF-κB p50 p65

GLUT4

p50 p65 IL-6, TNF-α

Insulin
resistance
Nucleus

Cytokines

Figure 3. Oleic Acid Prevents the Impairment in the Function of Cellular Organelles Caused by Palmitic Acid.
Oleic acid prevents the reduction in AMP-activated protein kinase (AMPK) activity caused by palmitic acid and ultimately
inhibits endoplasmic reticulum (ER) stress and inflammation as well as the activation of the mammalian target of rapamycin
complex (mTORC)1–S6K1 pathway. Oleic acid also prevents the increase in the levels of the ER stress-induced
pseudokinase TRB3 caused by palmitic acid. Moreover, oleic acid attenuates reactive oxygen species (ROS) generation
and protects the mitochondria from palmitic acid-induced oxidative stress. Abbreviations: Akt, mammalian homolog of
retroviral oncogene v or protein kinase B; FAT, fatty acid translocase; FATP, fatty acid transporter protein; IkB, inhibitor of
nuclear factor (NF)-kB; IKKb, IkB kinase subunit b; IL, interleukin; IRS, insulin receptor substrate; p50/p65, NF-kB
subunits; PI3K, phosphatidylinositol 3-kinase; pS, phosphorylated serine; pY, phosphorylated tyrosine; TNF-a, tumor
necrosis factor a.

184 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
has also been associated with an increase in the levels of phosphorylated ribosomal protein S6
kinase 1 (S6K1), a downstream kinase of mammalian target of rapamycin (mTOR) that
attenuates the insulin signaling pathway by phosphorylating IRS-1 at serine residues [38].
Oleic acid does not affect the phosphorylation of S6K1 and co-incubation of palmitic acid-
exposed myotubes with oleic acid prevents the increase caused by the SFA. In another study in
human and mouse hepatocytes, oleic acid protected against the deleterious effects of palmitic
acid on ER stress, apoptosis, and the insulin signaling pathway by preventing S6K1 activation
[39]. In a similar way, co-incubation of palmitic acid-exposed b cells with oleic acid protects the
cells by activating prosurvival pathways of the ER stress response involved in protein folding
and antioxidative defense [40].

Tribbles 3 (TRB3) is a pseudokinase, which contains a kinase domain without enzymatic

activity, and is responsible for strikingly different metabolic functions depending on the tissue
studied. In the liver TRB3 binds to Akt and inhibits its activity, leading to impaired insulin
signaling [41]. In hepatocytes TRB3 upregulation occurs through palmitic acid-induced ER
stress and the increased levels of this protein are sufficient to modulate FA-induced insulin
resistance [42]. Oleic acid does not increase TRB3 levels and co-incubation of palmitic acid-
exposed cells with oleic acid prevents the increase in the levels of this protein.

Mitochondria are a major producer of ROS and exposure of skeletal muscle cells to palmitic
acid causes a significant increase of mitochondrial ROS production and concomitant mito-
chondrial DNA damage and dysfunction, induction of JNK, apoptosis, and inhibition of insulin
signaling [43]. By contrast, supplementation with oleic acid reduces ROS generation and
protects the mitochondria from palmitic acid-induced oxidative stress, apoptosis, and attenu-
ation of insulin signaling [43,44].

Oleic Acid-Mediated Mechanisms That Prevent Palmitic Acid-Induced

Inflammation
Interleukin (IL)-1b is a potent cytokine that plays a key role in inflammation and insulin resistance
[45]. Lack of IL-1b signaling results in improved insulin sensitivity in high-fat diet (HFD)-fed mice
[46]. The release of this potent cytokine requires two steps (Figure 4). First, activation of the TLR4–
NF-kB pathway by palmitic acid leads to the production of pro-IL-1b. Second, the NLRP3
inflammasome generates mature IL-1b through caspase-1-dependent processing activated
by several molecules, including ATP. It should be noted that substitution of SFA by an oleic
acid-enriched diet in HFD-fed mice results in improved insulin sensitivity, reduced pro-IL-1b levels
and adipose IL-1b secretion, and sustained adipose AMPK activation [47]. Furthermore, oleic acid
prevents ATP-induced IL-1b secretion from LPS- and palmitic acid-exposed macrophages
through an AMPK-dependent mechanism. The findings of this study indicate that sustained
activation of AMPK by oleic acid disrupts NLRP3 inflammasome activation, reducing the proc-
essing of IL-1b and the attenuation of insulin signaling caused by this cytokine.

