Background: This study assesses the temporal responses of cardiovascular function, fibro-inflammation, and glucometabolic profiles in asymptomatic adults with type 2 diabetes, following a low-energy ...meal replacement plan (MRP) or exercise training. Methods: Secondary analysis of DIASTOLIC: a randomised, open-label, blinded-endpoint trial of 12 weeks MRP (~810 kcal/day) or exercise training. Cardiac magnetic resonance, plasma fibroinflammatory, and metabolic markers were undertaken at baseline, 4, and 12 weeks. Results: Out of 24 participants in the MRP group and 22 in exercise training, 18 and 11 completed all three visits. MRP resulted in early (0–4 weeks) improvement in insulin resistance (HOMA-IR: 10.82 to 4.32), decrease in FABP-4 (4.87 ± 0.19 to 5.15 ± 0.32 mg/L), and improvement in left ventricular remodelling LV mass: volume (0.86 ± 0.14 to 0.78 ± 0.11), all with large effect sizes. MMP8 levels increased moderately at 4–12 weeks. Peak early diastolic strain rate (cPEDSR) initially decreased, then improved. Exercise training led to minor improvements in insulin resistance and MMP-8 levels, with no significant changes in cPEDSR or LV remodelling. Conclusions: MRP resulted in early improvements in insulin resistance, cardiac remodelling, and inflammation, but with an initial decrease in diastolic function, improving by 12 weeks. Exercise training showed minor early benefits in insulin resistance and inflammation, but no significant cardiac changes.
Abstract only
Background
SCD1 is a lipogenic enzyme responsible for the formation of monounsaturated fatty acids, the main precursors of triglycerides. High SCD1 expression is associated with ...expansion of adipose tissue and ectopic fat accumulation (in various tissues). Seipin is the human Berardinelli‐Seip congenital lipodystrophy 2 gene product which regulates adipogenesis and lipid droplets (LD) formation but whose function remains to be elucidated.
Aim
In the present study we evaluated the role of SCD1 and seipin in LD formation in hepatic cells and the effect of SCD1 or Seipine deficiency in the lipogenesis and insulin pathways. The results were also validated in seipin‐deficient mice.
Methods
In human hepato‐carcinoma cell line (HepG2), the expression of the two proteins was either silenced. LD formation was monitored by confocal microscopy upon addition of oleate. Under these conditions was also evaluated the activation of insulin and lipogenesis signaling pathways.
Results
We observed that silencing SCD1 in HepG2 cells decreases the number and the size of LD, does not affect the lipogenic gene expression, increases insulin sensitivity (pAKT and pERK1). While silencing seipin has an opposite effect in the number of LDs. The mice develop a major hepatic steatosis. But the seipin deficiency does not affect lipogenesis but increases the expression of SCD1 and CD36 (in both HepG2 cells and liver of KO mice). Surprisingly, it increases significantly the insulin sensitivity in HepG2 cells
Conclusion
Our study demonstrated for the first time that low seipin expression in hepatic cells is directly associated with the development of hepatic steatosis. Seipin function appears to be inversely associated with SCD1 function. Finally, our work also suggests that variation of SCD1 and seipin expression influence insulin responses in hepatic cells.
The hepatic CYP4A enzymes are important fatty acid and prostaglandin ω-hydroxylases that are highly inducible by fibric acid hypolipidemic agents and other peroxisome proliferators. Induction of the ...CYP4A enzymes by peroxisome proliferators is mediated through the nuclear peroxisome proliferator-activated receptor α (PPARα). Fatty acids have recently been identified as endogenous ligands of PPARα, and this receptor has been implicated in the regulation of lipid homeostasis. In the present report we characterized the induction of the hepatic CYP4A genes in rats during the altered lipid metabolism associated with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2, and CYP4A3 were induced 7–17-fold in the livers of fasted animals and 3–8-fold in the livers of diabetic animals. This was accompanied by corresponding changes in CYP4A protein levels and arachidonic and lauric acid ω-hydroxylase activity. Interestingly, feeding animals after the fasting period caused as much as an 80% suppression of CYP4A mRNA levels, whereas CYP4A protein levels and functional activity returned to control values. A second PPARα-responsive gene, acyl-CoA oxidase, was also induced in rat liver by diabetes and fasting. By using PPARα-deficient mice, we unambiguously demonstrated that PPARα is strictly required for hepatic CYP4A induction by starvation and diabetes. Similarly, induction of hepatic thiolase and bifunctional enzyme also required expression of PPARα. This represents the first evidence for the pathophysiologically induced activation of a nuclear receptor.
The hepatic CYP4A enzymes are important fatty acid and prostaglandin Ï-hydroxylases that are highly inducible by fibric acid
hypolipidemic agents and other peroxisome proliferators. Induction of the ...CYP4A enzymes by peroxisome proliferators is mediated
through the nuclear peroxisome proliferator-activated receptor α (PPARα). Fatty acids have recently been identified as endogenous
ligands of PPARα, and this receptor has been implicated in the regulation of lipid homeostasis. In the present report we characterized
the induction of the hepatic CYP4A genes in rats during the altered lipid metabolism associated with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2,
and CYP4A3 were induced 7â17-fold in the livers of fasted animals and 3â8-fold in the livers of diabetic animals. This was
accompanied by corresponding changes in CYP4A protein levels and arachidonic and lauric acid Ï-hydroxylase activity. Interestingly,
feeding animals after the fasting period caused as much as an 80% suppression of CYP4A mRNA levels, whereas CYP4A protein
levels and functional activity returned to control values. A second PPARα-responsive gene, acyl-CoA oxidase, was also induced
in rat liver by diabetes and fasting. By using PPARα-deficient mice, we unambiguously demonstrated that PPARα is strictly
required for hepatic CYP4A induction by starvation and diabetes. Similarly, induction of hepatic thiolase and bifunctional
enzyme also required expression of PPARα. This represents the first evidence for the pathophysiologically induced activation
of a nuclear receptor.
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