Some of the effects of oleic acid are mediated by preventing the reduction in palmitic acid-mediated AMPK activity, resembling the action of metformin.

The hypothalamus also senses oleic acid, where it activates a neuronal network that suppresses VLDL-TAG secretion in liver.

Preclinical studies have shed light on the molecular mechanisms by which oleic acid prevents palmitic acid-induced inflammation and insulin resistance in adipose tissue, liver, skeletal muscle, and pancreas.

Substituting SFAs by oleic acid in the diet improves insulin sensitivity in humans.

Increased plasma non-esterified fatty acids (NEFAs) link obesity with insulin resistance and type 2 diabetes mellitus (T2DM). However, in contrast to the saturated FA (SFA) palmitic acid, the monounsaturated FA (MUFA) oleic acid elicits beneficial effects on insulin sensitivity, and the dietary palmitic acid:oleic acid ratio impacts diabetes risk in humans. Here we review recent mechanistic insights into the beneficial effects of oleic acid compared with palmitic acid on insulin resistance and T2DM, including its anti-inflammatory actions, and its capacity to inhibit endoplasmic reticulum (ER) stress, prevent attenuation of the insulin signaling pathway, and improve β cell survival. Understanding the molecular mechanisms of the antidiabetic effects of oleic acid may contribute to understanding the benefits of this FA in the prevention or delay of T2DM.

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Position of the Academy of Nutrition and Dietetics: dietary fatty acids for healthy adults.

The role of diet in the prevention of type 2 diabetes.

Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process.

Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol.

Associations of fatty acids in cerebrospinal fluid with peripheral glucose concentrations and energy metabolism.

The cytoprotective effects of oleoylethanolamide in insulin-secreting cells do not require activation of GPR119.

Essential role for protein kinase Cζ in oleic acid-induced glucagon-like peptide-1 secretion in vivo in the rat.

Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A.

Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes.

Opposite cross-talk by oleate and palmitate on insulin signaling in hepatocytes through macrophage activation.

Effects of obesity/fatty acids on the expression of GPR120.

Dietary fatty acids and their potential for controlling metabolic diseases through activation of FFA4/GPR120.

The pro-/anti-inflammatory effects of different fatty acids on visceral adipocytes are partially mediated by GPR120.

Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function?.

The cellular and signaling networks linking the immune system and metabolism in disease.

Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress.

Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity.

Oleate protects beta-cells from the toxic effect of palmitate by activating pro-survival pathways of the ER stress response.

Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection.

Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: reversal by oleate is similar to metformin.

Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism.

PPARδ is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction.

Oleate rescues INS-1E β-cells from palmitate-induced apoptosis by preventing activation of the unfolded protein response.

Palmitate-induced impairments of β-cell function are linked with generation of specific ceramide species via acylation of sphingosine.

Fatty acid-induced oxidation and triglyceride formation is higher in insulin producing MIN6 cells exposed to oleate compared to palmitate.

Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes.

Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes.

New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond.

Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.

A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults.

Olive oil consumption and risk of type 2 diabetes in US women.

TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation.

Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle.

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment.

Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study.

Glossary

the presence of high levels of triglycerides, small-dense low-density lipoprotein, and low levels of high-density lipoprotein cholesterol. It is often observed in patients with metabolic syndrome, obesity, insulin resistance, and T2DM.

a small protein secreted by cells that has a specific effect on the interactions and communication between cells.

the result of any stimulus that provokes the accumulation of misfolded proteins in the lumen of the ER; triggers the unfolded protein response (UPR), an adaptive (defensive) ER stress response that involves the activation of a signaling pathway to restore folding capacity. If ER homeostasis is not restored, apoptosis is induced.

a gut peptide secreted by endocrine L cells of the ileum that suppresses glucagon secretion and stimulates glucose-dependent insulin secretion.

when excess lipids are driven into an alternative non-oxidative pathway that promotes programmed cell death.

when excess lipids in non-adipose tissues are driven into an alternative non-oxidative pathway that promotes metabolically relevant cellular dysfunction.

obesity-induced inflammation that differs from inflammation in classical immunity through being low grade and producing much lower levels of circulating cytokines. It is also considered chronic inflammation because a relatively long duration of treatment with a high-fat diet is required (>8 weeks in animal models) before inflammation is observed in adipose tissue. Obesity-induced inflammation is the result of exposure to an excess of nutrients, resulting in adipocyte hypertrophy, macrophage infiltration and polarization, and activation of inflammatory pathways.

to fulfill their functionally distinct roles, macrophages are capable of polarizing toward different phenotypes, which include classical (proinflammatory, M1) and alternative (anti-inflammatory, M2) activation states.

the first-line drug prescribed following the diagnosis of T2DM in the absence of contraindications such as severe renal or hepatic insufficiency; one of the few oral drugs for T2DM that promotes weight loss rather than weight gain.

loss of efficiency in the electron transport chain and reductions in the synthesis of high-energy molecules such as ATP; characteristic of aging, and essentially of all chronic diseases.

FA released from triglycerides by the action of the enzyme lipase and transported in the blood bound to albumin.