Protectin DX ameliorates palmitate- or high-fat diet-induced insulin resistance and inflammation through an AMPK-PPARα-dependent pathway in mice

Abstract

Protectin DX (PDX), a double lipoxygenase derivative of docosahexaenoic acid, has been reported to attenuate inflammation and insulin resistance. In the current study, we explored the effects of PDX on hyperlipidemia-induced insulin resistance and inflammation through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). PDX attenuated the impairment of insulin receptor substrate 1/Akt–mediated insulin signaling in palmitate-treated differentiated C2C12 cells and soleus skeletal muscle of HFD-fed mice. Furthermore, PDX treatment significantly ameliorated HFD-induced weight gain and improved glucose tolerance in mice. Nuclear factor kB nuclear translocation, inhibitory kBα phosphorylation, and expression of proinflammatory cytokines were markedly attenuated by PDX in both in vitro and in vivo models. PDX treatment markedly augmented AMPK phosphorylation and PPARα expression in C2C12 cells and in skeletal muscle of mice. AMPK- and PPARα-specific siRNAs significantly abrogated the suppressive effects of PDX on palmitate-induced insulin resistance and inflammation. Furthermore, PDX markedly stimulated the expression of genes related to fatty acid oxidation. These effects of PDX were significantly suppressed by AMPK and PPARα siRNAs. In conclusion, our results demonstrate that PDX ameliorates insulin resistance and inflammation and stimulates fatty acid oxidation through AMPK- and PPARα-mediated pathways in skeletal muscle.

Protectin DX ameliorates palmitate‐induced hepatic insulin resistance through AMPK/SIRT1‐mediated modulation of fetuin‐A and SeP expression

“…PDX ameliorates hepatic gluconeogenesis and systemic insulin resistance via inducing IL‐6 release from skeletal muscle, similar to the effects of exercise. In previous studies, PDX has been reported to attenuate insulin resistance in skeletal muscle and adipocytes through an AMPK‐dependent pathway. Additionally, exercise has been reported to improve hepatic insulin resistance through downregulation of serum fetuin‐A .…”

“…As reported by White et al, PDX could ameliorate hyperlipidaemia‐induced inflammation and insulin resistance via skeletal muscle‐secreted IL‐6 signalling, mediating the modulation of hepatic glucose metabolism. Recently, PDX was demonstrated to alleviate inflammation and insulin resistance in mouse skeletal muscle and adipocytes through the AMP‐activated protein kinase (AMPK)‐signalling pathway . To the best of our knowledge, no clear evidence for the direct effects of PDX on insulin resistance in hepatocytes has been found.…”

Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

“…LA biosynthesis and metabolism requires some of the same enzymes used for EPA synthesis and metabolism, including the production of downstream metabolites 32,33 . Moreover, LA's consumption in the western diet is [14][15][16][17][18] times the amount required to prevent LA deficiency 22,46 and LA's effects on insulin sensitivity are strongly debated [46][47][48][49][50][51][52][53] .…”

“…Furthermore, overexpression of RvE1's receptor ERV1/ChemR23 improves hyperglycemia and hepatic steatosis of male mice 15 . There is also rigorous evidence that DHA-derived SPMs ameliorate insulin resistance 10,13,[16][17][18][19] . The DHA-derived SPM protectin D1 alleviates insulin resistance by controlling skeletal muscle IL-6 secretion and resolvin D1 enhances glucose tolerance by targeting adipose tissue macrophage polarization 13,17 .…”

Shifts in gut microbiome and metabolome are associated with risk of recurrent atrial fibrillation

“…Emerging evidence suggests that metabolic impairment is important for AF pathophysiology [45]. Notably, PPARα-dependent AMPK activation could result in suppressed inflammation [46]. Therefore, we speculate that reduction of fecal metabolites such as palmitoleic acid in RAF patients might contribute to excessive inflammation and facilitate AF recurrence.…”