Several factors can increase the diabetogenic effect of visceral adipose tissue, including
increased production of adipokines, which can impair insulin sensitivity. This production of
cytokines is enhanced by the infiltration of macrophages into visceral adipose tissue [48].
Macrophages undergo specific differentiation depending on the local tissue environment, to
fulfill their functionally distinct roles, and are capable of polarizing toward different phenotypes,
which include the classical (proinflammatory, M1) and alternative (anti-inflammatory, M2)
activation states. In obesity, adipose tissue M1 macrophage numbers increase and are
correlated with adipose tissue inflammation and insulin resistance, whereas in lean humans
and mice M2 macrophages predominate [49].

Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 185
 Oleic acid Palmic acid
Oleic acid
IL-6 IL-10
FFAR4/GPR120 TNF-α Adiponecn
Palmic acid NLRP3
IL-1β
Insulin M2 genes
An-inflammatory
TLR4 β-Arresn
CD14 effects
AdipoR1/R2
MYD88 M2-like macrophage
Ceramide pY pY
an-inflammatory
NLRP3 AMPK insulin sensivity

Caspase-1 IRS
pY
pro-IL-1β Insulin PTP1B
IL1β
resistance
PI3K
PIP2 PIP3
PTEN
LTB4
p
Akt
NF-κB p50 p65 pro-IL-1β

Glucose
Nucleus GLUT4

Figure 4. Oleic Acid Prevents Palmitic Acid-Induced Inflammation. Oleic acid elicits anti-inflammatory effects by
reducing the levels of cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)-a] while increasing the levels of the anti-
inflammatory cytokine IL-10 and adiponectin. These effects of oleic acid might be mediated by free fatty acid receptor 4/G
protein-coupled receptor 120 (FFAR4/GPR120). The increase in the levels of adiponectin caused by oleic acid can activate
AMP-activated protein kinase (AMPK) and reduce the levels of palmitic acid-induced ceramide synthesis. By preventing
the reduction in AMPK caused by palmitic acid, oleic acid can inhibit the increase in IL-1b caused by the saturated fatty
acid (SFA) through the nod-like receptor containing a pyrin domain (NLRP3) inflammasome in adipocytes and macro-
phages that infiltrate adipose tissue. Oleic acid might also favor the polarization of adipose tissue-infiltrating macrophages
to the M2 anti-inflammatory phenotype. Oleic acid induces polarization of macrophages to the M2 anti-inflammatory
phenotype, reducing the secretion of leukotriene B4 (LTB4), which in turn decreases the activity of the phosphatases
phosphatase and tensin homolog (PTEN) and protein tyrosine phosphatase (PTP)1B, thereby enhancing insulin sensitivity.
Abbreviations: Akt, mammalian homolog of retroviral oncogene v or protein kinase B; IRS: insulin receptor substrate; NF-
kB: nuclear factor-kB; PIP2, phosphatidylinositol 2-phosphate; PIP3, phosphatidylinositol 3-phosphate; PI3K, phospha-
tidylinositol 3-kinase; pY, phosphorylated tyrosine; p50/p65, NF-kB subunits;TLR4, Toll-like receptor 4.

