Cannabinoid receptor type 1 mediates high-fat diet-induced insulin resistance by increasing forkhead box O1 activity in a mouse model of obesity

Abstract

Hepatic glucose production is promoted by forkhead box O1 (FoxO1) under conditions of insulin resistance. The overactivity of cannabinoid receptor type 1 (CB1R) partly causes increased liver fat deposits and metabolic dysfunction in obese rodents by decreasing mitochondrial function. The aim of the present study was to investigate the role of FoxO1 in CB1R-mediated insulin resistance through the dysregulation of mitochondrial function in the livers of mice with high-fat diet (HFD)-induced obesity. For this purpose, male C57BL/6 mice were randomly assigned to groups and either fed a standard diet (STD), a HFD, or a HFD with 1-week treatment of the CB1R inverse agonist, AM251, at 1 or 5 mg/kg. For in vitro experiments, AML12 hepatocytes were incubated with FoxO1 siRNA prior to challenge with arachidonyl-2'-chloroethylamide (ACEA) or a high concentration of free fatty acids (HFFA). Plasma parameters were analyzed using colorimetric methods. Liver histopathology and hepatic status markers were examined. The HFD-fed mice exhibited an increase in CB1R levels in the liver. Moreover, in response to increased hepatic oxidative stress, the HFD-fed mice also displayed hepatic mitochondrial dysfunction, as indicated by the decreased mRNA levels of carnitine palmitoyltransferase-1 (CPT-1), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and citrate synthase. On the contrary, these effects in the HFD-fed mice were reversed by treatment with 5 mg/kg AM251. The administration of AM251 suppressed the induction of FoxO1, phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) expression in the livers of the mice fed a HFD by enhancing the phosphorylation of insulin signaling cascades thus, further lowering the high level of the homeostatic model assessment of insulin resistance (HOMA‑IR) index. In our in vitro experiments, transfection with FoxO1 siRNA prevented the HFFA- and ACEA-induced decrease in the gene expression of mitochondrial biogenesis-related factors, and abrogated the HFFA- and ACEA-induced increase in PEPCK and G6Pase expression. Taken together, our findings suggest that the anti-insulin resistance effect of AM251, which leads to an improvement of mitochondrial function in hepatic steatosis, is mediated through FoxO1.

miR‐96 and autophagy are involved in the beneficial effect of grape seed proanthocyanidins against high‐fat‐diet‐induced dyslipidemia in mice

“…It is known that mTOR and p‐mTOR (ser2448) can activate AKT signaling, which disrupts lipid metabolism and results in hyperlipidemia (Khalifeh‐Soltani et al, ; Kim et al, ). On the other hand, FOXO1 upregulated by HFD may cause insulin resistance and inflammation (Chen, Lee, Kwok, et al, ; Iyer et al, ). Furthermore, AKT promotes FOXO1 phosphorylation and down‐regulate FOXO1 expression to regulate glucose metabolism (Jiang, Le, Zhai, et al, ).…”

Cannabis: A Treasure Trove or Pandora's Box?

“…Below we review the physiopharmacology of the endocannabinoid system and the therapeutic potential of cannabis in selected health conditions. Unfortunately, due to space constraints, we can only refer to other excellent reviews and original works for additional (patho)physiological cases, including but not limited to analgesia, inflammation and pain [610][611][612], immunomodulation and beyond [613][614][615]; neuroinflammation and neurodegeneration [23,[616][617][618], stroke and subacute brain trauma [619][620][621], multiple sclerosis and spasticity [622][623][624], normal and pathological brain aging [618,625], suicide [626,627], liver diseases and hepatic encephalopathy [628][629][630], food intake and eating disorders [631][632][633][634], systemic energy balance and metabolic disorders [260][261][262]490,[635][636][637], mitochondrial function [458,[638][639][640][641], cancer and cancer care [642][643][644]…”

Using proteomics to discover novel biomarkers for fatty liver development and response to CB1R antagonist treatment in an obese mouse model

“…This discrepancy might be due to that our HFD‐fed mouse model was solely at a state of mild hepatosteatosis rather than NASH as indicted by the results of liver histopathological assay (Fig. A, upper panel) and the insignificant elevations of serum ALT and AST in HFD mice . Despite the discrepancy, AM251 supplementation still significantly enhanced the level of GRP78 in the HFD mice (see Fig.…”