Obesity develops through progressive metabolic alterations that arise long before overt disease, highlighting the need for pharmacological strategies capable of targeting the earliest tissue adaptations to fat nutrient excess. Skeletal muscle plays a central role in systemic metabolic homeostasis and is among the first organs affected by high-fat diet (HFD) exposure. Oleoylethanolamide (OEA), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, exerts broad metabolic actions in obesity, yet its impact on early skeletal muscle remodeling remains unknown. We investigated whether OEA could intercept the initial metabolic adaptations induced by HFD exposure in young rats. Male rats were exposed to HFD for seven weeks and treated with OEA (10mg/kg, i.p.) during the final two weeks. Short-term HFD induced a coordinated remodeling of skeletal muscle characterized by lipid accumulation, suppression of the PPAR-α/CPT-1 axis, altered mitochondrial and redox homeostasis, extracellular matrix remodeling, impaired myogenic signaling, and a shift toward a glycolytic contractile program despite only modest body-weight gain. OEA largely attenuated such alterations, preserving skeletal muscle metabolic and structural homeostasis through coordinated improvement of lipid oxidative metabolism, mitochondrial energetic status, and tissue remodeling. These findings identify skeletal muscle as an early target of fat-induced metabolic dysfunction and support further investigation of OEA as a promising pharmacological strategy to intercept obesity-associated metabolic deterioration before overt obesity develops.
M. Friuli, B. Eramo, Nisha Zahid et al.· Pharmacological Research· 0 citations
BACKGROUND
Chronic fatty acid (FA) elevation drives metabolic dysfunction-associated liver disease (MASLD). Hepatocytes buffer transient lipid overload via coordinated adaptive mechanisms, but the temporal limits of this capacity remain undefined.
OBJECTIVES
We characterized early, intermediate, and prolonged hepatocellular responses to sustained lipid excess.
METHODS
HuH7 hepatocytes were exposed to an equimolar palmitic/oleic acid (PA/OA) mixture for 1, 14, or 28 days. Viability, lipid accumulation, stress-response pathways, insulin signaling, metabolic regulators, mitochondrial markers, [14C]-PA uptake, and exo-metabolomic profiles were assessed (n≥3/group). Data (mean ± SEM) were analyzed by two-way ANOVA with Bonferroni post hoc testing; cumulative cell death by linear regression. P<0.05 was significant.
RESULTS
FA treatment increased lipid droplet accumulation 1.4- to 1.7-fold vs. time-matched BSA controls at all time points (p<0.001) and increased the rate of cumulative cell death ∼4.3-fold (1.556±0.083 vs. 0.365±0.054%/day, p<0.001). Exo-metabolomic PCA explained 88.5% of variance (Q2=0.758), with peak lactate release at Day 14 and progressively rising acetate through Day 28. [14C]-PA accumulation at Day 28 was ∼30% lower than Day 1 (∼800 vs. ∼500 cpm/mg protein), with a declining rather than plateauing profile between 20-60 s. By Day 28, FA-treated cells showed lower FASN (p<0.001), CD36 (p<0.05), FABP1 (p<0.001), SIRT1 (p<0.005), and CLOCK (p<0.01) protein levels, and higher CPT1A (p<0.001), pAMPK/AMPK (p<0.01), p53 (p<0.001), Bax/Bcl2 (p<0.005), and respiratory complex I-V abundance (p<0.05-p<0.001) vs. controls.
CONCLUSIONS
Sustained PA/OA exposure induces a staged hepatocellular response, early lipid-buffering adaptation, intermediate metabolic compensation, and late decompensation, indicating that chronic lipotoxicity reflects progressive loss of regulatory coordination despite persistent metabolic adaptation.
I. Serra, Elisa Bisconti, Francesco Vari et al.· Journal of NutriLife· 0 citations
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