The effects of different FAs have been evaluated in mature visceral adipocytes from non-obese
and morbidly obese subjects [50]. Palmitic acid shows a direct inflammatory effect in adipo-
cytes from non-obese subjects, increasing the expression of the proinflammatory cytokines
tumor necrosis factor (TNF)-a and IL-6 and decreasing the mRNA levels of the anti-inflamma-
tory cytokine IL-10 and adiponectin – the most abundant peptide secreted by adipocytes,
reduction of which plays a central role in insulin resistance/T2DM. These proinflammatory
effects of palmitic acid are more pronounced in adipocytes from morbidly obese patients. By
contrast, oleic acid decreases the expression of proinflammatory cytokines and causes a
pronounced increase in IL-10 and adiponectin expression in adipocytes from non-obese
patients (Figure 4). Interestingly, adiponectin increases cellular ceramidase activity, which
catalyzes ceramide degradation and activates AMPK, which in turn can activate FA oxidation
[51]. The anti-inflammatory effect of oleic acid was abolished by knocking down the expression
of FFAR4/GPR120, a receptor with anti-inflammatory effects that is activated by long-chain

186 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
FAs, mainly n-3 PUFA, but also by oleic acid [52]. It is noteworthy that the proinflammatory
effect of palmitic acid was also reversed by silencing FFAR4/GPR120, although no explanation
was provided for this finding. Interestingly, the anti-inflammatory effect of oleic acid was not
observed in adipocytes from morbidly obese subjects [50]. This might be a consequence of the
reported reduced expression of FFAR4/GPR120 in the visceral adipose tissue of morbidly
obese patients [53]. Consistent with FFAR4/GPR120 playing a role in the mediation of the
effects of oleic acid, an oleic acid-enriched diet improved whole-body insulin resistance in an
animal model of diet-induced obesity by reducing inflammation in adipose tissue, liver, and
skeletal muscle, decreasing macrophage infiltration, and increasing IL-10 levels, and all of these
effects were abolished by FFAR4/GPR120 knockdown [54]. Additionally, oleic acid increases
M2 macrophage markers in mesenteric adipose tissue, suggesting that this MUFA induces M2
macrophage polarization [55].

Oleic and palmitic acid also elicit opposite effects on macrophages/Kupffer cells and hep-
atocytes [56]. A conditioned medium from macrophages stimulated with palmitic acid induces
ER stress and inflammatory signaling that impairs insulin signaling in mouse hepatocytes. By
contrast, oleic acid-stimulated macrophages result in M2 polarization and the conditioned
medium from these cells enhances insulin sensitivity in hepatocytes. This is due to a reduction in
the levels of leukotriene B4, which in turn leads to a reduction in hepatocytes of both protein
tyrosine phosphatase 1B (PTP1B), and phosphatase and tensin homolog (PTEN), two phos-
phatases that negatively modulate insulin receptors and Akt, respectively. Oleic acid also
upregulates miRNA-21, inducing PTEN degradation, whereas palmitic acid has no effect [57].
Moreover, oleic acid increases the expression of PPARb/d in human hepatocytes via a FFAR1/
GPR40-mediated and calcium-dependent mechanism. The increase in PPARb/d caused by
oleic acid then negatively regulates PTEN and thereby increases insulin sensitivity [58].

Attenuation of insulin-induced tyrosine phosphorylation and methylation of the catalytic subunit

of PP2A are involved in the activation of this enzyme by palmitic acid and ultimately result in the
repression of Akt activation/phosphorylation. In rat and human skeletal myotubes, the effect of
palmitic acid on PP2A is antagonized by oleic acid through increased tyrosine phosphorylation
and demethylation of the catalytic subunit of PP2A [59], which results in the repression of the
phosphatase activity of this enzyme.

Additional Antidiabetic Effects of Oleic Acid

Part of the effects resulting from dietary intake of oleic acid may be mediated by its derived
endogenous lipid mediator oleoylethanolamide (OEA). Dietary intake of oleic acid elevates the
levels of OEA by increasing substrate availability for its biosynthesis from membrane glycer-
ophospholipids [60]. Interestingly, OEA decreases food intake and body weight gain through
PPARa activation. The reduction in body weight caused by OEA has been attributed to its
anorectic activity as well as to its capacity to increase lipolysis in adipocytes and the subse-
quent stimulation of FA oxidation in skeletal muscle [60]. Additionally, oleic acid ingestion
stimulates OEA mobilization into the mucosal cells of the gut, which activates a PPARa-
mediated signal that travels through the afferent vagus nerve to the hypothalamus, where it
increases satiety [61].

