Decreased Metabolic Flexibility in Skeletal Muscle of Rat Fed with a High-Fat Diet Is Recovered by Individual CLA Isomer Supplementation via Converging Protective Mechanisms

Abstract

Energy balance, mitochondrial dysfunction, obesity, and insulin resistance are disrupted by metabolic inflexibility while therapeutic interventions are associated with improved glucose/lipid metabolism in skeletal muscle. Conjugated linoleic acid mixture (CLA) exhibited anti-obesity and anti-diabetic effects; however, the modulatory ability of its isomers (cis9, trans11, C9; trans10, cis12, C10) on the metabolic flexibility in skeletal muscle remains to be demonstrated. Metabolic inflexibility was induced in rat by four weeks of feeding with a high-fat diet (HFD). At the end of this period, the beneficial effects of C9 or C10 on body lipid content, energy expenditure, pro-inflammatory cytokines, glucose metabolism, and mitochondrial efficiency were examined. Moreover, oxidative stress markers, fatty acids, palmitoyletanolamide (PEA), and oleyletanolamide (OEA) contents along with peroxisome proliferator-activated receptors-alpha (PPARα), AKT, and adenosine monophosphate-activated protein kinase (AMPK) expression were evaluated in skeletal muscle to investigate the underlying biochemical mechanisms. The presented results indicate that C9 intake reduced mitochondrial efficiency and oxidative stress and increased PEA and OEA levels more efficiently than C10 while the anti-inflammatory activity of C10, and its regulatory efficacy on glucose homeostasis are associated with modulation of the PPARα/AMPK/pAKT signaling pathway. Our results support the idea that the dissimilar efficacy of C9 and C10 against the HFD-induced metabolic inflexibility may be consequential to their ability to activate different molecular pathways.

Conjugated Linoleic Acid and Brain Metabolism: A Possible Anti-Neuroinflammatory Role Mediated by PPARα Activation

“…Several data suggest that also in the brain some of the effects exerted by CLA can be ascribed to its activation of PPARα. In fact, we have previously shown that PPARα activation by synthetic agonists increased PEA and OEA biosynthesis, as we also showed in liver and muscle in vivo ( Melis et al, 2013a ; Trinchese et al, 2018 ; Trinchese et al, 2020 ).…”

“…OEA reduces food intake and body weight gain in obese rats ( Fu et al, 2005 ), stimulates lipolysis and FA oxidation ( Guzman et al, 2004 ), reduces the content of triacylglycerol (TAG) in both the liver and adipose tissue ( Guzman et al, 2004 ). All of these properties may be attributed to CLA ability to activate specific receptors such as peroxisome proliferator-activated receptors (PPAR) α, β/δ and AMP-activated protein kinase (AMPK) ( Trinchese et al, 2020 ). Despite the high brain expression of PPARβ and its possible role in regulating the metabolism of FAs and/or cholesterol, in inflammation processes and antioxidant mechanisms brain ( Hall et al, 2008 ), very little is known nowadays about how CLA regulates this nuclear receptor in the healthy and diseased brain.…”

Interplay between Peripheral and Central Inflammation in Obesity-Promoted Disorders: The Impact on Synaptic Mitochondrial Functions

“…AMPK modulates cell metabolism based on the availability of nutrients and their capacity to produce ATP through mitochondrial oxidative phosphorylation. Chronic low-grade inflammation induced by obesity reduces AMPK activity in multiple tissues including skeletal muscle [ 18 , 19 , 20 ], liver [ 21 , 22 , 23 ] and adipose tissue [ 23 , 24 ], with a mechanism still partly unknown but probably involving altered mitochondrial fatty acid oxidation.…”

“…Thus, altered mitochondrial functions are part of the wide spectrum of metabolic changes induced by overnutrition-dependent low-grade inflammation [ 18 , 21 ]. In particular, mitochondrial dysfunction in liver and skeletal muscle leads to reduced FAs oxidation, impaired glucose homeostasis, increased ectopic lipid accumulation and decreased insulin sensitivity [ 15 , 19 ]. This is a hallmark of IR and type 2 diabetes [ 27 , 28 , 29 , 30 , 31 ].…”

“…Thus, AMPK can be hypothesized as a potential target for treating metabolic dysfunctions, including diabetes, obesity and fatty liver diseases, and cancer, which is often associated with changes in metabolism. Indeed, several results show that the activation of AMPK, by appropriate diet supplementation, reduces obesity and IR [ 18 , 19 , 41 ] ( Figure 2 ).…”