Dietary fat is known to stimulate the release by intestinal L-cells of glucagon-like peptide 1
(GLP-1), which in turn increases GSIS, among other physiological effects. The release of GLP-
1 by dietary fat is mediated by NEFA through FFAR1/GPR40. In addition, oleic acid can induce
GLP-1 secretion in vivo via PKCz [62]. Meanwhile, GPR119 is an antidiabetic target expressed
in b cells and in incretin-secreting enteroendocrine cells in the intestine [63]. Activation of

Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 187
GPR119 can increase insulin secretion directly by acting at the level of the b cell or indirectly by Outstanding Questions
increasing circulating levels of GLP-1 released from intestinal L cells. Of all of the endogenous Which oleic acid-activated molecular
GPR119 agonists, OEA is the more potent [63]. There are three additional oleic acid derivatives mechanism is the most important for
preventing palmitic acid-induced insu-
that are GPR119 agonists [63]. However, there are conflicting reports regarding whether these lin resistance?
compounds are responsible for fat-induced GPR119 activation and GLP-1 release [63]. OEA
can also elicit a powerful cytoprotective effect on palmitic acid-exposed rat b cells. However, Are the molecular mechanisms acti-
this effect is not mediated by GPR119, since OEA was internalized and subjected to hydrolysis vated by oleic acid reported in preclini-
cal models also observed in humans?
by FA amide hydrolase (FAAH) to release free oleic acid, which in turn mediated cytoprotection
[64].
How much does OEA contribute to the
effects of oleic acid? Are the effects of
Some of the effects of oleic acid might also be mediated by its effects on the hypothalamus, a OEA on the release of GLP-1 mediated
region that regulates energy homeostasis. The hypothalamus matches energy intake to energy by GPR119 activation or are other
molecular mechanisms involved?
expenditure to prevent obesity through satiety (leptin) and hormonal (insulin) signals. In addition,
the hypothalamus interacts with the liver through the vagus nerve. On sensing FA the hypo-
Could an oleic acid-enriched diet be
thalamus lowers food intake and glucose production [65]. For instance, central oleic infusion considered a non-pharmacological
inhibits glucose production and food intake [66]. Exposure to palmitic acid, but not oleic acid, treatment to increase AMPK activity
by oral gavage or direct infusion results in PKCu activation in the hypothalamus, which was in humans, especially in populations
with low consumption of this MUFA?
associated with impaired hypothalamic insulin and leptin signaling [67]. In humans increased
levels of oleic acid in cerebrospinal fluid were associated with improved glucose tolerance [68].
What is the contribution of oleic acid
consumption to the beneficial effects
Cardiovascular disease is a major cause of morbidity and mortality in T2DM patients and the of the Mediterranean diet on the pre-
presence in these patients of atherogenic dyslipidemia is among the major factors contrib- vention of insulin resistance and
T2DM?
uting to increased cardiovascular risk. It is now generally accepted that the various components
of atherogenic dyslipidemia are closely linked and are initiated by insulin resistance through
overproduction of TAG-rich very-low-density lipoproteins (VLDLs) [69]. Interestingly, infusion of
oleic acid in the hypothalamus of rats activates a neuronal network that suppresses VLDL-TAG
secretion in the liver [70]. Oleic acid also shows a beneficial effect at the cardiovascular level
compared with palmitic acid [71].

Concluding Remarks and Future Perspectives

There is compelling evidence that insulin resistance and T2DM can be prevented or their onset
delayed by lifestyle interventions and it is critical to promote changes in diet that reduce the
incidence of T2DM [72]. It is now well accepted that the total amount of fat intake has an impact
on insulin sensitivity only if it exceeds 37% of total energy intake [4]. However, below this value a
critical factor in the induction of insulin resistance is not the total amount of fat but its FA
composition [4]. Insights gained from preclinical studies have shown that substitution of part of
the palmitic acid by oleic acid strongly attenuates the deleterious effects of the SFA on adipose
tissue, skeletal muscle, liver, and b cells. Consistent with this, substituting dietary SFA for a
high-oleic-acid diet enhances insulin sensitivity in humans [4]. Several mechanisms account for
the protective effects of oleic acid with respect to T2DM. However, the studies have some
limitations and many questions remain regarding the effects of oleic acid on humans (see
Outstanding Questions). Interestingly, oleic acid activates or prevents the reduction in AMPK
activity caused by palmitic acid. AMPK is a recognized therapeutic target for T2DM [37] and is
the main target activated by metformin, the most commonly prescribed drug for T2DM in the
world [37]. Some studies have demonstrated that oleic acid and metformin have similar
protective effects, both preventing the deleterious effects of palmitic acid [38]; this suggests
that oleic acid might have some metformin-like effects. Current and future studies should
elucidate the mechanisms responsible for the protective effects of oleic acid against T2DM
development in humans.

188 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
Acknowledgments
The authors apologize to contributors to this field of research whose work is not cited here owing to space restrictions.
Funding for this work came from the Ministerio de Economía y Competitividad of the Spanish Government (SAF2015-
64146-R) and from CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). CIBERDEM is an initiative of
the Instituto de Salud Carlos III (ISCIII) – Ministerio de Economía y Competitividad. The authors thank the University of
Barcelona’s Language Advisory Service for revising the manuscript.
References
1. Samuel, V.T. and Shulman, G.I. (2016) The pathogenesis of
insulin resistance: integrating signaling pathways and substrate
flux. J. Clin. Invest. 126, 12–22
2. Biden, T.J. et al. (2014) Lipotoxic endoplasmic reticulum stress, b
cell failure, and type 2 diabetes mellitus. Trends Endocrinol.
Metab. 25, 389–398
3. Staiger, H. et al. (2004) Palmitate-induced interleukin-6 expres-
sion in human coronary artery endothelial cells. Diabetes 53,
3209–3216
4. Vessby, B. et al. (2001) Substituting dietary saturated for mono-
unsaturated fat impairs insulin sensitivity in healthy men and
women: The KANWU Study. Diabetologia 44, 312–319
5. Martínez-González, M.A. et al. (2014) Prevention of diabetes with
Mediterranean diets. Ann. Intern. Med. 161, 157–15
6. Listenberger, L.L. et al. (2003) Triglyceride accumulation protects
against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci.
U. S. A. 100, 3077–3082
7. Ertunc, M.E. and Hotamisligil, G.S. (2016) Lipid signaling and
lipotoxicity in metaflammation: indications for metabolic disease
pathogenesis and treatment. J. Lipid Res. 57, 2099–2114
8. Bergman, B.C. et al. (2012) Localisation and composition of
skeletal muscle diacylglycerol predicts insulin resistance in
humans. Diabetologia 55, 1140–1150
9. Chaurasia, B. and Summers, S.A. (2015) Ceramides – lipotoxic
inducers of metabolic disorders. Trends Endocrinol. Metab. 26,
538–550
10. Salvadó, L. et al. (2015) Targeting endoplasmic reticulum stress in
insulin resistance. Trends Endocrinol. Metab. 26, 438–448
11. Gonzalez-Franquesa, A. and Patti, M.E. (2017) Insulin resistance
and mitochondrial dysfunction. Adv. Exp. Med. Biol. 982,
465–520
12. Tumova, J. et al. (2016) Excess of free fatty acids as a cause of
metabolic dysfunction in skeletal muscle. Physiol. Res. 65,
193–207
13. Kim, Y.W. et al. (2012) Inhibition of fatty acid translocase cluster
determinant 36 (CD36), stimulated by hyperglycemia, prevents
glucotoxicity in INS-1 cells. Biochem. Biophys. Res. Commun.
420, 462–466
14. Velloso, L.A. et al. (2015) TLR4 at the crossroads of nutrients, gut
microbiota, and metabolic inflammation. Endocr. Rev. 36,
245–271
15. Cani, P.D. et al. (2007) Metabolic endotoxemia initiates obesity
and insulin resistance. Diabetes 56, 1761–1772
16. Nakamura, T. et al. (2010) Double-stranded RNA-dependent
protein kinase links pathogen sensing with stress and metabolic
homeostasis. Cell 140, 338–348
17. Youssef, O.A. et al. (2015) Potential role for snoRNAs in PKR
activation during metabolic stress. Proc. Natl. Acad. Sci. U. S. A.
112, 5023–5028
18. Guasch-Ferré, M. et al. (2015) Olive oil consumption and risk of
type 2 diabetes in US women. Am. J. Clin. Nutr. 102, 479–486
19. Kien, C.L. et al. (2013) A lipidomics analysis of the relationship
between dietary fatty acid composition and insulin sensitivity in
young adults. Diabetes 62, 1054–1063
20. DeFronzo, R.A. et al. (1985) Effects of insulin on peripheral and
splanchnic glucose metabolism in noninsulin-dependent (type II)
diabetes mellitus. J. Clin. Invest. 76, 149–155
21. Erion, D.M. and Shulman, G.I. (2010) Diacylglycerol-mediated
insulin resistance. Nat. Med. 16, 400–402
22. Coll, T. et al. (2008) Oleate reverses palmitate-induced insulin
resistance and inflammation in skeletal muscle cells. J. Biol.
Chem. 283, 11107–11116
23. Peng, G. et al. (2001) Oleate blocks palmitate-induced abnormal
lipid distribution, endoplasmic reticulum expansion and stress,
and insulin resistance in skeletal muscle. Endocrinology 152,
2206–2218
24. Villena, J.A. (2015) New insights into PGC-1 coactivators: rede-
fining their role in the regulation of mitochondrial function and
beyond. FEBS J. 282, 647–672
25. Cantó, C. et al. (2009) AMPK regulates energy expenditure by
modulating NAD metabolism and SIRT1 activity. Nature 458,
1056–1060
26. Lim, J.H. et al. (2013) Oleic acid stimulates complete oxidation of
fatty acids through protein kinase A-dependent activation of
SIRT1–PGC1a complex. J. Biol. Chem. 288, 7117–7126
27. Henique, C. et al. (2010) Increased mitochondrial fatty acid oxi-
dation is sufficient to protect skeletal muscle cells from palmitate-
induced apoptosis. J. Biol. Chem. 285, 36818–36827
28. Hu, W. (2011) Differential regulation of dihydroceramide desatur-
ase by palmitate versus monounsaturated fatty acids: implica-
tions for insulin resistance. J. Biol. Chem. 286, 16596–16605
29. Ricchi, M. et al. (2009) Differential effect of oleic and palmitic acid
on lipid accumulation and apoptosis in cultured hepatocytes. J.
Gastroenterol. Hepatol. 24, 830–840
30. Mei, S. et al. (2011) Differential roles of unsaturated and saturated
fatty acids on autophagy and apoptosis in hepatocytes. J. Phar-
macol. Exp. Ther. 339, 487–498
31. Kristinsson, H. et al. (2015) Free fatty acid receptor 1 (FFAR1/
GPR40) signaling affects insulin secretion by enhancing mito-
chondrial respiration during palmitate exposure. Biochim. Bio-
phys. Acta 1853, 3248–3257
32. Thorn, K. and Bergsten, P. (2010) Fatty acid-induced oxidation
and triglyceride formation is higher in insulin producing MIN6 cells
exposed to oleate compared to palmitate. J. Cell. Biochem. 111,
497–507
33. Manukyan, L. et al. (2015) Palmitate-induced impairments of
b-cell function are linked with generation of specific ceramide
species via acylation of sphingosine. Endocrinology 156,
802–812
34. Sommerweiss, D. et al. (2013) Oleate rescues INS-1E b-cells
from palmitate-induced apoptosis by preventing activation of the
unfolded protein response. Biochem. Biophys. Res. Commun.
441, 770–776
35. Ravnskjaer, K. et al. (2010) PPARd is a fatty acid sensor that
enhances mitochondrial oxidation in insulin-secreting cells and
protects against fatty acid-induced dysfunction. J. Lipid Res. 51,
1370–1379
36. Salvadó, L. et al. (2013) Oleate prevents saturated-fatty-acid-
induced ER stress, inflammation and insulin resistance in skeletal
muscle cells through an AMPK-dependent mechanism. Diabe-
tologia 56, 1372–1382
37. Day, E.A. et al. (2017) AMPK as a therapeutic target for treating
metabolic diseases. Trends Endocrinol. Metab. 28, 545–560
38. Kwon, B. and Querfurth, H.W. (2015) Palmitate activates mTOR/
p70S6K through AMPK inhibition and hypophosphorylation of
Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3 189
 raptor in skeletal muscle cells: reversal by oleate is similar to
metformin. Biochimie 118, 141–150
39. Pardo, V. et al. (2015) Role of hepatocyte S6K1 in palmitic acid-
induced endoplasmic reticulum stress, lipotoxicity, insulin resis-
tance and in oleic acid-induced protection. Food Chem. Toxicol.
80, 298–309
40. Sargsyan, E. et al. (2016) Oleate protects beta-cells from the toxic
effect of palmitate by activating pro-survival pathways of the ER
stress response. Biochim. Biophys. Acta 1861, 1151–1160
41. Du, K. et al. (2003) TRB3: a tribbles homolog that inhibits Akt/PKB
activation by insulin in liver. Science 300, 1574–1577
42. Geng, T. et al. (2013) Fatty acids differentially regulate insulin
resistance through endoplasm reticulum stress-mediated induc-
tion of tribbles homologue 3: a potential link between dietary fat
composition and the pathophysiological outcomes of obesity.
Diabetologia 56, 2078–2087
43. Yuzefovych, L. et al. (2010) Different effects of oleate vs. palmitate
on mitochondrial function, apoptosis, and insulin signaling in L6
skeletal muscle cells: role of oxidative stress. Am. J. Physiol.
Endocrinol. Metab. 299, E1096–E1105
44. Nakamura, S. et al. (2009) Palmitate induces insulin resistance in
H4IIEC3 hepatocytes through reactive oxygen species produced
by mitochondria. J. Biol. Chem. 284, 14809–14818
45. Osborn, O. and Olefsky, J.M. (2012) The cellular and signaling
networks linking the immune system and metabolism in disease.
Nat. Med. 18, 363–374
46. McGillicuddy, F.C. et al. (2011) Lack of interleukin-1 receptor I (IL-
1RI) protects mice from high-fat diet-induced adipose tissue
inflammation coincident with improved glucose homeostasis.
Diabetes 60, 1688–1698
47. Finucane, O.M. et al. (2015) Monounsaturated fatty acid-enriched
high-fat diets impede adipose NLRP3 inflammasome-mediated
IL-1b secretion and insulin resistance despite obesity. Diabetes
64, 2116–2128
48. Bai, Y. and Sun, Q. (2015) Macrophage recruitment in obese
adipose tissue. Obes. Rev. 16, 127–136
49. Kraakman, M.J. et al. (2014) Macrophage polarization in obesity
and type 2 diabetes: weighing down our understanding of mac-
rophage function? Front. Immunol. 5, 470
50. Rodriguez-Pacheco, F. et al. (2017) The pro-/anti-inflammatory
effects of different fatty acids on visceral adipocytes are partially
mediated by GPR120. Eur. J. Nutr. 56, 1743–1752
51. Holland, W.L. et al. (2011) Receptor-mediated activation of
ceramidase activity initiates the pleiotropic actions of adiponectin.
Nat. Med. 17, 55–63
52. Ulven, T. and Christiansen, E. (2015) Dietary fatty acids and their
potential for controlling metabolic diseases through activation of
FFA4/GPR120. Annu. Rev. Nutr. 35, 239–263
53. Rodriguez-Pacheco, F. et al. (2014) Effects of obesity/fatty acids
on the expression of GPR120. Mol. Nutr. Food Res. 58,
1852–1860
54. Oliveira, V. et al. (2015) Containing a-linolenic (v3) or oleic (v9)
fatty acids rescues obese mice from insulin resistance. Endocri-
nology 156, 4033–4046
190 Trends in Endocrinology & Metabolism, March 2018, Vol. 29, No. 3
55. Camell, C. and Smith, C.W. (2013) Dietary oleic acid increases
M2 macrophages in the mesenteric adipose tissue. PLoS One 8,
e75147
56. Pardo, V. et al. (2015) Opposite cross-talk by oleate and palmitate
on insulin signaling in hepatocytes through macrophage activa-
tion. J. Biol. Chem. 290, 11663–11677
57. Vinciguerra, M. et al. (2009) Unsaturated fatty acids inhibit the
expression of tumor suppressor phosphatase and tensin
homolog (PTEN) via microRNA-21 up-regulation in hepatocytes.
Hepatology 49, 1176–1184
58. Wu, H.T. et al. (2012) Oleic acid activates peroxisome proliferator-
activated receptor d to compensate insulin resistance in steatotic
cells. J. Nutr. Biochem. 23, 1264–1270
59. Nardi, F. et al. (2014) Enhanced insulin sensitivity associated with
provision of mono and polyunsaturated fatty acids in skeletal
muscle cells involves counter modulation of PP2A. PLoS One
9, e92255
60. Bowen, K.J. et al. (2017) Oleic acid-derived oleoylethanolamide: a
nutritional science perspective. Prog. Lipid Res. 67, 1–15
61. Piomelli, D. (2013) A fatty gut feeling. Trends Endocrinol. Metab.
24, 332–341
62. Iakoubov, R. et al. (2011) Essential role for protein kinase Cz in
oleic acid-induced glucagon-like peptide-1 secretion in vivo in the
rat. Endocrinology 152, 1244–1252
63. Hansen, H.S. et al. (2012) GPR119 as a fat sensor. Trends
Pharmacol. Sci. 33, 374–381
64. Stone, V.M. et al. (2012) The cytoprotective effects of oleoyle-
thanolamide in insulin-secreting cells do not require activation of
GPR119. Br. J. Pharmacol. 165, 2758–2770
65. Jessica, T.Y. et al. (2012) Lipid sensing and insulin resistance in
the brain. Cell Metab. 15, 646–655
66. Obici, S. et al. (2002) Central administration of oleic acid inhibits
glucose production and food intake. Diabetes 51, 271–275
67. Benoit, S.C. et al. (2009) Palmitic acid mediates hypothalamic
insulin resistance by altering PKC-u subcellular localization in
rodents. J. Clin. Invest. 119, 2577–2589
68. Jumpertz, R. et al. (2012) Associations of fatty acids in cerebro-
spinal fluid with peripheral glucose concentrations and energy
metabolism. PLoS One 7, e41503
69. Xiao, C. et al. (2016) Pharmacological targeting of the atherogenic
dyslipidemia complex: the next frontier in CVD prevention beyond
lowering LDL cholesterol. Diabetes 65, 1767–1778
70. Yue, J.T. et al. (2015) A fatty acid-dependent hypothalamic–DVC
neurocircuitry that regulates hepatic secretion of triglyceride-rich
lipoproteins. Nat. Commun. 6, 5970
71. Perdomo, L. et al. (2015) Protective role of oleic acid against
cardiovascular insulin resistance and in the early and late cellular
atherosclerotic process. Cardiovasc. Diabetol. 14, 75
72. Salas-Salvadó, J. et al. (2011) The role of diet in the prevention of
type 2 diabetes. Nutr. Metab. Cardiovasc. Dis. 21 (Suppl. 2),
B32–B48
73. Vannice, G. and Rasmussen, H. (2014) Position of the Academy
of Nutrition and Dietetics: dietary fatty acids for healthy adults.
J. Acad. Nutr. Diet 114, 136–153